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Hyperoxia sensing: From molecular mechanisms to significance in disease

Hyperoxia sensing: From molecular mechanisms to significance in disease Oxygen therapy using mechanical ventilation with hyperoxia is necessary to treat patients with respiratory failure and distress. However, prolonged exposure to hyperoxia leads to the generation of excessive reactive oxygen spe- cies (ROS), causing cellular damage and multiple organ dysfunctions. As the lungs are directly exposed, hyperoxia can cause both acute and chronic inflammatory lung injury and compromise innate immunity. ROS may contribute to pulmonary oxygen toxicity by overwhelming redox homeostasis, altering signaling cascades that affect cell fate, ultimately leading to hyperoxia-induced acute lung injury (HALI). HALI is characterized by pronounced inflamma - tory responses with leukocyte infiltration, injury, and death of pulmonary cells, including epithelia, endothelia, and macrophages. Under hyperoxic conditions, ROS mediate both direct and indirect modulation of signaling molecules such as protein kinases, transcription factors, receptors, and pro- and anti-apoptotic factors. The focus of this review is to elaborate on hyperoxia-activated key sensing molecules and current understanding of their signaling mechanisms in HALI. A better understanding of the signaling pathways leading to HALI may provide valuable insights on its pathogenesis and may help in designing more effective therapeutic approaches. Keywords: Hyperoxia; inflammation; sensing; apoptosis; cell death; signaling; acute lung injury; ROS American intensive care units (ICU), mechanical ventilation Introduction is administered to at least 40% of the patients on a daily basis Mechanical ventilation with supraphysiological concentrations (ICARE, 1999). Patients requiring mechanical ventilation are of oxygen (O ) is routinely used to treat patients with difficul- often critically ill with conditions such as respiratory failure, IMT ties in maintaining adequate oxygenation and ventilation. spinal cord injury, cardiac complications, cerebrovascu- Our atmosphere consists of 21% O , which is corresponding lar accident, and neurological disorders (Windhorst et al., 492254 to 160 mm Hg partial pressure of oxygen (pO ). Patients with 2009). Although mechanical ventilation with hyperoxia has hypoxemia and acute respiratory failure require administra- improved survival in these patients, prolonged exposure to tion of elevated concentrations of inspired oxygen (> 21% O ) hyperoxia can result in adverse ee ff cts on multiple organ 16 April 2010 for basic life support (Snider and Rinaldo, 1980; Carvalho systems. Prolonged hyperoxia at normal pressure primarily et al., 1998; Seta et al., 2004). Hyperoxia is defined as either causes pulmonary and ocular toxicity due to oxidative damage excess O or higher than normal physiological pO , which to endothelial and epithelial cells. Oxygen toxicity can lead 2 2 05 May 2010 varies from organ to organ and from venous blood to arte- to the collapse of the alveoli, acute and chronic lung injury, rial blood. e Th level of hyperoxia administered to patients central nervous system disorders manifested as seizures and 06 May 2010 varies depending on their clinical situation. Up to 100% O convulsions, cardiovascular and gastrointestinal disorders, is used in supporting patients suffering from severe acute erythrocyte damage, and retinopathy (Bostek, 1989). cardio-respiratory decline. Oxygen concentrations ranging Among various organ systems, the toxic effects of pro- 1547-691X from 50% to 60% are routinely used for the long-term man- longed hyperoxia have been particularly well studied in the agement of these patients under more stable conditions. In lung. Its large epithelial surface and anatomical location make 1547-6901 Address for Correspondence: Dr. Lin L. Mantell, Department of Pharmaceutical Sciences, St. John’s University College of Pharmacy, 128/SB28 St. Albert Hall, 8000 Utopia Parkway, Queens, NY 11439, USA; E-mail: mantelll@stjohns.edu © 2010 Informa Healthcare USA, Inc. (Received 16 April 2010; revised 05 May 2010; accepted 06 May 2010) ISSN 1547-691X print/ISSN 1547-6901 online © 2010 Informa Healthcare USA, Inc. 10.3109/1547691X.2010.492254 DOI: 10.3109/1547691X.2010.492254 http://www.informahealthcare.com/imt 240 Ashwini Gore et al. the lungs vulnerable to oxidative damage and both chronic exacerbate formation and accumulation of excessive ROS and acute inflammatory lung injury. Oxygen toxicity has been (Carvalho et al., 1998; Lukkarinen et al., 2003). Oxygen toxicity shown to contribute to the morbidity of bronchopulmonary develops as the production of ROS overwhelms the capacity dysplasia (BPD) in pre-term infants (Jobe, 1999). According of lung antioxidant systems that are designed to preserve nor- to the National Nosocomial Infection Survey, 86% of noso- mal cellular functions (Tang et al., 1993; Asikainen and White, comial pneumonia cases in ICUs have been associated 2004). An initial ROS formed by hyperoxia is the superoxide with mechanical ventilation with hyperoxia, which has an anion radical (·O ; Carvalho et al., 1998; Lukkarinen et al., approximately 1% per day relative risk of acquiring ventilator- 2003). i Th s species can be further converted into other ROS associated pneumonia (ICARE, 1999; Richards et al., 1999). such as hydrogen peroxide (H O ) or hydroxyl radical (OH·; 2 2 Results from a post-mortem study showed that an alarming Adler et al., 1999). Superoxide dismutase (SOD) can rapidly 67% of the patients who received mechanical ventilation had catalyze the dismutation of superoxide anion to H O (please 2 2 developed pneumonia (Marquette et al., 1995). Numerous refer to Figure 1). Over-expression of any of the isoforms of studies show that exposure to prolonged hyperoxia signifi- SOD in mouse models has been shown to provide limited to cantly contributes to the pathogenesis of acute lung injury complete protection, depending on the promoter and site of (ALI) and play an important role in the poor clinical outcome expression with hyperoxic lung injury (Wispe and Roberts, of acute respiratory distress syndrome (ARDS) patients. Lung 1987; White et al., 1991; Ahmed et al., 2003). Additionally, injury consequent to prolonged hyperoxia is characterized an earlier onset of edema and reduced survival has been by an overwhelming production of reactive oxygen spe- reported in mice lacking extracellular SOD when challenged cies (ROS), which play an essential role in the subsequent with prolonged hyperoxia. Taken together, these data suggest extensive inflammatory response, destruction of the alveolar- ·O plays a pivotal role in hyperoxia-mediated ALI (Carlsson capillary barrier, impaired gas exchange, and pulmonary et al., 1995). edema (Slutsky, 1999; Waxman et al., 1999; Corne et al., 2000). A small steady-state concentration of ROS is maintained Therefore, a clear understanding of the underlying cellular as part of normal physiological metabolism (Cadenas and and molecular mechanisms mediating hyperoxia-induced Davies, 2000). The mitochondrial electron transport chain can acute lung injury (HALI) is crucial to successful therapies. generate ·O by the transfer of an electron to molecular O at 2 2 e Th ability to sense and respond to changes in the concen - Complex I, II, or III, in lieu of complete transfer to Complex tration of O is essential for the survival of prokaryotic and IV where O is consumed to form water. Under conditions 2 2 eukaryotic organisms. Oxygen plays a central role maintain- of hyperoxia, the generation of ROS from mitochondria ing cellular and tissue homeostasis and is n fi al acceptor of electrons, at the end of the mitochondrial respiratory chain. e Th nature of how cells sense and adapt to hyperoxia is NO •- complicated and remains to be further explored. e Th focus - 2 ONOO of this review is to elaborate on key hyperoxia-activated sensing molecules and the current understanding of their NOX/ signaling mechanisms in HALI. Many of these transcription SOD Mitochondrial electron factors, receptors, protein kinases, ion channels, and pro- and transport anti-apoptotic factors may serve as a paradigm for hyperoxia sensing at the molecular level. H O O 2 2 Role of ROS in mediating oxygen toxicity 2+ Fenton Fe , − Cl The respiratory system is uniquely adapted to optimize pO 1+ Reaction Cu MPO relative to the external atmosphere and meet the needs of metabolism. Inspired air is warmed and humidie fi d as it is drawn through the nose and mouth to the trachea and lower HOCl OH bronchial tree, which causes a decrease in pO . As air reaches the alveolus, O concentration equilibrates to balance the processes of removal into the blood capillaries and delivery by Figure 1. Formation of ROS/free radicals from exposure to molecular inspiration/ventilation. As a result, alveolar pO is ≈ 100 mm oxygen. One-electron reduction of molecular oxygen (O ) by NADPH Hg or 14% (Roy et al., 2004). Homeostasis of cellular oxygen oxidase/mitrochondrial oxidative phosphorylation results in forma- − − tion of superoxide anion radical (·O ). The ·O is converted to H O by concentrations within a narrow range minimizes the risk of 2 2 2 2 superoxide dismutase (SOD) via a dismutation reaction. H O can gener- 2 2 oxidative damage from either excess oxygen or metabolic 2+ ate OH· radical in the presence of transition metals such as iron (Fe ) or death due to hypoxia (Semenza, 2001). + − copper (Cu ). Peroxynitrite (ONOO ) is formed when nitric oxide (NO) In the setting of hospitalization requiring hyperoxic ther- reacts with superoxide. Peroxidases use H O to catalyze the oxidation of 2 2 apy, O homeostatic balance is disrupted consequent to both diverse substrates, for example myeloperoxidase oxidizes Cl to HOCl. MPO, myeloperoxidase; NO, nitric oxide; NOX, NADPH oxidase; OH, the underlying pathology and treatment. While immediate hydroxyl radicals; SOD, superoxide dismutase. clinical needs must be met, supplemental O therapy can 2 Molecular mechanisms in hyperoxia sensing 241 increases linearly with oxygen tension (Turrens, 2003). localize ROS signaling to selective signal transduction clients Electron leak and proportionate increased ·O formation (Ushio-Fukai, 2006). Both NOX1 and NOX2 are expressed in during hyperoxia results in a concomitant increase in H O mouse lung, and NOX1 has been detected in human alveolar 2 2 production, catalyzed by manganese SOD (MnSOD) local- epithelial cells (AEC; A549) and endothelial cells (Freeman ized in the mitochondrial matrix (please refer to Figure 2). and Crapo, 1981; Mittal et al., 2007). Using knockout mice, Targeted over-expression of MnSOD in the matrix has Carnesecchi et al. (2009) demonstrated that NOX1, but not been shown to improve survival of either lung microvessel NOX2, was an important mediator of hyperoxia-induced ALI. endothelial or lung epithelial cells exposed to hyperoxia ROS generated by NOX1 under hyperoxic conditions, medi- (Hori et al., 1995; Li et al., 1997). Over-expression of MnSOD ated alveolar cell death through c-Jun N-terminal kinases protects lung epithelial cells against oxidant injury (Koo (JNKs) and extracellular signal-regulated kinases-mediated et al., 2005). Related enzymes, such as cytosolic catalase, (ERK-mediated) pathways (Carnesecchi et al., 2009). e Th se Cu/ZnSOD in the mitochondrial intermembrane space, and data were consistent with the n fi ding that NOX1 in lung matrix glutathione (GSH) peroxidase do not appear to change epithelium promoted JNK-mediated cell death via tumor in these models relative to non-MnSOD transgene controls. necrosis factor (TNF) receptor-1 (TNF-RI), TNF-receptor- These data illustrate that appropriate compartmentalization associated factor 2, as well as apoptosis signal-regulating of augmented MnSOD activity to the mitochondrial matrix kinase 1 (Pantano et al., 2007). Additional evidence sup- can ameliorate hyperoxia-induced cytotoxicity, despite H O porting the role of NOX in ALI was the attenuation of ROS 2 2 also being a ROS. production in mouse epithelial cells exposed to hyperoxia A second source of ROS under hyperoxic conditions is the following administration of diphenyleneiodonium chloride nicotinamide adenine dinucleotide phosphate (NADPH) oxi- (Zhang et al., 2003), albeit this was a non-specic fi chemical dase (NOX) family (Zhang et al., 2003). As the name implies, inhibitor of NOX. NOXs utilize NADPH/NADH as the electron donor to catalyze An influx of neutrophils and monocytes, which accu- reduction of molecular oxygen to ·O at the extracellular face mulate within the pulmonary circulation, interstitium, of the plasma membrane (Tsan, 2001; Lambeth, 2004; please and air spaces under hyperoxic conditions, represents a refer to Figure 2). Recent analysis has entertained intracellular source for additional ROS (Fox et al., 1981; Raj et al., 1985; trafficking to endosomal compartments as a mechanism to Chollet-Martin et al., 1996; Goodman et al., 1996). Phagocyte ECSOD •− O H O 2 2 2 NOX 2+ Fe 1+ Cu •− Cu/ZnSOD O • 2 H O OH 2 2 Complex I Complex IIIComplex IV Complex II MITOCHONDRIA •− 2+ Fe MnSOD MnSOD 1+ Cu OH H O 2 2 Figure 2. Schematic diagram illustrating the sources of ROS under hyperoxic conditions. Molecular oxygen can be reduced to superoxide anion by electron leak from mitochondrial electron transport chain or via NADPH oxidase catalysis. Most of these excess ROS are generated in the mitochondria through an increased flux of electrons at Site III in the mitochondrial electron transport chain. Superoxide dismutases catalyze formation of H O . In 2 2 2+ the presence of reduced transition metals (such as Fe ), H O can form the highly oxidizing hydroxyl radicals (OH·). Cu/ZnSOD, Cu/Zn superoxide 2 2 dismutases; ECSOD, extracellular superoxide dismutases; NOX, NADPH oxidase. 242 Ashwini Gore et al. NOX2 is a complex containing v fi e catalytic subunits and i.e., necrosis and apoptosis, or non-classical pathways, i.e., regulatory proteins which are required for its activation and oncosis (Polunovsky et al., 1993; Matute-Bello et al., 1997; formation of ·O (Lambeth, 2004; Bedard and Krause, 2007). Mantell et al., 1999). Depending on the concentration of Overwhelming production of ROS from these sources under hyperoxia, duration of exposure, and cell type, cell death hyperoxic conditions can lead to oxidative modic fi ations may occur either via distinct or overlapping mechanisms of macromolecules, leading to pulmonary cell death that is (Bhandari and Elias, 2006; Zaher et al., 2007). characteristic of hyperoxic lung injury (Mantell et al., 1999; O’Reilly, 2001). Numerous studies have shown that cells Pro- and anti-apoptotic factors exposed to prolonged hyperoxia undergo growth inhibi- The critical role of apoptotic death of pulmonary cells has tion, cell cycle arrest, and even cell death, with oxidation of been established in animal models of hyperoxic lung injury DNA, lipids, and protein (Cacciuttolo et al., 1993; Janssen as well as other animal models of ALI (Mantell et al., 1997, et al., 1993; O’Reilly, 2001; Wang et al., 2003). Hyperoxic 1999; Mantell and Lee, 2000). e Th re have been numerous murine macrophages, b fi roblastic cell lines, primary lung studies illustrating the role of both pro- and anti-apoptotic fibroblasts, and endothelial cells each display biochemical factors in the regulation of pulmonary cell death in hyperoxia. and morphological features of apoptosis (Hogg et al., 1999; Apoptotic cell death can be initiated by either of two general Petrache et al., 1999; Budinger et al., 2002; Pagano et al., 2005) pathways—an extrinsic initiation regulated by extracellular whereas epithelial cells (A549 and murine lung epithelial cell signals, or an intrinsic initiation regulated by intracellular 12 (MLE-12)) show morphological features of necrosis, apop- physiological changes. tosis, and oncosis following exposure to high O concentra- The extrinsic apoptotic pathway is triggered following tions (Lee and Choi, 2003; Romashko et al., 2003; Wang et al., formation of a death-inducing signal complex (DISC), upon 2003). As a result of damage to both endothelial and epithelial the binding of death ligands (Fas ligand (FasL)) with their cells, alveolor-capillary barrier integrity is lost—leading to cell-surface receptors (Fas; Walsh et al., 2003). Stimulation interstitial edema and impairment in gas exchange (Mantell of Fas by FasL results in the recruitment of Fas-associated et al., 1999). Although beyond the scope of this review, it is death domain protein and caspase-8 to the cytoplasmic important to note that despite the activation of leukocytes death domain of Fas. Caspase-8 is then activated and can and allied NOX/ROS systems in HALI, pulmonary coloniza- then cleave Bid to form truncated Bid (tBid). The tBid sub- tion with infectious microbes is still a leading complication of sequently translocates from the cytosol to the mitochondrial patients on mechanical ventilation with hyperoxia (Richards membrane, where it stimulates cytochrome c release and et al., 1999). caspase-9 activation (Walsh et al., 2003). The role of extrinsic In addition to directly modifying macromolecules, pathway in the development of lung injury in hyperoxia has exposure to hyperoxia also involves direct and indirect been demonstrated by the involvement of Fas-associated modulation of many hyperoxia-sensing molecules. A clearer death domain interleukin-1β-converting enzyme-like understanding of hyperoxia-induced signal transduction inhibitory protein (FLIP) in both in vitro and in vivo mod- pathways is critical to provide the foundation for designing els. FLIP, a natural inhibitor of the extrinsic apoptosis path- successful therapeutic strategies. A number of published way, is known as FLIP (Rasper et al., 1998; Micheau, 2003). review articles have discussed many aspects of HALI, some Apoptosis induced by death receptors, such as Fas or the of which have been discussed in great detail (Lee and Choi, TNF-related apoptosis-inducing ligand receptors, can be 2003; Bhandari and Elias, 2006; Zaher et al., 2007; Bhandari, inhibited by FLIP (Rasper et al., 1998; Micheau, 2003). One 2008). The focus of this review is to discuss some of the of the splice variants of cellular FLIP (c-FLIP), contains recent studies characterizing hyperoxia-sensing moieties. tandem death effector domains and a caspase-like domain The reader should keep in mind that hyperoxia is solely a which lacks amino acid residues that are critical for caspase man-made condition of modern medical therapy. Unlike activity. c-FLIP prevents the recruitment and activation of hypoxia (e.g., wound healing), humans have not evolved any caspase-8 to the DISC by acting as a competitive inhibitor specific adaptive response to hyperoxia. Therefore, hyperoxia (Rasper et al., 1998; Barnhart et al., 2003). However, the role sensing—by definition—is an amalgam of factors respond- of the extrinsic apoptotic pathway in hyperoxic cell death ing to the stress of unnaturally high local O levels. Cellular is nonetheless, still contentious. Mice that are deficient in hyperoxia responses occur along with signaling initiated by −/− Fas (Fas ) and tumor necrosis factor receptor TNF recep- the underlying pathology for which the patient is receiving −/− tor (TNFR; tnfrI/II ) exhibited no resistance to prolonged treatment. hyperoxia (Pryhuber et al., 2000; Wang et al., 2003). Hence, further investigation is required to confirm the role of extrin- Role of hyperoxia-sensing moieties in HALI sic apoptotic pathway related-proteins in HALI. Moreover, Numerous factors contribute to the pathophysiology of the engagement of the extrinsic death receptor-mediated HALI. i Th s section will discuss in detail the endogenous apoptosis by hyperoxia is as yet unclear. molecules that function as hyperoxia-sensing moieties and The intrinsic pathway is also known as mitochondria- their signaling pathways. One of the primary pathologi- dependent pathway. Bax, a member of pro-apoptotic Bcl-2 cal effects of hyperoxia exposure is cell death. Hyperoxia- family proteins, can initiate apoptosis by forming specific induced cell death can occur via either classical pathways, channels in the outer mitochondrial membrane (Antonsson Molecular mechanisms in hyperoxia sensing 243 et al., 2000; Huang and Strasser, 2000; Martinou and Green, resistant to hyperoxia-induced cell death (Budinger et al., 2001). As a consequence, these channels can increase the 2002). Increased Bcl-2 levels in mice were found to cor- outer mitochondrial membrane permeability and facilitates relate with diminished hyperoxia-induced lung injury and the release of cytochrome c and other pro-apoptotic fac- improved survival (Ward et al., 2000). Bcl-2 over-expression tors from the mitochondrial intermembrane space into the has been shown to prevent oxidative stress via up-regulation cytosol (Hofmann et al., 1999; Annis et al., 2001; Martinou of antioxidant enzymes expression and elevation of cellular and Green, 2001). Once in the cytosol, cytochrome c forms GSH content (Jang and Surh, 2003). Moreover, in hyperoxia- an apoptosome complex with Apaf-1 which subsequently exposed fibroblastic cells (L929), Bcl-2 exhibited a protec - activates caspase-9 and caspase-3, leading to apoptosis of tive ee ff ct on mitochondria by reducing cytochrome c and these cells (Walsh et al., 2003). An additional determinant apoptosis-inducing factor release. Over-expression of Bcl-2 of apoptotic cell death is the Bcl-2 family members that can also decreased caspase-3 activity and nuclear condensation be either pro-apoptotic (Bax, Bcl-Xs, Bak, and Bad) or anti- in cells exposed to prolonged hyperoxia, preventing apoptotic apoptotic (Bcl-2, Bcl-XL, and Bcl-w; Cory and Adams, 1998). cell death (Métrailler-Ruchonnet et al., 2007). Interestingly, e Th pro- and anti-apoptotic members of the Bcl-2 family treatment with the caspase inhibitor Z-VAD.fmk did not res- exert most of their functions at the mitochondrial level (Gross cue cells from oxygen toxicity, suggesting that protection con- et al., 1999). e Th anti-apoptotic molecule Bcl-2, localized in ferred by Bcl-2 might entail a caspase-independent pathway the endoplasmic reticulum and mitochondrial membrane, (Métrailler-Ruchonnet et al., 2007). In hyperoxia, reduced exerts its protective effect by preventing Bax oligomerization, Bid activation and increased Bax protein expression was −/− −/− translocation to mitochondria and the subsequent release of observed in Fas (lpr) and FasL (gld) mice (Wang et al., −/− pro-apoptotic mitochondrial proteins, such as cytochrome 2003). Additionally, Bid knockout (Bid ) mice or lung fibrob- −/− c (Kroemer et al., 1998; Annis et al., 2001). Modulation of lasts derived from Bid mice exhibited marked resistance Bcl-2 family molecules has been shown to affect hyperoxia- to oxygen toxicity (> 95% O ) compared to wild-type controls induced cell death. Over-expression of the anti-apoptotic or their corresponding cells (Wang et al., 2003). e Th se data molecule Bcl-XL in rodent b fi roblasts (Rat 1 cells) prevented indicate that targeting Bid signaling pathway plays a critical oxygen-induced apoptosis. role in mediating HALI; however, the sensing molecules acti- Likewise, murine embryonic b fi roblasts derived from vated or inhibited by hyperoxia remain elusive (please refer mice dec fi ient in pro-apoptotic Bax and Bak molecules were to Figure 3). Hyperoxia Bax or FAS Bak Mitochondria DISC FADD Caspase 8 Activated Caspase 8 Cyt C Bid tBid Apaf-1 Apoptosis Caspase 9 Caspase 3 Figure 3. Schematic representation of the hyperoxia induced apoptotic pathways. Under hyperoxic conditions, the extrinsic apoptotic pathway is trig- gered following formation of a death-inducing signal complex (DISC), upon the binding of death ligands like FasL with their cell surface receptors (Fas) leading to the recruitment of FADD and caspase-8 which can then cleave Bid to form truncated Bid (tBid). The tBid then translocates from the cytosol to the mitochondrial membrane. In addition, Bax or Bak, a member of intrinsic apoptotic pathway, can initiate apoptosis by forming specific channels in the outer mitochondrial membrane and increasing the outer mitochondrial membrane permeability in hyperoxia. The mechanism by which hyperoxia activates Bax or Bak remains unclear. tBid and activated Bax facilitates the release of cytochrome c from mitochondira which forms an apoptosome complex with Apaf-1 which subsequently activates caspase-9 and caspase-3, leading to the apoptosis. Apaf-1, apoptotic peptidase activating factor 1; FADD, Fas-associated death domain protein; FasL, Fas ligand. Cell membrane 244 Ashwini Gore et al. Weber, 1999; Widmann et al., 1999). Among them, the role of Ion channels the ERKs, the JNKs (also referred to as stress-activated protein Fluid balance is a crucial feature of appropriate barrier kinases) and the p38 MAPKs (p38s) have been characterized function of the lung epithelium. The sodium-potassium- in hyperoxia-induced cell death. + + + adenosinetriphosphatase (Na -K -ATPase) and apical Na Exposure of MLE-12 cells to 95% O triggered a sustained channels are present predominantly on the alveolar Type II activation of the transcription factor activator protein 1 + + (ATII) epithelial cells. ATII cells use Na and K ion gradients (AP-1), as well as p38 and JNK. Importantly, survival of to regulate osmotic control of water, thereby maintaining an MLE-12 cells in hyperoxia was signic fi antly enhanced when essentially fluid-free alveolar lumen with appropriate amount AP-1, p38, or JNK activation was inhibited by either specic fi of airway water vapor. Hyperoxia can elicit fluid shifts result - inhibitors or dominant negative DNA constructs, suggesting ing in pulmonary edema. A compensatory regulation of that hyperoxia-induced cell death involves JNK/p38 and AP-1 Na and u fl id absorption can improve outcome during lung pathways that could be used as potential targets for reducing injury with pulmonary edema (Carter et al., 1997; Borok et al., lung injury (Romashko et al., 2003). Parinandi et al. (2003) 1999). have demonstrated that, under hyperoxic conditions, p38 Borok et al. (1999) demonstrated that hyperoxic expo- MAPK and ERK1/2 pathways are activated in human pul- sure (48 h) reduced the expression of Na channel β-subunit monary endothelial cells. Additionally, inhibition of p38 in AEC, whereas the expression of α- and γ-subunits was MAPK and MEK1/2 attenuated hyperoxia-induced ROS gen- unchanged. The net decrease in ion transport could be par - eration. On the other hand, Wang et al. (2007) observed that tially reversed by treatment with keratinocyte growth factor only MEK1/2—but not p38MAPK—played a crucial role in (KGF). In contrast, Wendt et al. (1999) demonstrated that hyperoxia-induced ROS generation in endothelial cells. These hyperoxia increased the gene expression of the Na, K-ATPase studies highlight the fact that there are significant differences α and β subunit in an in vitro model of Type II cell injury 1 1 in MAPK signaling pathways leading to ROS production due (≥ 95% O for 48 h). Those investigators concluded that an to cell type and species-specific variations which are yet-to-be + + increase in Na -K -ATPase activity might assist in maintaining further elucidated (Wang et al., 2007). gas exchange during HALI-induced alveolar flooding. e Th role of the JNK pathway in hyperoxic lung injury has Precise control of the air–liquid interface at the alveolar been explored in JNK1-dec fi ient mice. It was observed that level balances efficient O absorption, barrier control from deficiency in JNK1 enhanced susceptibility to hyperoxia and pathogens, and abatement of O toxicity. Further study of ion increased lung epithelial cell apoptosis (Morse et al., 2003). channel responses to hyperoxia is necessary to manage pul- It is believed that transient activation of the JNK pathway by monary edema and infection associated with the immediate hyperoxia is protective, while prolonged exposure leads to therapeutic goals of increasing O absorption, while limiting transcription of genes involved in apoptotic cell death (Chang HALI. and Karin, 2001; Tang et al., 2002). e Th ERK1/2 pathway has usually been associated with cell growth in response to mitogenic stimuli. Exposure to hyperoxia has been shown to Protein kinases activate ERK1/2 in MLEs, murine macrophages and rat pheo- There is accumulating evidence highlighting the importance chromocytoma cells (Katoh et al., 1999; Petrache et al., 1999). of protein kinases, such as mitogen-activated protein kinases In primary rat AEC2 isolated from hyperoxia-exposed ats, (MAPK), phosphoinositide-3 kinases and protein kinase C increased activation of ERK1/2 was observed. Furthermore, (PKC), in the regulation of hyperoxic cell death. protection against hyperoxia-induced DNA breakage and apoptosis was conferred by ERK1/2 activation (Buckley et al., 1999). Although ERK1/2 has been implicated in the protec- Mitogen-activated protein kinases tive action of growth factors against cell death, it has also been reported that ERK1/2 mediates hyperoxic cell death in The MAPK signaling cascade is evolutionarily well conserved mouse macrophages (Petrache et al., 1999). Consistent with and includes three hierarchical protein kinases such as MAPK, this observation in mouse macrophages, inhibition of ERK1/2 MAPK ERK/MAP ERK (MAPKK/MEK) and MAPKK kinase activation prior to hyperoxic exposure in MLEs resulted in (MAPKKK; Errede and Levin, 1993; Davis, 1994; Waskiewicz attenuation of cell death (Zhang et al., 2003). Conflicting and Cooper, 1995; Schaeffer and Weber, 1999 ; Widmann data on the protective role of MAPK pathways in hyperoxia- et al., 1999). MAPKKK phosphorylates and, in turn, activates induced apoptosis may ree fl ct the complexity of signaling MAPKK. Activated MAPKK phosphorylates and activates pathway regulation in die ff rent cell types under die ff rent MAPK. Activated MAPK phosphorylates transcription factors culturing conditions. or other downstream kinases, consequently regulating gene expression and cellular functions. MAPKs belong to the sig- nal transduction superfamily of ser/thr protein kinases and Protein kinase C play an essential part in cell proliferation/die ff rentiation, responses to environmental stimuli, and cell survival and cell PKCs are ser/thr kinases and can be activated by exposure death (Kyriakis, 1999). At least six independent MAPK signal- to hyperoxia (Das et al., 2001; Villalba et al., 2001). Based on ing units are functional in mammalian systems (Schaeffer and their requirements for activation, the family of PKC consists of Molecular mechanisms in hyperoxia sensing 245 12 isozymes. e Th y are classie fi d into three groups—the novel injury in HLMVEC. Hyperoxia-induced cell death was sig- PKCs (δ, ε, φ, μ, and η), the conventional PKCs (α, β , β , and nificantly reduced in the myrAkt-expressing cells compared 1 2 γ), and the atypical PKCs (ζ, λ, and τ; Villalba et al., 2001). to controls. Ultrastructural morphometric analyses showed Under normoxic conditions, PKC is found to be associated that in hyperoxic myrAkt cells, the mitochondria and endo- with Bax in lung endothelial cells and this association may plasmic reticulum were less swollen (Ahmad et al., 2006). inhibit the Bax-dependent apoptotic pathway (Wang et al., These results indicate that early activation of Akt in hyperoxia 2005). Wang et al. explored the role of PKC in FLIP-mediated has a beneficial role in protecting against hyperoxic stress protection against hyperoxic injury. In their study, following by maintaining mitochondrial integrity. Similar findings a 24–72 h hyperoxic exposure, murine lung endothelial cells were observed by Lu et al. (2001), who demonstrated that showed an increase in the activated form of Bax. Interestingly, targeted delivery of myrAkt to lung epithelium attenuated over-expression of FLIP inhibited hyperoxia-induced cell hyperoxia-mediated ALI and delayed death in mice. In death, in part, via attenuation of ROS generation, suppres- addition, Ray et al. (2003) showed that KGF offered protec - sion of PKC activity, and increased association of PKC with tion against hyperoxic insult to the epithelium via an Akt- Bax. Moreover, over-expression of FLIP activated Bax phos- dependent pathway, although, no improvement in survival phorylation through the p38 MAP kinase signaling pathway, was observed in these mice. In summary, PI3-kinase/Akt which inhibited Bax-mediated apoptosis (Wang et al., 2007). appears to have significant potential as effective therapeutic Taken together, these studies indicate that FLIP inhibits the target in attenuating HALI (please refer to Figure 4). dissociation of PKC and Bax, resulting in the prevention of Bax activation and its consequent downstream activation of Redox-sensitive transcription factors the intrinsic apoptotic pathway. Nuclear factor erythroid derived 2 (NF-E2)-related transcrip- tion factor 2 (Nrf2), nuclear factor-κB (NF-κB), and AP-1 are PI3-kinase/Akt proteins that play an important role in initiating, stimulat- The activation of PI3-kinase is associated with elevated cel- ing, and terminating transcription (Adler et al., 1999). e Th y lular glucose metabolism and improved cell survival under may be viewed as master regulators of signal transduction by stress (Plas and Thompson, 2002 ; Whiteman et al., 2002). A regulating the expression of proteins involved in modulation key downstream effector of PI3-kinase is the serine-threonine of cell survival in response to various oxidants and inflamma- kinase Akt. Following the activation of PI3-kinase, Akt phos- tory stimuli (Schreck et al., 1991; Beg and Baltimore, 1996; phorylates and regulates the activity of numerous protein Van Antwerp et al., 1996). kinases, transcription factors, and other regulatory molecules (Paez and Sellers, 2003). Multiple proteins involved in regu- lation of cell survival, like Bcl-2-associated death promoter, Hyperoxia Forkhead box 03a/Forkhead in rhabdomysacoma-like-1, Cell membrane cAMP-response element binding protein (CREB), IκBα kinase (IKK-kinase), glycogen synthase kinase-3, and murine double minute 2, are phosphorylated by Akt that, in turn, is activated by PI3-kinase. Akt also contributes to maintaining mitochondrial integrity by inhibiting cytochrome c release ROS Mitochondria and up-regulation of mitochondrial hexokinases (Gottlob et al., 2001; Majewski et al., 2004). Prolonged exposure to hyperoxia results in loss of mitochondrial integrity (Bassett Akt MAPK PKC and Fisher, 1979; Crapo et al., 1980; Freeman and Crapo, 1981). An integral part of adaptation to hyperoxia exposure includes an increase in the utilization of alternative substrates Nrf2 NF-κB AP1 such as glucose and glutamine (Schoonen et al., 1990; Allen and White, 1998; Ahmad et al., 2001). In this regard, hyperoxia is ironically similar to a physiological response to hypoxia. Cell Death Cell Growth arrest Pathways utilizing alternative substrates may be tar- Inflammation Stress Response geted to mitigate hyperoxic injury (Ahmad et al., 2001; Ahmad et al., 2006). To address the role of Akt in hyperoxic Figure 4. Schematic diagram illustrating the signaling pathways mediated injury, primary human lung microvascular endothelial via Akt, MAPK and PKC under hyperoxic conditions. Protein kinases such as Akt, MAPK, and PKC are activated by ROS under hyperoxic conditions. cells (HLMVEC) were used by Ahmed et al. as the damage This results in stimulation of transcription factors such as Nrf2, NF-κB, to endothelium is an early target of hyperoxic lung injury. and AP-1 that are associated with pathophysiological responses including In these cells, transient Akt activation and increase in Akt stress response, inflammation, cell growth arrest, and death. AP-1, activa- phosphorylation was observed after 1- and 24-h hyperoxia tor protein 1; MAPKs, mitogen-activated protein kinases; NF-κB, nuclear exposure, respectively. A constitutively-active myristylated factor-κB; NOX, NADPH oxidase; Nrf2, NF-E2-related transcription factor 2; PKC, protein kinase C. form of Akt (myrAkt) conferred protection against hyperoxic 246 Ashwini Gore et al. e Th following is a general regulatory paradigm for these ALI, bleomycin-induced b fi rosis, allergen-induced asthma, responses. In the cytoplasm, these transcription factors are elastase-induced emphysema, cigarette smoke-induced sequestered in an inactive state. However, in response to dif- chronic obstructive pulmonary disease, and diesel exhaust- ferent stimuli, they are phosphorylated and translocated into induced oxidative DNA damage (Hackett et al., 2003; the nucleus and initiate transcription (Adler et al., 1999). The Rangasamy et al., 2004, 2005). regulation of transcription factors could thus play a key role In addition, the role of Nrf2 in the pathogenesis of hyper- in ameliorating oxidative stress mediated diseases. Various oxia-induced lung toxicity has also been examined in great redox-sensitive transcription factors including Nrf2, NF-κB, detail. Cho et al. (2002) were the r fi st to demonstrate that and AP-1 have been linked to the development of inflamma- that Nrf2 confers protection against hyperoxic lung injury tory lung disorders (Crapo et al., 1980; Lee and Choi, 2003). in mice. Mice lacking Nrf2 expression and activity evinced Emerging evidence has established that these transcription significantly greater lung damage, characterized by increased factors play critical roles in regulating pulmonary responses, protein permeability, leukocyte inl fi tration, and epithelial including cell death under hyperoxic conditions (Choi et al., injury, after hyperoxic exposure compared to wild-type mice. 1995; Li et al., 1997). Furthermore, a significant attenuation in hyperoxia-induced expression of genes modulated by Nrf2 was observed in these Nrf2-deficient hosts. Nrf2-mediated protection against hyper - Nuclear factor erythroid derived 2-related oxic lung injury was thus attributed, at least partly, to these transcription factor 2 downstream genes (Cho et al., 2002). Nrf2-mediated GSH Nrf2 was cloned and characterized in by Moi et al. (1994) expression improved the resolution of hyperoxic lung injury. as a factor that binds to the NF-E2 repeat of the β-globin Nrf2-deficient mice exposed (for 48 h) to sub-lethal hyper- gene promoter. It belongs to the cap ‘n’ collar sub-family of oxia were shown to have impaired alveolar epithelium and transcription factors. Nrf2 is a b-Zip transcription factor as it endothelium regeneration, cellular damage, and increased contains a basic leucine zipper DNA binding domain (b-Zip) macrophage and lymphocyte infiltration during their post- at the C-terminus. In the constitutive state, Nrf2 is mainly exposure recovery. However, administration of GSH imme- localized in the cytosol. Following exposure to oxidants, Nrf2 diately following hyperoxic exposure had a rescuing effect in −/− translocates into the nucleus where it binds to the antioxidant the Nrf2 mice. This outcome suggested that Nrf2-regulated response element (ARE) and up-regulates gene expression GSH synthesis could attenuate hyperoxia-induced lung injury (Moi et al., 1994; Zhang, 2006). Identification of Keap1 as (Reddy et al., 2009). In an AEC culture system, the molecular the key repressor of Nrf2 transcriptional activity has lead to basis of Nrf2-mediated protection against hyperoxia-induced a great progress in the understanding of Keap1-mediated pulmonary toxicity was further investigated (Papaiahgari negative regulation of Nrf2 activation. Keap1 functions as et al., 2004). It was observed that NOX and ERK-1 signaling a molecular switch in the Nrf2-mediated cellular defense play a crucial role in regulating hyperoxia-induced, ARE- response by two mechanisms. Keap1 has a sensing function mediated, Nrf2-dependent transcription in lung epithelial that determines changes in intracellular redox environments cells. Taken together, the overwhelming body of evidence (Zhang and Hannink, 2003; Eggler et al., 2005, 2007; Luo et al., now shows that activation of Nrf2 plays a benec fi ial role in 2007). Secondly, the Keap1 switch function controls the levels hyperoxic lung injury. of Nrf2 via ubiquitin-mediated degradation machinery by functioning as a subunit of E3 ubiquitin ligase (McMahon Nuclear factor-κB et al., 2003; Stewart et al., 2003; Kobayashi et al., 2004). It was demonstrated by Rushmore et al. (1991) that most The NF-κ B family of proteins is responsible for the expres- of the downstream genes of Nrf2 contained an ARE sequence sion of a wide variety of genes, particularly those involved in in the promoter region (Rushmore et al., 1991). These down- inflammation and stress response (Baldwin, 1996 ). The NF-κ B stream genes have been classified into several categories like family is comprised of v fi e members; RelA (also called p65), intracellular redox-balancing proteins, Phase II detoxifying RelB, c-Rel, p50/p105, and p52/p100. These members are enzymes, transporters, and multidrug resistance-associated usually present as heterodimeric or homodimeric complexes. protein (Ishii et al., 2000; Kim et al., 2001; Banning et al., The NF-κ B heterodimer composed of p50 and p65/RelA 2005; Sakurai et al., 2005; Vollrath et al., 2006). Although it subunits is involved in the regulation of various physiologic is ubiquitously expressed in many organs, Nrf2 was found to processes, including differentiation, proliferation, inflamma- be non-essential for the normal development of mice (Chan tion, and survival (Chen and Greene, 2004). In unstimulated et al., 1996). On the other hand, Nrf2 knockout mice showed cells, NF-κB is sequestered in the cytoplasm by an inhibitory decreased levels of both constitutive and inducible phase II protein known as IκB (inhibitor of NF-κB) in an inactive non- enzymes as well as endogenous antioxidants. It is well estab- DNA-binding form. IκB blocks the nuclear translocation sig- lished that an Nrf2-mediated antioxidant response is one of nal of NF-κB and thus prevents it from entering the nucleus. the crucial mechanisms that aids survival following cellular Following exposure to various stimuli/inducers, IκB is rapidly stress. Several studies have shown that activation of Nrf2 phosphorylated on two serine residues, ubiquitinated, and can protect cells against oxidative stress in various in vitro degraded by the 26S proteosome. The phosphorylation of I κB and in vivo models of butylated hydroxytoluene-induced is mediated by various IKKs and ROS are vital in the upstream Molecular mechanisms in hyperoxia sensing 247 pathological changes (Tsan et al., 1995; Shea et al., 1996). events that lead to IKK activation. The released NF-κ B then Treatment with an anti-TNFα antibody improved survival translocates into the nucleus where it activates target genes following hyperoxic exposure (Jensen et al., 1992; Tsan et al., (Baldwin, 1996; Rahman and MacNee, 2000). 1995). Pulmonary levels of IL-1β and IL-6 were also elevated Activation of NF-κB in hyperoxia has been observed in following exposure to hyperoxia (Lindsey et al., 1994; Johnston several lung cell types, including alveolar macrophages, lung et al., 1997). Interestingly, NF-κB activation-induced by other epithelial cells, human pulmonary artery endothelial cells, cytokines like TNFα and IL-1β can be further enhanced by monocytic THP-1 cells, and in rat and mouse lungs (Shea hyperoxia exposure, resulting in amplification of pro-inflam- et al., 1996; Suzuki et al., 2000; Pepperl et al., 2001; Franek matory responses (Wong et al., 2002; Odoms et al., 2004). On et al., 2004; Sue et al., 2004; Guthmann et al., 2005). In neo- the other hand, over-expression of IL-6 confers protection natal mice, activation of NF-κB was more pronounced and against HALI (Ward et al., 2000). In light of the dual ee ff cts sustained upon exposure to hyperoxia as compared to adult on hyperoxia-induced death, and pro-inflammatory cytokine mice (Yang et al., 2004). Hyperoxia has also been shown to production, a universal approach of either activating or enhance lipopolysaccharide and interferon γ (IFNγ)-induced inhibiting pulmonary NF-κB will not be beneficial in reduc - NF-κB activation (Shenkar et al., 1996). Using lung epithelial ing pro-inflammatory hyperoxic lung injury. Instead, studies cells, Franek et al. (2001) showed that exposure to hyperoxia directed at understanding the effect of NF-κ B modulation in conferred resistance against subsequent oxidant triggered specific cell types may reveal a better strategy for attenuating cell death. In a subsequent report, these investigators dem- hyperoxia-induced lung injury (please refer to Figure 5). onstrated that in lung epithelial cells, NF-κB reduced sus- ceptibility to hyperoxia-induced non-apoptotic cell death. In mouse pulmonary lymphocytes, exposure to hyperoxia for cAMP-response element binding protein 24–48 h resulted in NF-κB activation, followed by an increase CREB, is a redox transcriptional regulatory factor activated in TNFα and IFNγ production (Shea et al., 1996). in the lungs following hyperoxic exposure (Jamieson et al., The protection conferred by NF-κ B activation is most 1986; Schreck et al., 1991; Shenkar and Abraham, 1997; likely mediated by NF-κB-induced expression of Bcl-2 and George et al., 1999). Both binding sites for CREB and NF-κB other cytoprotective enzymes, such as MnSOD and GSH are present in the promoter regions of a number of cytokines, peroxidase—each of which are regulated by NF-κB (Rahman including TNFα, NF-κB, IL-1β, and IL-6. Increased pro-in- and MacNee, 2000; Franek et al., 2004; Choi et al., 2006). In amm fl atory cytokine expression as a consequence of ROS- fetal lung fibroblasts, NF-κ B activation prevents hyperoxia- induced activation of these transcription factors could play induced apoptosis. e Th alteration of the normal pattern an essential role in triggering HALI (Shenkar and Abraham, of b fi roblast apoptosis may contribute to abnormal lung 1997). Abraham et al. showed that treatment with lisofylline development upon exposure to hyperoxia. Together with suppressed CREB activation in mice exposed to hyperoxia. hyperoxia-induced b fi roblast trans-die ff rentiation, altered Lisofylline also inhibited hyperoxia-induced expression of elastin synthesis, and decreased fibroblast growth factor-7 TNFα, IL-1β, and IL-6 in lungs and decreased hyperoxia- activity, these studies indicate that exposure of fibroblasts to induced serum oxidized free fatty acids. Moreover, lisofyl- hyperoxia impairs normal lung development (Bruce et al., line treatment reduced the lung wet-to-dry weight ratios and 1989; Boros et al., 2002; Rehan and Torday, 2003). Designing enhanced survival in hyperoxia. us Th , these studies suggest a therapeutic approach to target NF-κB mediated hyperoxic that inhibiting CREB activation could be protective in hyper- signaling in the adult and developing lung needs further oxia-induced lung injury and warrants further investigation investigation of the unique responses in each scenario. for clinical application (George et al., 1999). While NF-κB plays a critical role in protecting lung cells against hyperoxia-induced cell death, many of the genes encoding pro-ina fl mmatory cytokines such as interleukin CXC2 receptors 8 (IL-8) and TNFα are also regulated by NF-κB-dependent mechanisms. e Th se particular cytokines promote the Chemokines are a family of low molecular weight proteins recruitment of neutrophils, eosinophils, macrophages, and that regulate leukocyte recruitment to ina fl mmatory sites lymphocytes that, in turn, enhance inflammation (Schreck (Bhandari and Elias, 2006). e Th y play a key role in the et al., 1992; Baldwin, 1996; Shea et al., 1996; Abraham, 2003). pathogenesis of HALI by acting as potent neutrophil che- An early response in the lung to hyperoxic exposure is an moattractants; therefore, these proteins are important in increase in NF-κB activation that precedes an increase in understanding the specific mechanisms involved in recruit - cytokine levels (Shea et al., 1996; Shenkar et al., 1996). e Th ment of neutrophils to the lung for management of HALI. presence of an active NF-κB site in the IL-8 promoter is nec- Levels of neutrophil chemokines such as IL-8 are elevated in essary for hyperoxia-induced IL-8 secretion from U937 cells both adults with ALI and premature neonates who develop (D’Angio et al., 2004). BPD (Bhandari and Elias, 2006). Chemokines such as IL-8, The increased levels of pro-inflammatory cytokines could chemokine (C-X-C motif ) ligand 1 (CXCL1), and CXCL2/3 contribute to the development of hyperoxic lung injury. function via binding to C-X-C chemokine receptor-2 (CXCR2; Elevated levels of TNFα are present in the lungs during early G-protein-coupled receptors; Ludwig et al., 2000; Parsons stages of hyperoxic exposure prior to any visible histological et al., 2005). Upon activation, CXCR2 is phosphorylated and 248 Ashwini Gore et al. Hyperoxia INFLAMMATION ROS Active NF-κB IL-1β, lL-8, Bcl-2,Akt TNF-α SURVIVAL GENES DNA MnSOD IL-6, IL-11 Promotes Hyperoxia-Induced Acute Lung Injury Figure 5. Schematic diagram illustrating the effects of NF-κ B under hyperoxic conditions. Hyperoxia induces activation of NF-κB resulting in its nuclear translocation. In the nucleus NF-κB regulates genes involved in inflammation like IL-8 and TNFα. On the other hand NF-κB also up-regulates survival genes like Bcl-2, Akt and enzyme MnSOD that confers protection against hyperoxic cell death. IL, interleukin; MnSOD, manganese superoxide dismutase; NF-κB, nuclear factor-κB; TNFα, tumor necrosis factor-α. rapidly internalized via arrestin/dynamin-dependent mecha- hyperoxia-induced neutrophil accumulation and lung injury nisms, resulting in receptor desensitization (Mueller et al., (please refer to Figure 6). 1994; Feniger-Barish et al., 1999; Hall et al., 1999). Activation of CXCR2 sequentially stimulates the release Receptor for advanced glycation end-products of intracellular inositol phosphates and an increase in intracellular calcium levels (Richardson et al., 1998). In Receptor for advanced glycation end-products (RAGE) is a addition, CXCR2 activation stimulates the phosphorylation member of an immunoglobulin superfamily of cell- surface of intracellular proteins involved in directed cell migration receptors (Thornalley, 1998 ). The expression of RAGE is pre- by ERK1/2-dependent mechanisms (Loetscher et al., 1994; dominant in the lung, particularly in alveolar Type I cells (AT1) Hall et al., 1999). Sue et al. (2004) have demonstrated that that can amplify injury triggered by acute stress (Sternberg the ligand-receptor (C-X-C chemokine—CXCR2) biological et al., 2008). RAGE is a single membrane spanning receptor axis is crucial during the pathogenesis of hyperoxia-induced consisting of a short (40 residue) cytosolic domain and a large lung injury. In their cited study, these investigators exposed extracellular portion containing three Ig-like domains (V, C1, C57BL/6 mice to 80% O for 6 days and then examined pul- and C2 domains; Dattilo et al., 2007). RAGE is a multi-ligand monary inflammation and host survival. Along with a marked receptor that binds to several ligands including AGE, ampho- increase in neutrophil sequestration and lung injury (evi- terins (high-mobility group protein-1), S100/calgranulins, denced by myeloperoxidase assay and histopathology), a 50% amyloid-β peptide, β-fibrils, and Mac-1 (Neeper et al., 1992; mortality rate was observed in these mice. It was also noted Hori et al., 1995; Yan et al., 1996; Hofmann et al., 1999). High that an increased expression of CXCR2 ligands and CXCR2 levels of RAGE have been observed during lung develop- mRNA expression paralleled the neutrophil recruitment to ment, suggesting that it plays an important role in pulmonary the lung. An inhibition of C-X-C chemokine ligands/CXCR2 functionality and morphogenesis (Reynolds et al., 2008). This interaction resulted in a signic fi ant reduction in neutrophil is consistent with the observation that RAGE receptors are sequestration and lung injury in mice exposed to hyperoxia. involved with the cellular spreading, thinning, and adherence −/− Furthermore, CXCR2 mice displayed significantly increased that characterizes the transition of ATII cells to squamous +/+ survival in response to hyperoxia as compared with CXCR2 (ATI) cells (Schmidt et al., 2001). In patients and in animal mice (Sue et al., 2004). Kotecha et al. (2003) showed that a models of ALI, it was observed that RAGE levels were elevated blockade of CXCR2 (using SB-265610 injections) reduced in both plasma and lung lavage u fl ids, and that this elevation hyperoxia-induced neutrophil accumulation and pulmonary correlated directly with extent of lung injury (Uchida et al., vascular injury in newborn rats. These studies suggest that the 2006). An increase in lung RAGE levels was also observed in use of a pharmacological inhibitor of CXCR2 may attenuate pulmonary ina fl mmation caused by smoke-related damage Molecular mechanisms in hyperoxia sensing 249 and various pneumonias, suggesting an important role for called endogenous secretory RAGE. Using recombinant RAGE in lung inflammatory responses. gene technology, Hanford et al. (2004) recently synthesized A potential involvement of RAGE signaling in hyperoxic a soluble form of RAGE called sRAGE (Hanford et al., 2004). lung injury was investigated in mice deficient in RAGE. RAGE Administration of sRAGE produced a therapeutic ee ff ct via ablation prolonged the survival under hyperoxic conditions. blocking the action of RAGE in experimental animal models, Following hyperoxic exposure, RAGE expression was signifi- suggesting that sRAGE attenuates RAGE-mediated HALI by cantly increased in wild-type mouse lung parenchyma and acting as a decoy receptor (Park et al., 1998). Further research primary AECs (Reynolds et al., 2009). Compared to their wild- on RAGE signaling in the lung is needed to effectively identify type counterparts, RAGE knockout mice showed a significant novel targets that are likely to be important in mitigating lung decrease in protein leakage, lung wet-to-dry weight ratios, injury and associated inflammation. For a greater under - and ina fl mmatory cell inl fi tration into the airspaces after standing and a more complete review on the role of RAGE exposure to hyperoxia. Data from a recent large randomized in pulmonary health and diseases, please refer to Mukherjee controlled trial showed that baseline levels of plasma RAGE et al. (2008; and also please refer to Figure 7). were linked with the clinical outcomes in ALI/ARDS patients exposed to higher tidal volume ventilation. Higher plasma Toll-like receptors RAGE levels correlated with increased mortality, organ fail- Toll-like receptors (TLR) belong to a conserved family of ure, and fewer ventilator free days. With administration of innate immune recognition receptors that are important lower tidal volume ventilation, a decline in RAGE levels was mediators of microbe detection and immune responses noted with time (Calfee et al., 2008). Yonekura et al. (2003) (Aderem and Ulevitch, 2000). Structurally, TLRs consist of showed that under certain conditions, the large extracellu- an extracellular (ectodomain) and a cytoplasmic domain. lar region of RAGE is endogenously secreted into the lung Subsequent to ligand binding, they undergo dimerization and and other organs thereby forming a soluble isoform of RAGE conformational changes that are required for the recruitment of downstream signaling molecules. TLR activation initiates Hyperoxia intracellular signaling which is either dependent or inde- pendent of adaptor protein myeloid die ff rentiation factor 88 Alveolar and interstitial macrophage (Weber et al., 2003). e Th signaling cascade ultimately results in NF-κB translocation into the nucleus where it mediates the expression of inflammatory genes (Oshiumi et al., 2003; IL1,TNF Covert et al., 2005). e Th TLR family consists of 10 members, e.g., TLR1-TLR10 (Takeda and Akira, 2004). Among TLR Epithelial, endothelial cells, family members, TLR3 and TLR4 have been implicated in monocytes and lymphocytes mediating HALI. CNC-1 (IL8), CXCL1 ,CXCL2/3 CXCR2 Attract Neutrophils Inflammation, Vascular Acute Lung Injury permeability Bronchopulmonary Dysplasia PLASMA MEMBRANE Figure 6. Summary of events underlying how hyperoxia-induced acute RAGE lung injury (HALI) and bronchopulmonary dysplasia (BPD) are mediated LIGAND via selected cytokines upon interaction with the CXCR2 chemokine recep- MAPK MAPK sRAGE tor. Exposure to hyperoxia causes alveolar or interstitial macrophages in NF-κB NF-κB lung to release early response cytokines (IL-1 and TNF). These cytokines, RAGE in turn, activate resident lung endothelial cells, epithelial cells, monocytes, TRANSCRIPTION RECEPTOR and lymphocytes, leading to the production of chemokines such as IL-8, CXCL1, and CXCL2/3. These chemokines function via binding to CXCR2 Figure 7. Diagrammatic representation of RAGE signaling. Binding of chemokine receptor and regulate neutrophils recruitment to inflamma- RAGE with its ligands activates MAPKs and NF-κB. In the presence of tory sites leading to increase in vascular permeability and inflammation sRAGE, the RAGE ligand binding is prevented and hence it’s downstream observed in hyperoxia-induced acute lung injury and bronchopulmonary signaling through MAPKs and NF-κB is inhibited. MAPKs, mitogen- dysplasia. BPD, bronchopulmonary dysplasia; IL, interleukin; CINC-1, activated protein kinases; NF-κB, nuclear factor-κB; RAGE, receptor for cytokine-induced neutrophil chemoattractant-1; CXCL, chemokine (C-X-C advanced glycation end-products; sRAGE, soluble from of RAGE; TNF, motif ) ligand; CXCR2, C-X-C chemokine receptor-2; HALI, hyperoxia-in- tumor necrosis factor. duced acute lung injury. 250 Ashwini Gore et al. Murray et al. (2008) showed that mice dec fi ient in TLR3 generated in hyperoxia and the accumulation of inflammatory −/− (TLR3 ) exhibited a lower occurrence of ALI, activation mediators within the lungs (Crapo et al., 1980; Matalon and of apoptotic cascades, and extracellular matrix deposition Egan, 1984). Exposure to prolonged hyperoxia results in cell +/+ following hyperoxia compared to wild-type (TLR3 ) mice. injury and death, outcomes that could be mitigated by the Administration of a monoclonal anti-TLR3 antibody to wild- over-expression of anti-cell death cytoprotective molecules type mice protected them from hyperoxic lung injury and like Bcl-XL. Current evidence suggests that effective target - ina fl mmation. Additionally, increased expression of TLR3 ing of receptors such as RAGE, CXCR2, TLR3, and TLR4, as was observed in not only hyperoxia-exposed cultured human well as protein kinases like MAPK, PI3, and PKC may attenu- epithelial cells but also airway epithelial cells obtained from ate hyperoxic lung injury and promote cell remodeling and patients with ARDS. e Th se results suggest that TLR3 plays resolution of ina fl mmation. As transcription factors such as a signic fi ant role in the development of ALI in hyperoxia Nrf2, NF-κB, and CREB play essential roles in modulating (Murray et al., 2008). expression of cytoprotective genes and inflammatory media- TLR4 has been extensively studied in relation to patho- tors, they could also potentially act as important therapeutic gen-mediated host responses. Recently, studies have been targets. carried out to elucidate its role in hyperoxia-mediated In summary, HALI involves the participation of multiple inflammation. A study by Zhang et al. (2005) reported that pathways, each mediated by distinct hyperoxia sensing moie- TLR4-dec fi ient mice exhibited increased mortality and lung ties. Hence, the benec fi ial ee ff cts of using a combination of injury in hyperoxia suggesting that TLR4 is required for the agents that simultaneously target multiple pathways could survival and lung integrity in hyperoxia. The enhanced sus - far outweigh the benefits of targeting a single pathway. On ceptibility of the TLR4-deficient mice to hyperoxia was linked the other hand, the true physiological duties of hyperoxia with an inability to up-regulate Bcl-2 and phospho-Akt. In sensing molecules are multifaceted in signaling throughout addition, a significant reduction in hyperoxia-induced pul- the body. Ee ff ctive therapeutic strategies in treating HALI will monary apoptosis was observed in the transgenic mice with require a cautious design that does not impose off-target risk. constitutively-active form of TLR4. A significant reduction in A thorough understanding of the roles hyperoxia-sensing pulmonary apoptosis was observed in the transgenic mice factors play in specic fi cell types will require use of animal with constitutively-active form of TLR4 exposed to hyper- models where multiple system interactions can be exam- oxia compared to the controls. A sustained up-regulation of ined. These approaches will help pave the way for investi- anti-apoptotic molecules such as heme oxygenase-1 (HO-1) gating combination therapies aimed at modulating multiple and Bcl-2 was associated with this phenotype (Qureshi hyperoxia-sensing moieties to attenuate HALI. et al., 2006). Furthermore, in vivo knockdown of pulmonary HO-1 or Bcl-2 expression by intranasal administration of Acknowledgements short interfering RNA blocked the ee ff ct of TLR4 signaling on hyperoxia-induced lung apoptosis. These results indicate The authors would like to thank Ravi Sitapara for the excel- that TLR4 activation protects against hyperoxia-mediated lent technical assistance in constucting the g fi ures in this lung injury via up-regulation of anti-apoptotic molecules. manuscript. Contradictory to these observations, Ogawa et al. (2007) showed that TLR4-dependent NF-κB activation signic fi antly contributed to hyperoxic lung injury. e Th y showed that TLR4 Declaration of interest played a critical role in up-regulation of pro-ina fl mmatory i Th s work was supported by grants from the National Heart mediators and neutrophil accumulation into the lung in and Blood Institute (HL093708, LLM), St. John’s University hyperoxia. Exposure to hyperoxia for 96 h caused an NF-κB and the Feinstein Institute for Medical Research at the North translocation in the wild-type mice (C3H/HeN); in contrast, Shore-Long Island Jewish Health System. e Th authors are this response was significantly attenuated in the TLR4 mutant alone responsible for the content and writing of the paper. mice (C3H/HeJ). The lack of TLR4 signaling also suppressed any expected hyperoxia-mediated elevations of TNFα and IL-6 in the bronchoalveolar lavage fluid (Ogawa et al., 2007). In References conclusion, the data from this 2007 study indicated that TLR4- Abraham, E. 2003. Neutrophils and acute lung injury. Crit. Care Med. dependent NF-κB activation might promote up-regulation of 31:S195–S199. pro-inflammatory mediators and consequent neutrophil infil- Aderem, A. and Ulevitch, R.J. 2000. Toll-like receptors in the induction of the innate immune response. Nature 406:782–787. tration leading to HALI. 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Hyperoxia sensing: From molecular mechanisms to significance in disease

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Taylor & Francis
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© 2010 Informa Healthcare USA, Inc.
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1547-6901
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10.3109/1547691X.2010.492254
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Abstract

Oxygen therapy using mechanical ventilation with hyperoxia is necessary to treat patients with respiratory failure and distress. However, prolonged exposure to hyperoxia leads to the generation of excessive reactive oxygen spe- cies (ROS), causing cellular damage and multiple organ dysfunctions. As the lungs are directly exposed, hyperoxia can cause both acute and chronic inflammatory lung injury and compromise innate immunity. ROS may contribute to pulmonary oxygen toxicity by overwhelming redox homeostasis, altering signaling cascades that affect cell fate, ultimately leading to hyperoxia-induced acute lung injury (HALI). HALI is characterized by pronounced inflamma - tory responses with leukocyte infiltration, injury, and death of pulmonary cells, including epithelia, endothelia, and macrophages. Under hyperoxic conditions, ROS mediate both direct and indirect modulation of signaling molecules such as protein kinases, transcription factors, receptors, and pro- and anti-apoptotic factors. The focus of this review is to elaborate on hyperoxia-activated key sensing molecules and current understanding of their signaling mechanisms in HALI. A better understanding of the signaling pathways leading to HALI may provide valuable insights on its pathogenesis and may help in designing more effective therapeutic approaches. Keywords: Hyperoxia; inflammation; sensing; apoptosis; cell death; signaling; acute lung injury; ROS American intensive care units (ICU), mechanical ventilation Introduction is administered to at least 40% of the patients on a daily basis Mechanical ventilation with supraphysiological concentrations (ICARE, 1999). Patients requiring mechanical ventilation are of oxygen (O ) is routinely used to treat patients with difficul- often critically ill with conditions such as respiratory failure, IMT ties in maintaining adequate oxygenation and ventilation. spinal cord injury, cardiac complications, cerebrovascu- Our atmosphere consists of 21% O , which is corresponding lar accident, and neurological disorders (Windhorst et al., 492254 to 160 mm Hg partial pressure of oxygen (pO ). Patients with 2009). Although mechanical ventilation with hyperoxia has hypoxemia and acute respiratory failure require administra- improved survival in these patients, prolonged exposure to tion of elevated concentrations of inspired oxygen (> 21% O ) hyperoxia can result in adverse ee ff cts on multiple organ 16 April 2010 for basic life support (Snider and Rinaldo, 1980; Carvalho systems. Prolonged hyperoxia at normal pressure primarily et al., 1998; Seta et al., 2004). Hyperoxia is defined as either causes pulmonary and ocular toxicity due to oxidative damage excess O or higher than normal physiological pO , which to endothelial and epithelial cells. Oxygen toxicity can lead 2 2 05 May 2010 varies from organ to organ and from venous blood to arte- to the collapse of the alveoli, acute and chronic lung injury, rial blood. e Th level of hyperoxia administered to patients central nervous system disorders manifested as seizures and 06 May 2010 varies depending on their clinical situation. Up to 100% O convulsions, cardiovascular and gastrointestinal disorders, is used in supporting patients suffering from severe acute erythrocyte damage, and retinopathy (Bostek, 1989). cardio-respiratory decline. Oxygen concentrations ranging Among various organ systems, the toxic effects of pro- 1547-691X from 50% to 60% are routinely used for the long-term man- longed hyperoxia have been particularly well studied in the agement of these patients under more stable conditions. In lung. Its large epithelial surface and anatomical location make 1547-6901 Address for Correspondence: Dr. Lin L. Mantell, Department of Pharmaceutical Sciences, St. John’s University College of Pharmacy, 128/SB28 St. Albert Hall, 8000 Utopia Parkway, Queens, NY 11439, USA; E-mail: mantelll@stjohns.edu © 2010 Informa Healthcare USA, Inc. (Received 16 April 2010; revised 05 May 2010; accepted 06 May 2010) ISSN 1547-691X print/ISSN 1547-6901 online © 2010 Informa Healthcare USA, Inc. 10.3109/1547691X.2010.492254 DOI: 10.3109/1547691X.2010.492254 http://www.informahealthcare.com/imt 240 Ashwini Gore et al. the lungs vulnerable to oxidative damage and both chronic exacerbate formation and accumulation of excessive ROS and acute inflammatory lung injury. Oxygen toxicity has been (Carvalho et al., 1998; Lukkarinen et al., 2003). Oxygen toxicity shown to contribute to the morbidity of bronchopulmonary develops as the production of ROS overwhelms the capacity dysplasia (BPD) in pre-term infants (Jobe, 1999). According of lung antioxidant systems that are designed to preserve nor- to the National Nosocomial Infection Survey, 86% of noso- mal cellular functions (Tang et al., 1993; Asikainen and White, comial pneumonia cases in ICUs have been associated 2004). An initial ROS formed by hyperoxia is the superoxide with mechanical ventilation with hyperoxia, which has an anion radical (·O ; Carvalho et al., 1998; Lukkarinen et al., approximately 1% per day relative risk of acquiring ventilator- 2003). i Th s species can be further converted into other ROS associated pneumonia (ICARE, 1999; Richards et al., 1999). such as hydrogen peroxide (H O ) or hydroxyl radical (OH·; 2 2 Results from a post-mortem study showed that an alarming Adler et al., 1999). Superoxide dismutase (SOD) can rapidly 67% of the patients who received mechanical ventilation had catalyze the dismutation of superoxide anion to H O (please 2 2 developed pneumonia (Marquette et al., 1995). Numerous refer to Figure 1). Over-expression of any of the isoforms of studies show that exposure to prolonged hyperoxia signifi- SOD in mouse models has been shown to provide limited to cantly contributes to the pathogenesis of acute lung injury complete protection, depending on the promoter and site of (ALI) and play an important role in the poor clinical outcome expression with hyperoxic lung injury (Wispe and Roberts, of acute respiratory distress syndrome (ARDS) patients. Lung 1987; White et al., 1991; Ahmed et al., 2003). Additionally, injury consequent to prolonged hyperoxia is characterized an earlier onset of edema and reduced survival has been by an overwhelming production of reactive oxygen spe- reported in mice lacking extracellular SOD when challenged cies (ROS), which play an essential role in the subsequent with prolonged hyperoxia. Taken together, these data suggest extensive inflammatory response, destruction of the alveolar- ·O plays a pivotal role in hyperoxia-mediated ALI (Carlsson capillary barrier, impaired gas exchange, and pulmonary et al., 1995). edema (Slutsky, 1999; Waxman et al., 1999; Corne et al., 2000). A small steady-state concentration of ROS is maintained Therefore, a clear understanding of the underlying cellular as part of normal physiological metabolism (Cadenas and and molecular mechanisms mediating hyperoxia-induced Davies, 2000). The mitochondrial electron transport chain can acute lung injury (HALI) is crucial to successful therapies. generate ·O by the transfer of an electron to molecular O at 2 2 e Th ability to sense and respond to changes in the concen - Complex I, II, or III, in lieu of complete transfer to Complex tration of O is essential for the survival of prokaryotic and IV where O is consumed to form water. Under conditions 2 2 eukaryotic organisms. Oxygen plays a central role maintain- of hyperoxia, the generation of ROS from mitochondria ing cellular and tissue homeostasis and is n fi al acceptor of electrons, at the end of the mitochondrial respiratory chain. e Th nature of how cells sense and adapt to hyperoxia is NO •- complicated and remains to be further explored. e Th focus - 2 ONOO of this review is to elaborate on key hyperoxia-activated sensing molecules and the current understanding of their NOX/ signaling mechanisms in HALI. Many of these transcription SOD Mitochondrial electron factors, receptors, protein kinases, ion channels, and pro- and transport anti-apoptotic factors may serve as a paradigm for hyperoxia sensing at the molecular level. H O O 2 2 Role of ROS in mediating oxygen toxicity 2+ Fenton Fe , − Cl The respiratory system is uniquely adapted to optimize pO 1+ Reaction Cu MPO relative to the external atmosphere and meet the needs of metabolism. Inspired air is warmed and humidie fi d as it is drawn through the nose and mouth to the trachea and lower HOCl OH bronchial tree, which causes a decrease in pO . As air reaches the alveolus, O concentration equilibrates to balance the processes of removal into the blood capillaries and delivery by Figure 1. Formation of ROS/free radicals from exposure to molecular inspiration/ventilation. As a result, alveolar pO is ≈ 100 mm oxygen. One-electron reduction of molecular oxygen (O ) by NADPH Hg or 14% (Roy et al., 2004). Homeostasis of cellular oxygen oxidase/mitrochondrial oxidative phosphorylation results in forma- − − tion of superoxide anion radical (·O ). The ·O is converted to H O by concentrations within a narrow range minimizes the risk of 2 2 2 2 superoxide dismutase (SOD) via a dismutation reaction. H O can gener- 2 2 oxidative damage from either excess oxygen or metabolic 2+ ate OH· radical in the presence of transition metals such as iron (Fe ) or death due to hypoxia (Semenza, 2001). + − copper (Cu ). Peroxynitrite (ONOO ) is formed when nitric oxide (NO) In the setting of hospitalization requiring hyperoxic ther- reacts with superoxide. Peroxidases use H O to catalyze the oxidation of 2 2 apy, O homeostatic balance is disrupted consequent to both diverse substrates, for example myeloperoxidase oxidizes Cl to HOCl. MPO, myeloperoxidase; NO, nitric oxide; NOX, NADPH oxidase; OH, the underlying pathology and treatment. While immediate hydroxyl radicals; SOD, superoxide dismutase. clinical needs must be met, supplemental O therapy can 2 Molecular mechanisms in hyperoxia sensing 241 increases linearly with oxygen tension (Turrens, 2003). localize ROS signaling to selective signal transduction clients Electron leak and proportionate increased ·O formation (Ushio-Fukai, 2006). Both NOX1 and NOX2 are expressed in during hyperoxia results in a concomitant increase in H O mouse lung, and NOX1 has been detected in human alveolar 2 2 production, catalyzed by manganese SOD (MnSOD) local- epithelial cells (AEC; A549) and endothelial cells (Freeman ized in the mitochondrial matrix (please refer to Figure 2). and Crapo, 1981; Mittal et al., 2007). Using knockout mice, Targeted over-expression of MnSOD in the matrix has Carnesecchi et al. (2009) demonstrated that NOX1, but not been shown to improve survival of either lung microvessel NOX2, was an important mediator of hyperoxia-induced ALI. endothelial or lung epithelial cells exposed to hyperoxia ROS generated by NOX1 under hyperoxic conditions, medi- (Hori et al., 1995; Li et al., 1997). Over-expression of MnSOD ated alveolar cell death through c-Jun N-terminal kinases protects lung epithelial cells against oxidant injury (Koo (JNKs) and extracellular signal-regulated kinases-mediated et al., 2005). Related enzymes, such as cytosolic catalase, (ERK-mediated) pathways (Carnesecchi et al., 2009). e Th se Cu/ZnSOD in the mitochondrial intermembrane space, and data were consistent with the n fi ding that NOX1 in lung matrix glutathione (GSH) peroxidase do not appear to change epithelium promoted JNK-mediated cell death via tumor in these models relative to non-MnSOD transgene controls. necrosis factor (TNF) receptor-1 (TNF-RI), TNF-receptor- These data illustrate that appropriate compartmentalization associated factor 2, as well as apoptosis signal-regulating of augmented MnSOD activity to the mitochondrial matrix kinase 1 (Pantano et al., 2007). Additional evidence sup- can ameliorate hyperoxia-induced cytotoxicity, despite H O porting the role of NOX in ALI was the attenuation of ROS 2 2 also being a ROS. production in mouse epithelial cells exposed to hyperoxia A second source of ROS under hyperoxic conditions is the following administration of diphenyleneiodonium chloride nicotinamide adenine dinucleotide phosphate (NADPH) oxi- (Zhang et al., 2003), albeit this was a non-specic fi chemical dase (NOX) family (Zhang et al., 2003). As the name implies, inhibitor of NOX. NOXs utilize NADPH/NADH as the electron donor to catalyze An influx of neutrophils and monocytes, which accu- reduction of molecular oxygen to ·O at the extracellular face mulate within the pulmonary circulation, interstitium, of the plasma membrane (Tsan, 2001; Lambeth, 2004; please and air spaces under hyperoxic conditions, represents a refer to Figure 2). Recent analysis has entertained intracellular source for additional ROS (Fox et al., 1981; Raj et al., 1985; trafficking to endosomal compartments as a mechanism to Chollet-Martin et al., 1996; Goodman et al., 1996). Phagocyte ECSOD •− O H O 2 2 2 NOX 2+ Fe 1+ Cu •− Cu/ZnSOD O • 2 H O OH 2 2 Complex I Complex IIIComplex IV Complex II MITOCHONDRIA •− 2+ Fe MnSOD MnSOD 1+ Cu OH H O 2 2 Figure 2. Schematic diagram illustrating the sources of ROS under hyperoxic conditions. Molecular oxygen can be reduced to superoxide anion by electron leak from mitochondrial electron transport chain or via NADPH oxidase catalysis. Most of these excess ROS are generated in the mitochondria through an increased flux of electrons at Site III in the mitochondrial electron transport chain. Superoxide dismutases catalyze formation of H O . In 2 2 2+ the presence of reduced transition metals (such as Fe ), H O can form the highly oxidizing hydroxyl radicals (OH·). Cu/ZnSOD, Cu/Zn superoxide 2 2 dismutases; ECSOD, extracellular superoxide dismutases; NOX, NADPH oxidase. 242 Ashwini Gore et al. NOX2 is a complex containing v fi e catalytic subunits and i.e., necrosis and apoptosis, or non-classical pathways, i.e., regulatory proteins which are required for its activation and oncosis (Polunovsky et al., 1993; Matute-Bello et al., 1997; formation of ·O (Lambeth, 2004; Bedard and Krause, 2007). Mantell et al., 1999). Depending on the concentration of Overwhelming production of ROS from these sources under hyperoxia, duration of exposure, and cell type, cell death hyperoxic conditions can lead to oxidative modic fi ations may occur either via distinct or overlapping mechanisms of macromolecules, leading to pulmonary cell death that is (Bhandari and Elias, 2006; Zaher et al., 2007). characteristic of hyperoxic lung injury (Mantell et al., 1999; O’Reilly, 2001). Numerous studies have shown that cells Pro- and anti-apoptotic factors exposed to prolonged hyperoxia undergo growth inhibi- The critical role of apoptotic death of pulmonary cells has tion, cell cycle arrest, and even cell death, with oxidation of been established in animal models of hyperoxic lung injury DNA, lipids, and protein (Cacciuttolo et al., 1993; Janssen as well as other animal models of ALI (Mantell et al., 1997, et al., 1993; O’Reilly, 2001; Wang et al., 2003). Hyperoxic 1999; Mantell and Lee, 2000). e Th re have been numerous murine macrophages, b fi roblastic cell lines, primary lung studies illustrating the role of both pro- and anti-apoptotic fibroblasts, and endothelial cells each display biochemical factors in the regulation of pulmonary cell death in hyperoxia. and morphological features of apoptosis (Hogg et al., 1999; Apoptotic cell death can be initiated by either of two general Petrache et al., 1999; Budinger et al., 2002; Pagano et al., 2005) pathways—an extrinsic initiation regulated by extracellular whereas epithelial cells (A549 and murine lung epithelial cell signals, or an intrinsic initiation regulated by intracellular 12 (MLE-12)) show morphological features of necrosis, apop- physiological changes. tosis, and oncosis following exposure to high O concentra- The extrinsic apoptotic pathway is triggered following tions (Lee and Choi, 2003; Romashko et al., 2003; Wang et al., formation of a death-inducing signal complex (DISC), upon 2003). As a result of damage to both endothelial and epithelial the binding of death ligands (Fas ligand (FasL)) with their cells, alveolor-capillary barrier integrity is lost—leading to cell-surface receptors (Fas; Walsh et al., 2003). Stimulation interstitial edema and impairment in gas exchange (Mantell of Fas by FasL results in the recruitment of Fas-associated et al., 1999). Although beyond the scope of this review, it is death domain protein and caspase-8 to the cytoplasmic important to note that despite the activation of leukocytes death domain of Fas. Caspase-8 is then activated and can and allied NOX/ROS systems in HALI, pulmonary coloniza- then cleave Bid to form truncated Bid (tBid). The tBid sub- tion with infectious microbes is still a leading complication of sequently translocates from the cytosol to the mitochondrial patients on mechanical ventilation with hyperoxia (Richards membrane, where it stimulates cytochrome c release and et al., 1999). caspase-9 activation (Walsh et al., 2003). The role of extrinsic In addition to directly modifying macromolecules, pathway in the development of lung injury in hyperoxia has exposure to hyperoxia also involves direct and indirect been demonstrated by the involvement of Fas-associated modulation of many hyperoxia-sensing molecules. A clearer death domain interleukin-1β-converting enzyme-like understanding of hyperoxia-induced signal transduction inhibitory protein (FLIP) in both in vitro and in vivo mod- pathways is critical to provide the foundation for designing els. FLIP, a natural inhibitor of the extrinsic apoptosis path- successful therapeutic strategies. A number of published way, is known as FLIP (Rasper et al., 1998; Micheau, 2003). review articles have discussed many aspects of HALI, some Apoptosis induced by death receptors, such as Fas or the of which have been discussed in great detail (Lee and Choi, TNF-related apoptosis-inducing ligand receptors, can be 2003; Bhandari and Elias, 2006; Zaher et al., 2007; Bhandari, inhibited by FLIP (Rasper et al., 1998; Micheau, 2003). One 2008). The focus of this review is to discuss some of the of the splice variants of cellular FLIP (c-FLIP), contains recent studies characterizing hyperoxia-sensing moieties. tandem death effector domains and a caspase-like domain The reader should keep in mind that hyperoxia is solely a which lacks amino acid residues that are critical for caspase man-made condition of modern medical therapy. Unlike activity. c-FLIP prevents the recruitment and activation of hypoxia (e.g., wound healing), humans have not evolved any caspase-8 to the DISC by acting as a competitive inhibitor specific adaptive response to hyperoxia. Therefore, hyperoxia (Rasper et al., 1998; Barnhart et al., 2003). However, the role sensing—by definition—is an amalgam of factors respond- of the extrinsic apoptotic pathway in hyperoxic cell death ing to the stress of unnaturally high local O levels. Cellular is nonetheless, still contentious. Mice that are deficient in hyperoxia responses occur along with signaling initiated by −/− Fas (Fas ) and tumor necrosis factor receptor TNF recep- the underlying pathology for which the patient is receiving −/− tor (TNFR; tnfrI/II ) exhibited no resistance to prolonged treatment. hyperoxia (Pryhuber et al., 2000; Wang et al., 2003). Hence, further investigation is required to confirm the role of extrin- Role of hyperoxia-sensing moieties in HALI sic apoptotic pathway related-proteins in HALI. Moreover, Numerous factors contribute to the pathophysiology of the engagement of the extrinsic death receptor-mediated HALI. i Th s section will discuss in detail the endogenous apoptosis by hyperoxia is as yet unclear. molecules that function as hyperoxia-sensing moieties and The intrinsic pathway is also known as mitochondria- their signaling pathways. One of the primary pathologi- dependent pathway. Bax, a member of pro-apoptotic Bcl-2 cal effects of hyperoxia exposure is cell death. Hyperoxia- family proteins, can initiate apoptosis by forming specific induced cell death can occur via either classical pathways, channels in the outer mitochondrial membrane (Antonsson Molecular mechanisms in hyperoxia sensing 243 et al., 2000; Huang and Strasser, 2000; Martinou and Green, resistant to hyperoxia-induced cell death (Budinger et al., 2001). As a consequence, these channels can increase the 2002). Increased Bcl-2 levels in mice were found to cor- outer mitochondrial membrane permeability and facilitates relate with diminished hyperoxia-induced lung injury and the release of cytochrome c and other pro-apoptotic fac- improved survival (Ward et al., 2000). Bcl-2 over-expression tors from the mitochondrial intermembrane space into the has been shown to prevent oxidative stress via up-regulation cytosol (Hofmann et al., 1999; Annis et al., 2001; Martinou of antioxidant enzymes expression and elevation of cellular and Green, 2001). Once in the cytosol, cytochrome c forms GSH content (Jang and Surh, 2003). Moreover, in hyperoxia- an apoptosome complex with Apaf-1 which subsequently exposed fibroblastic cells (L929), Bcl-2 exhibited a protec - activates caspase-9 and caspase-3, leading to apoptosis of tive ee ff ct on mitochondria by reducing cytochrome c and these cells (Walsh et al., 2003). An additional determinant apoptosis-inducing factor release. Over-expression of Bcl-2 of apoptotic cell death is the Bcl-2 family members that can also decreased caspase-3 activity and nuclear condensation be either pro-apoptotic (Bax, Bcl-Xs, Bak, and Bad) or anti- in cells exposed to prolonged hyperoxia, preventing apoptotic apoptotic (Bcl-2, Bcl-XL, and Bcl-w; Cory and Adams, 1998). cell death (Métrailler-Ruchonnet et al., 2007). Interestingly, e Th pro- and anti-apoptotic members of the Bcl-2 family treatment with the caspase inhibitor Z-VAD.fmk did not res- exert most of their functions at the mitochondrial level (Gross cue cells from oxygen toxicity, suggesting that protection con- et al., 1999). e Th anti-apoptotic molecule Bcl-2, localized in ferred by Bcl-2 might entail a caspase-independent pathway the endoplasmic reticulum and mitochondrial membrane, (Métrailler-Ruchonnet et al., 2007). In hyperoxia, reduced exerts its protective effect by preventing Bax oligomerization, Bid activation and increased Bax protein expression was −/− −/− translocation to mitochondria and the subsequent release of observed in Fas (lpr) and FasL (gld) mice (Wang et al., −/− pro-apoptotic mitochondrial proteins, such as cytochrome 2003). Additionally, Bid knockout (Bid ) mice or lung fibrob- −/− c (Kroemer et al., 1998; Annis et al., 2001). Modulation of lasts derived from Bid mice exhibited marked resistance Bcl-2 family molecules has been shown to affect hyperoxia- to oxygen toxicity (> 95% O ) compared to wild-type controls induced cell death. Over-expression of the anti-apoptotic or their corresponding cells (Wang et al., 2003). e Th se data molecule Bcl-XL in rodent b fi roblasts (Rat 1 cells) prevented indicate that targeting Bid signaling pathway plays a critical oxygen-induced apoptosis. role in mediating HALI; however, the sensing molecules acti- Likewise, murine embryonic b fi roblasts derived from vated or inhibited by hyperoxia remain elusive (please refer mice dec fi ient in pro-apoptotic Bax and Bak molecules were to Figure 3). Hyperoxia Bax or FAS Bak Mitochondria DISC FADD Caspase 8 Activated Caspase 8 Cyt C Bid tBid Apaf-1 Apoptosis Caspase 9 Caspase 3 Figure 3. Schematic representation of the hyperoxia induced apoptotic pathways. Under hyperoxic conditions, the extrinsic apoptotic pathway is trig- gered following formation of a death-inducing signal complex (DISC), upon the binding of death ligands like FasL with their cell surface receptors (Fas) leading to the recruitment of FADD and caspase-8 which can then cleave Bid to form truncated Bid (tBid). The tBid then translocates from the cytosol to the mitochondrial membrane. In addition, Bax or Bak, a member of intrinsic apoptotic pathway, can initiate apoptosis by forming specific channels in the outer mitochondrial membrane and increasing the outer mitochondrial membrane permeability in hyperoxia. The mechanism by which hyperoxia activates Bax or Bak remains unclear. tBid and activated Bax facilitates the release of cytochrome c from mitochondira which forms an apoptosome complex with Apaf-1 which subsequently activates caspase-9 and caspase-3, leading to the apoptosis. Apaf-1, apoptotic peptidase activating factor 1; FADD, Fas-associated death domain protein; FasL, Fas ligand. Cell membrane 244 Ashwini Gore et al. Weber, 1999; Widmann et al., 1999). Among them, the role of Ion channels the ERKs, the JNKs (also referred to as stress-activated protein Fluid balance is a crucial feature of appropriate barrier kinases) and the p38 MAPKs (p38s) have been characterized function of the lung epithelium. The sodium-potassium- in hyperoxia-induced cell death. + + + adenosinetriphosphatase (Na -K -ATPase) and apical Na Exposure of MLE-12 cells to 95% O triggered a sustained channels are present predominantly on the alveolar Type II activation of the transcription factor activator protein 1 + + (ATII) epithelial cells. ATII cells use Na and K ion gradients (AP-1), as well as p38 and JNK. Importantly, survival of to regulate osmotic control of water, thereby maintaining an MLE-12 cells in hyperoxia was signic fi antly enhanced when essentially fluid-free alveolar lumen with appropriate amount AP-1, p38, or JNK activation was inhibited by either specic fi of airway water vapor. Hyperoxia can elicit fluid shifts result - inhibitors or dominant negative DNA constructs, suggesting ing in pulmonary edema. A compensatory regulation of that hyperoxia-induced cell death involves JNK/p38 and AP-1 Na and u fl id absorption can improve outcome during lung pathways that could be used as potential targets for reducing injury with pulmonary edema (Carter et al., 1997; Borok et al., lung injury (Romashko et al., 2003). Parinandi et al. (2003) 1999). have demonstrated that, under hyperoxic conditions, p38 Borok et al. (1999) demonstrated that hyperoxic expo- MAPK and ERK1/2 pathways are activated in human pul- sure (48 h) reduced the expression of Na channel β-subunit monary endothelial cells. Additionally, inhibition of p38 in AEC, whereas the expression of α- and γ-subunits was MAPK and MEK1/2 attenuated hyperoxia-induced ROS gen- unchanged. The net decrease in ion transport could be par - eration. On the other hand, Wang et al. (2007) observed that tially reversed by treatment with keratinocyte growth factor only MEK1/2—but not p38MAPK—played a crucial role in (KGF). In contrast, Wendt et al. (1999) demonstrated that hyperoxia-induced ROS generation in endothelial cells. These hyperoxia increased the gene expression of the Na, K-ATPase studies highlight the fact that there are significant differences α and β subunit in an in vitro model of Type II cell injury 1 1 in MAPK signaling pathways leading to ROS production due (≥ 95% O for 48 h). Those investigators concluded that an to cell type and species-specific variations which are yet-to-be + + increase in Na -K -ATPase activity might assist in maintaining further elucidated (Wang et al., 2007). gas exchange during HALI-induced alveolar flooding. e Th role of the JNK pathway in hyperoxic lung injury has Precise control of the air–liquid interface at the alveolar been explored in JNK1-dec fi ient mice. It was observed that level balances efficient O absorption, barrier control from deficiency in JNK1 enhanced susceptibility to hyperoxia and pathogens, and abatement of O toxicity. Further study of ion increased lung epithelial cell apoptosis (Morse et al., 2003). channel responses to hyperoxia is necessary to manage pul- It is believed that transient activation of the JNK pathway by monary edema and infection associated with the immediate hyperoxia is protective, while prolonged exposure leads to therapeutic goals of increasing O absorption, while limiting transcription of genes involved in apoptotic cell death (Chang HALI. and Karin, 2001; Tang et al., 2002). e Th ERK1/2 pathway has usually been associated with cell growth in response to mitogenic stimuli. Exposure to hyperoxia has been shown to Protein kinases activate ERK1/2 in MLEs, murine macrophages and rat pheo- There is accumulating evidence highlighting the importance chromocytoma cells (Katoh et al., 1999; Petrache et al., 1999). of protein kinases, such as mitogen-activated protein kinases In primary rat AEC2 isolated from hyperoxia-exposed ats, (MAPK), phosphoinositide-3 kinases and protein kinase C increased activation of ERK1/2 was observed. Furthermore, (PKC), in the regulation of hyperoxic cell death. protection against hyperoxia-induced DNA breakage and apoptosis was conferred by ERK1/2 activation (Buckley et al., 1999). Although ERK1/2 has been implicated in the protec- Mitogen-activated protein kinases tive action of growth factors against cell death, it has also been reported that ERK1/2 mediates hyperoxic cell death in The MAPK signaling cascade is evolutionarily well conserved mouse macrophages (Petrache et al., 1999). Consistent with and includes three hierarchical protein kinases such as MAPK, this observation in mouse macrophages, inhibition of ERK1/2 MAPK ERK/MAP ERK (MAPKK/MEK) and MAPKK kinase activation prior to hyperoxic exposure in MLEs resulted in (MAPKKK; Errede and Levin, 1993; Davis, 1994; Waskiewicz attenuation of cell death (Zhang et al., 2003). Conflicting and Cooper, 1995; Schaeffer and Weber, 1999 ; Widmann data on the protective role of MAPK pathways in hyperoxia- et al., 1999). MAPKKK phosphorylates and, in turn, activates induced apoptosis may ree fl ct the complexity of signaling MAPKK. Activated MAPKK phosphorylates and activates pathway regulation in die ff rent cell types under die ff rent MAPK. Activated MAPK phosphorylates transcription factors culturing conditions. or other downstream kinases, consequently regulating gene expression and cellular functions. MAPKs belong to the sig- nal transduction superfamily of ser/thr protein kinases and Protein kinase C play an essential part in cell proliferation/die ff rentiation, responses to environmental stimuli, and cell survival and cell PKCs are ser/thr kinases and can be activated by exposure death (Kyriakis, 1999). At least six independent MAPK signal- to hyperoxia (Das et al., 2001; Villalba et al., 2001). Based on ing units are functional in mammalian systems (Schaeffer and their requirements for activation, the family of PKC consists of Molecular mechanisms in hyperoxia sensing 245 12 isozymes. e Th y are classie fi d into three groups—the novel injury in HLMVEC. Hyperoxia-induced cell death was sig- PKCs (δ, ε, φ, μ, and η), the conventional PKCs (α, β , β , and nificantly reduced in the myrAkt-expressing cells compared 1 2 γ), and the atypical PKCs (ζ, λ, and τ; Villalba et al., 2001). to controls. Ultrastructural morphometric analyses showed Under normoxic conditions, PKC is found to be associated that in hyperoxic myrAkt cells, the mitochondria and endo- with Bax in lung endothelial cells and this association may plasmic reticulum were less swollen (Ahmad et al., 2006). inhibit the Bax-dependent apoptotic pathway (Wang et al., These results indicate that early activation of Akt in hyperoxia 2005). Wang et al. explored the role of PKC in FLIP-mediated has a beneficial role in protecting against hyperoxic stress protection against hyperoxic injury. In their study, following by maintaining mitochondrial integrity. Similar findings a 24–72 h hyperoxic exposure, murine lung endothelial cells were observed by Lu et al. (2001), who demonstrated that showed an increase in the activated form of Bax. Interestingly, targeted delivery of myrAkt to lung epithelium attenuated over-expression of FLIP inhibited hyperoxia-induced cell hyperoxia-mediated ALI and delayed death in mice. In death, in part, via attenuation of ROS generation, suppres- addition, Ray et al. (2003) showed that KGF offered protec - sion of PKC activity, and increased association of PKC with tion against hyperoxic insult to the epithelium via an Akt- Bax. Moreover, over-expression of FLIP activated Bax phos- dependent pathway, although, no improvement in survival phorylation through the p38 MAP kinase signaling pathway, was observed in these mice. In summary, PI3-kinase/Akt which inhibited Bax-mediated apoptosis (Wang et al., 2007). appears to have significant potential as effective therapeutic Taken together, these studies indicate that FLIP inhibits the target in attenuating HALI (please refer to Figure 4). dissociation of PKC and Bax, resulting in the prevention of Bax activation and its consequent downstream activation of Redox-sensitive transcription factors the intrinsic apoptotic pathway. Nuclear factor erythroid derived 2 (NF-E2)-related transcrip- tion factor 2 (Nrf2), nuclear factor-κB (NF-κB), and AP-1 are PI3-kinase/Akt proteins that play an important role in initiating, stimulat- The activation of PI3-kinase is associated with elevated cel- ing, and terminating transcription (Adler et al., 1999). e Th y lular glucose metabolism and improved cell survival under may be viewed as master regulators of signal transduction by stress (Plas and Thompson, 2002 ; Whiteman et al., 2002). A regulating the expression of proteins involved in modulation key downstream effector of PI3-kinase is the serine-threonine of cell survival in response to various oxidants and inflamma- kinase Akt. Following the activation of PI3-kinase, Akt phos- tory stimuli (Schreck et al., 1991; Beg and Baltimore, 1996; phorylates and regulates the activity of numerous protein Van Antwerp et al., 1996). kinases, transcription factors, and other regulatory molecules (Paez and Sellers, 2003). Multiple proteins involved in regu- lation of cell survival, like Bcl-2-associated death promoter, Hyperoxia Forkhead box 03a/Forkhead in rhabdomysacoma-like-1, Cell membrane cAMP-response element binding protein (CREB), IκBα kinase (IKK-kinase), glycogen synthase kinase-3, and murine double minute 2, are phosphorylated by Akt that, in turn, is activated by PI3-kinase. Akt also contributes to maintaining mitochondrial integrity by inhibiting cytochrome c release ROS Mitochondria and up-regulation of mitochondrial hexokinases (Gottlob et al., 2001; Majewski et al., 2004). Prolonged exposure to hyperoxia results in loss of mitochondrial integrity (Bassett Akt MAPK PKC and Fisher, 1979; Crapo et al., 1980; Freeman and Crapo, 1981). An integral part of adaptation to hyperoxia exposure includes an increase in the utilization of alternative substrates Nrf2 NF-κB AP1 such as glucose and glutamine (Schoonen et al., 1990; Allen and White, 1998; Ahmad et al., 2001). In this regard, hyperoxia is ironically similar to a physiological response to hypoxia. Cell Death Cell Growth arrest Pathways utilizing alternative substrates may be tar- Inflammation Stress Response geted to mitigate hyperoxic injury (Ahmad et al., 2001; Ahmad et al., 2006). To address the role of Akt in hyperoxic Figure 4. Schematic diagram illustrating the signaling pathways mediated injury, primary human lung microvascular endothelial via Akt, MAPK and PKC under hyperoxic conditions. Protein kinases such as Akt, MAPK, and PKC are activated by ROS under hyperoxic conditions. cells (HLMVEC) were used by Ahmed et al. as the damage This results in stimulation of transcription factors such as Nrf2, NF-κB, to endothelium is an early target of hyperoxic lung injury. and AP-1 that are associated with pathophysiological responses including In these cells, transient Akt activation and increase in Akt stress response, inflammation, cell growth arrest, and death. AP-1, activa- phosphorylation was observed after 1- and 24-h hyperoxia tor protein 1; MAPKs, mitogen-activated protein kinases; NF-κB, nuclear exposure, respectively. A constitutively-active myristylated factor-κB; NOX, NADPH oxidase; Nrf2, NF-E2-related transcription factor 2; PKC, protein kinase C. form of Akt (myrAkt) conferred protection against hyperoxic 246 Ashwini Gore et al. e Th following is a general regulatory paradigm for these ALI, bleomycin-induced b fi rosis, allergen-induced asthma, responses. In the cytoplasm, these transcription factors are elastase-induced emphysema, cigarette smoke-induced sequestered in an inactive state. However, in response to dif- chronic obstructive pulmonary disease, and diesel exhaust- ferent stimuli, they are phosphorylated and translocated into induced oxidative DNA damage (Hackett et al., 2003; the nucleus and initiate transcription (Adler et al., 1999). The Rangasamy et al., 2004, 2005). regulation of transcription factors could thus play a key role In addition, the role of Nrf2 in the pathogenesis of hyper- in ameliorating oxidative stress mediated diseases. Various oxia-induced lung toxicity has also been examined in great redox-sensitive transcription factors including Nrf2, NF-κB, detail. Cho et al. (2002) were the r fi st to demonstrate that and AP-1 have been linked to the development of inflamma- that Nrf2 confers protection against hyperoxic lung injury tory lung disorders (Crapo et al., 1980; Lee and Choi, 2003). in mice. Mice lacking Nrf2 expression and activity evinced Emerging evidence has established that these transcription significantly greater lung damage, characterized by increased factors play critical roles in regulating pulmonary responses, protein permeability, leukocyte inl fi tration, and epithelial including cell death under hyperoxic conditions (Choi et al., injury, after hyperoxic exposure compared to wild-type mice. 1995; Li et al., 1997). Furthermore, a significant attenuation in hyperoxia-induced expression of genes modulated by Nrf2 was observed in these Nrf2-deficient hosts. Nrf2-mediated protection against hyper - Nuclear factor erythroid derived 2-related oxic lung injury was thus attributed, at least partly, to these transcription factor 2 downstream genes (Cho et al., 2002). Nrf2-mediated GSH Nrf2 was cloned and characterized in by Moi et al. (1994) expression improved the resolution of hyperoxic lung injury. as a factor that binds to the NF-E2 repeat of the β-globin Nrf2-deficient mice exposed (for 48 h) to sub-lethal hyper- gene promoter. It belongs to the cap ‘n’ collar sub-family of oxia were shown to have impaired alveolar epithelium and transcription factors. Nrf2 is a b-Zip transcription factor as it endothelium regeneration, cellular damage, and increased contains a basic leucine zipper DNA binding domain (b-Zip) macrophage and lymphocyte infiltration during their post- at the C-terminus. In the constitutive state, Nrf2 is mainly exposure recovery. However, administration of GSH imme- localized in the cytosol. Following exposure to oxidants, Nrf2 diately following hyperoxic exposure had a rescuing effect in −/− translocates into the nucleus where it binds to the antioxidant the Nrf2 mice. This outcome suggested that Nrf2-regulated response element (ARE) and up-regulates gene expression GSH synthesis could attenuate hyperoxia-induced lung injury (Moi et al., 1994; Zhang, 2006). Identification of Keap1 as (Reddy et al., 2009). In an AEC culture system, the molecular the key repressor of Nrf2 transcriptional activity has lead to basis of Nrf2-mediated protection against hyperoxia-induced a great progress in the understanding of Keap1-mediated pulmonary toxicity was further investigated (Papaiahgari negative regulation of Nrf2 activation. Keap1 functions as et al., 2004). It was observed that NOX and ERK-1 signaling a molecular switch in the Nrf2-mediated cellular defense play a crucial role in regulating hyperoxia-induced, ARE- response by two mechanisms. Keap1 has a sensing function mediated, Nrf2-dependent transcription in lung epithelial that determines changes in intracellular redox environments cells. Taken together, the overwhelming body of evidence (Zhang and Hannink, 2003; Eggler et al., 2005, 2007; Luo et al., now shows that activation of Nrf2 plays a benec fi ial role in 2007). Secondly, the Keap1 switch function controls the levels hyperoxic lung injury. of Nrf2 via ubiquitin-mediated degradation machinery by functioning as a subunit of E3 ubiquitin ligase (McMahon Nuclear factor-κB et al., 2003; Stewart et al., 2003; Kobayashi et al., 2004). It was demonstrated by Rushmore et al. (1991) that most The NF-κ B family of proteins is responsible for the expres- of the downstream genes of Nrf2 contained an ARE sequence sion of a wide variety of genes, particularly those involved in in the promoter region (Rushmore et al., 1991). These down- inflammation and stress response (Baldwin, 1996 ). The NF-κ B stream genes have been classified into several categories like family is comprised of v fi e members; RelA (also called p65), intracellular redox-balancing proteins, Phase II detoxifying RelB, c-Rel, p50/p105, and p52/p100. These members are enzymes, transporters, and multidrug resistance-associated usually present as heterodimeric or homodimeric complexes. protein (Ishii et al., 2000; Kim et al., 2001; Banning et al., The NF-κ B heterodimer composed of p50 and p65/RelA 2005; Sakurai et al., 2005; Vollrath et al., 2006). Although it subunits is involved in the regulation of various physiologic is ubiquitously expressed in many organs, Nrf2 was found to processes, including differentiation, proliferation, inflamma- be non-essential for the normal development of mice (Chan tion, and survival (Chen and Greene, 2004). In unstimulated et al., 1996). On the other hand, Nrf2 knockout mice showed cells, NF-κB is sequestered in the cytoplasm by an inhibitory decreased levels of both constitutive and inducible phase II protein known as IκB (inhibitor of NF-κB) in an inactive non- enzymes as well as endogenous antioxidants. It is well estab- DNA-binding form. IκB blocks the nuclear translocation sig- lished that an Nrf2-mediated antioxidant response is one of nal of NF-κB and thus prevents it from entering the nucleus. the crucial mechanisms that aids survival following cellular Following exposure to various stimuli/inducers, IκB is rapidly stress. Several studies have shown that activation of Nrf2 phosphorylated on two serine residues, ubiquitinated, and can protect cells against oxidative stress in various in vitro degraded by the 26S proteosome. The phosphorylation of I κB and in vivo models of butylated hydroxytoluene-induced is mediated by various IKKs and ROS are vital in the upstream Molecular mechanisms in hyperoxia sensing 247 pathological changes (Tsan et al., 1995; Shea et al., 1996). events that lead to IKK activation. The released NF-κ B then Treatment with an anti-TNFα antibody improved survival translocates into the nucleus where it activates target genes following hyperoxic exposure (Jensen et al., 1992; Tsan et al., (Baldwin, 1996; Rahman and MacNee, 2000). 1995). Pulmonary levels of IL-1β and IL-6 were also elevated Activation of NF-κB in hyperoxia has been observed in following exposure to hyperoxia (Lindsey et al., 1994; Johnston several lung cell types, including alveolar macrophages, lung et al., 1997). Interestingly, NF-κB activation-induced by other epithelial cells, human pulmonary artery endothelial cells, cytokines like TNFα and IL-1β can be further enhanced by monocytic THP-1 cells, and in rat and mouse lungs (Shea hyperoxia exposure, resulting in amplification of pro-inflam- et al., 1996; Suzuki et al., 2000; Pepperl et al., 2001; Franek matory responses (Wong et al., 2002; Odoms et al., 2004). On et al., 2004; Sue et al., 2004; Guthmann et al., 2005). In neo- the other hand, over-expression of IL-6 confers protection natal mice, activation of NF-κB was more pronounced and against HALI (Ward et al., 2000). In light of the dual ee ff cts sustained upon exposure to hyperoxia as compared to adult on hyperoxia-induced death, and pro-inflammatory cytokine mice (Yang et al., 2004). Hyperoxia has also been shown to production, a universal approach of either activating or enhance lipopolysaccharide and interferon γ (IFNγ)-induced inhibiting pulmonary NF-κB will not be beneficial in reduc - NF-κB activation (Shenkar et al., 1996). Using lung epithelial ing pro-inflammatory hyperoxic lung injury. Instead, studies cells, Franek et al. (2001) showed that exposure to hyperoxia directed at understanding the effect of NF-κ B modulation in conferred resistance against subsequent oxidant triggered specific cell types may reveal a better strategy for attenuating cell death. In a subsequent report, these investigators dem- hyperoxia-induced lung injury (please refer to Figure 5). onstrated that in lung epithelial cells, NF-κB reduced sus- ceptibility to hyperoxia-induced non-apoptotic cell death. In mouse pulmonary lymphocytes, exposure to hyperoxia for cAMP-response element binding protein 24–48 h resulted in NF-κB activation, followed by an increase CREB, is a redox transcriptional regulatory factor activated in TNFα and IFNγ production (Shea et al., 1996). in the lungs following hyperoxic exposure (Jamieson et al., The protection conferred by NF-κ B activation is most 1986; Schreck et al., 1991; Shenkar and Abraham, 1997; likely mediated by NF-κB-induced expression of Bcl-2 and George et al., 1999). Both binding sites for CREB and NF-κB other cytoprotective enzymes, such as MnSOD and GSH are present in the promoter regions of a number of cytokines, peroxidase—each of which are regulated by NF-κB (Rahman including TNFα, NF-κB, IL-1β, and IL-6. Increased pro-in- and MacNee, 2000; Franek et al., 2004; Choi et al., 2006). In amm fl atory cytokine expression as a consequence of ROS- fetal lung fibroblasts, NF-κ B activation prevents hyperoxia- induced activation of these transcription factors could play induced apoptosis. e Th alteration of the normal pattern an essential role in triggering HALI (Shenkar and Abraham, of b fi roblast apoptosis may contribute to abnormal lung 1997). Abraham et al. showed that treatment with lisofylline development upon exposure to hyperoxia. Together with suppressed CREB activation in mice exposed to hyperoxia. hyperoxia-induced b fi roblast trans-die ff rentiation, altered Lisofylline also inhibited hyperoxia-induced expression of elastin synthesis, and decreased fibroblast growth factor-7 TNFα, IL-1β, and IL-6 in lungs and decreased hyperoxia- activity, these studies indicate that exposure of fibroblasts to induced serum oxidized free fatty acids. Moreover, lisofyl- hyperoxia impairs normal lung development (Bruce et al., line treatment reduced the lung wet-to-dry weight ratios and 1989; Boros et al., 2002; Rehan and Torday, 2003). Designing enhanced survival in hyperoxia. us Th , these studies suggest a therapeutic approach to target NF-κB mediated hyperoxic that inhibiting CREB activation could be protective in hyper- signaling in the adult and developing lung needs further oxia-induced lung injury and warrants further investigation investigation of the unique responses in each scenario. for clinical application (George et al., 1999). While NF-κB plays a critical role in protecting lung cells against hyperoxia-induced cell death, many of the genes encoding pro-ina fl mmatory cytokines such as interleukin CXC2 receptors 8 (IL-8) and TNFα are also regulated by NF-κB-dependent mechanisms. e Th se particular cytokines promote the Chemokines are a family of low molecular weight proteins recruitment of neutrophils, eosinophils, macrophages, and that regulate leukocyte recruitment to ina fl mmatory sites lymphocytes that, in turn, enhance inflammation (Schreck (Bhandari and Elias, 2006). e Th y play a key role in the et al., 1992; Baldwin, 1996; Shea et al., 1996; Abraham, 2003). pathogenesis of HALI by acting as potent neutrophil che- An early response in the lung to hyperoxic exposure is an moattractants; therefore, these proteins are important in increase in NF-κB activation that precedes an increase in understanding the specific mechanisms involved in recruit - cytokine levels (Shea et al., 1996; Shenkar et al., 1996). e Th ment of neutrophils to the lung for management of HALI. presence of an active NF-κB site in the IL-8 promoter is nec- Levels of neutrophil chemokines such as IL-8 are elevated in essary for hyperoxia-induced IL-8 secretion from U937 cells both adults with ALI and premature neonates who develop (D’Angio et al., 2004). BPD (Bhandari and Elias, 2006). Chemokines such as IL-8, The increased levels of pro-inflammatory cytokines could chemokine (C-X-C motif ) ligand 1 (CXCL1), and CXCL2/3 contribute to the development of hyperoxic lung injury. function via binding to C-X-C chemokine receptor-2 (CXCR2; Elevated levels of TNFα are present in the lungs during early G-protein-coupled receptors; Ludwig et al., 2000; Parsons stages of hyperoxic exposure prior to any visible histological et al., 2005). Upon activation, CXCR2 is phosphorylated and 248 Ashwini Gore et al. Hyperoxia INFLAMMATION ROS Active NF-κB IL-1β, lL-8, Bcl-2,Akt TNF-α SURVIVAL GENES DNA MnSOD IL-6, IL-11 Promotes Hyperoxia-Induced Acute Lung Injury Figure 5. Schematic diagram illustrating the effects of NF-κ B under hyperoxic conditions. Hyperoxia induces activation of NF-κB resulting in its nuclear translocation. In the nucleus NF-κB regulates genes involved in inflammation like IL-8 and TNFα. On the other hand NF-κB also up-regulates survival genes like Bcl-2, Akt and enzyme MnSOD that confers protection against hyperoxic cell death. IL, interleukin; MnSOD, manganese superoxide dismutase; NF-κB, nuclear factor-κB; TNFα, tumor necrosis factor-α. rapidly internalized via arrestin/dynamin-dependent mecha- hyperoxia-induced neutrophil accumulation and lung injury nisms, resulting in receptor desensitization (Mueller et al., (please refer to Figure 6). 1994; Feniger-Barish et al., 1999; Hall et al., 1999). Activation of CXCR2 sequentially stimulates the release Receptor for advanced glycation end-products of intracellular inositol phosphates and an increase in intracellular calcium levels (Richardson et al., 1998). In Receptor for advanced glycation end-products (RAGE) is a addition, CXCR2 activation stimulates the phosphorylation member of an immunoglobulin superfamily of cell- surface of intracellular proteins involved in directed cell migration receptors (Thornalley, 1998 ). The expression of RAGE is pre- by ERK1/2-dependent mechanisms (Loetscher et al., 1994; dominant in the lung, particularly in alveolar Type I cells (AT1) Hall et al., 1999). Sue et al. (2004) have demonstrated that that can amplify injury triggered by acute stress (Sternberg the ligand-receptor (C-X-C chemokine—CXCR2) biological et al., 2008). RAGE is a single membrane spanning receptor axis is crucial during the pathogenesis of hyperoxia-induced consisting of a short (40 residue) cytosolic domain and a large lung injury. In their cited study, these investigators exposed extracellular portion containing three Ig-like domains (V, C1, C57BL/6 mice to 80% O for 6 days and then examined pul- and C2 domains; Dattilo et al., 2007). RAGE is a multi-ligand monary inflammation and host survival. Along with a marked receptor that binds to several ligands including AGE, ampho- increase in neutrophil sequestration and lung injury (evi- terins (high-mobility group protein-1), S100/calgranulins, denced by myeloperoxidase assay and histopathology), a 50% amyloid-β peptide, β-fibrils, and Mac-1 (Neeper et al., 1992; mortality rate was observed in these mice. It was also noted Hori et al., 1995; Yan et al., 1996; Hofmann et al., 1999). High that an increased expression of CXCR2 ligands and CXCR2 levels of RAGE have been observed during lung develop- mRNA expression paralleled the neutrophil recruitment to ment, suggesting that it plays an important role in pulmonary the lung. An inhibition of C-X-C chemokine ligands/CXCR2 functionality and morphogenesis (Reynolds et al., 2008). This interaction resulted in a signic fi ant reduction in neutrophil is consistent with the observation that RAGE receptors are sequestration and lung injury in mice exposed to hyperoxia. involved with the cellular spreading, thinning, and adherence −/− Furthermore, CXCR2 mice displayed significantly increased that characterizes the transition of ATII cells to squamous +/+ survival in response to hyperoxia as compared with CXCR2 (ATI) cells (Schmidt et al., 2001). In patients and in animal mice (Sue et al., 2004). Kotecha et al. (2003) showed that a models of ALI, it was observed that RAGE levels were elevated blockade of CXCR2 (using SB-265610 injections) reduced in both plasma and lung lavage u fl ids, and that this elevation hyperoxia-induced neutrophil accumulation and pulmonary correlated directly with extent of lung injury (Uchida et al., vascular injury in newborn rats. These studies suggest that the 2006). An increase in lung RAGE levels was also observed in use of a pharmacological inhibitor of CXCR2 may attenuate pulmonary ina fl mmation caused by smoke-related damage Molecular mechanisms in hyperoxia sensing 249 and various pneumonias, suggesting an important role for called endogenous secretory RAGE. Using recombinant RAGE in lung inflammatory responses. gene technology, Hanford et al. (2004) recently synthesized A potential involvement of RAGE signaling in hyperoxic a soluble form of RAGE called sRAGE (Hanford et al., 2004). lung injury was investigated in mice deficient in RAGE. RAGE Administration of sRAGE produced a therapeutic ee ff ct via ablation prolonged the survival under hyperoxic conditions. blocking the action of RAGE in experimental animal models, Following hyperoxic exposure, RAGE expression was signifi- suggesting that sRAGE attenuates RAGE-mediated HALI by cantly increased in wild-type mouse lung parenchyma and acting as a decoy receptor (Park et al., 1998). Further research primary AECs (Reynolds et al., 2009). Compared to their wild- on RAGE signaling in the lung is needed to effectively identify type counterparts, RAGE knockout mice showed a significant novel targets that are likely to be important in mitigating lung decrease in protein leakage, lung wet-to-dry weight ratios, injury and associated inflammation. For a greater under - and ina fl mmatory cell inl fi tration into the airspaces after standing and a more complete review on the role of RAGE exposure to hyperoxia. Data from a recent large randomized in pulmonary health and diseases, please refer to Mukherjee controlled trial showed that baseline levels of plasma RAGE et al. (2008; and also please refer to Figure 7). were linked with the clinical outcomes in ALI/ARDS patients exposed to higher tidal volume ventilation. Higher plasma Toll-like receptors RAGE levels correlated with increased mortality, organ fail- Toll-like receptors (TLR) belong to a conserved family of ure, and fewer ventilator free days. With administration of innate immune recognition receptors that are important lower tidal volume ventilation, a decline in RAGE levels was mediators of microbe detection and immune responses noted with time (Calfee et al., 2008). Yonekura et al. (2003) (Aderem and Ulevitch, 2000). Structurally, TLRs consist of showed that under certain conditions, the large extracellu- an extracellular (ectodomain) and a cytoplasmic domain. lar region of RAGE is endogenously secreted into the lung Subsequent to ligand binding, they undergo dimerization and and other organs thereby forming a soluble isoform of RAGE conformational changes that are required for the recruitment of downstream signaling molecules. TLR activation initiates Hyperoxia intracellular signaling which is either dependent or inde- pendent of adaptor protein myeloid die ff rentiation factor 88 Alveolar and interstitial macrophage (Weber et al., 2003). e Th signaling cascade ultimately results in NF-κB translocation into the nucleus where it mediates the expression of inflammatory genes (Oshiumi et al., 2003; IL1,TNF Covert et al., 2005). e Th TLR family consists of 10 members, e.g., TLR1-TLR10 (Takeda and Akira, 2004). Among TLR Epithelial, endothelial cells, family members, TLR3 and TLR4 have been implicated in monocytes and lymphocytes mediating HALI. CNC-1 (IL8), CXCL1 ,CXCL2/3 CXCR2 Attract Neutrophils Inflammation, Vascular Acute Lung Injury permeability Bronchopulmonary Dysplasia PLASMA MEMBRANE Figure 6. Summary of events underlying how hyperoxia-induced acute RAGE lung injury (HALI) and bronchopulmonary dysplasia (BPD) are mediated LIGAND via selected cytokines upon interaction with the CXCR2 chemokine recep- MAPK MAPK sRAGE tor. Exposure to hyperoxia causes alveolar or interstitial macrophages in NF-κB NF-κB lung to release early response cytokines (IL-1 and TNF). These cytokines, RAGE in turn, activate resident lung endothelial cells, epithelial cells, monocytes, TRANSCRIPTION RECEPTOR and lymphocytes, leading to the production of chemokines such as IL-8, CXCL1, and CXCL2/3. These chemokines function via binding to CXCR2 Figure 7. Diagrammatic representation of RAGE signaling. Binding of chemokine receptor and regulate neutrophils recruitment to inflamma- RAGE with its ligands activates MAPKs and NF-κB. In the presence of tory sites leading to increase in vascular permeability and inflammation sRAGE, the RAGE ligand binding is prevented and hence it’s downstream observed in hyperoxia-induced acute lung injury and bronchopulmonary signaling through MAPKs and NF-κB is inhibited. MAPKs, mitogen- dysplasia. BPD, bronchopulmonary dysplasia; IL, interleukin; CINC-1, activated protein kinases; NF-κB, nuclear factor-κB; RAGE, receptor for cytokine-induced neutrophil chemoattractant-1; CXCL, chemokine (C-X-C advanced glycation end-products; sRAGE, soluble from of RAGE; TNF, motif ) ligand; CXCR2, C-X-C chemokine receptor-2; HALI, hyperoxia-in- tumor necrosis factor. duced acute lung injury. 250 Ashwini Gore et al. Murray et al. (2008) showed that mice dec fi ient in TLR3 generated in hyperoxia and the accumulation of inflammatory −/− (TLR3 ) exhibited a lower occurrence of ALI, activation mediators within the lungs (Crapo et al., 1980; Matalon and of apoptotic cascades, and extracellular matrix deposition Egan, 1984). Exposure to prolonged hyperoxia results in cell +/+ following hyperoxia compared to wild-type (TLR3 ) mice. injury and death, outcomes that could be mitigated by the Administration of a monoclonal anti-TLR3 antibody to wild- over-expression of anti-cell death cytoprotective molecules type mice protected them from hyperoxic lung injury and like Bcl-XL. Current evidence suggests that effective target - ina fl mmation. Additionally, increased expression of TLR3 ing of receptors such as RAGE, CXCR2, TLR3, and TLR4, as was observed in not only hyperoxia-exposed cultured human well as protein kinases like MAPK, PI3, and PKC may attenu- epithelial cells but also airway epithelial cells obtained from ate hyperoxic lung injury and promote cell remodeling and patients with ARDS. e Th se results suggest that TLR3 plays resolution of ina fl mmation. As transcription factors such as a signic fi ant role in the development of ALI in hyperoxia Nrf2, NF-κB, and CREB play essential roles in modulating (Murray et al., 2008). expression of cytoprotective genes and inflammatory media- TLR4 has been extensively studied in relation to patho- tors, they could also potentially act as important therapeutic gen-mediated host responses. Recently, studies have been targets. carried out to elucidate its role in hyperoxia-mediated In summary, HALI involves the participation of multiple inflammation. A study by Zhang et al. (2005) reported that pathways, each mediated by distinct hyperoxia sensing moie- TLR4-dec fi ient mice exhibited increased mortality and lung ties. Hence, the benec fi ial ee ff cts of using a combination of injury in hyperoxia suggesting that TLR4 is required for the agents that simultaneously target multiple pathways could survival and lung integrity in hyperoxia. The enhanced sus - far outweigh the benefits of targeting a single pathway. On ceptibility of the TLR4-deficient mice to hyperoxia was linked the other hand, the true physiological duties of hyperoxia with an inability to up-regulate Bcl-2 and phospho-Akt. In sensing molecules are multifaceted in signaling throughout addition, a significant reduction in hyperoxia-induced pul- the body. Ee ff ctive therapeutic strategies in treating HALI will monary apoptosis was observed in the transgenic mice with require a cautious design that does not impose off-target risk. constitutively-active form of TLR4. A significant reduction in A thorough understanding of the roles hyperoxia-sensing pulmonary apoptosis was observed in the transgenic mice factors play in specic fi cell types will require use of animal with constitutively-active form of TLR4 exposed to hyper- models where multiple system interactions can be exam- oxia compared to the controls. A sustained up-regulation of ined. These approaches will help pave the way for investi- anti-apoptotic molecules such as heme oxygenase-1 (HO-1) gating combination therapies aimed at modulating multiple and Bcl-2 was associated with this phenotype (Qureshi hyperoxia-sensing moieties to attenuate HALI. et al., 2006). Furthermore, in vivo knockdown of pulmonary HO-1 or Bcl-2 expression by intranasal administration of Acknowledgements short interfering RNA blocked the ee ff ct of TLR4 signaling on hyperoxia-induced lung apoptosis. These results indicate The authors would like to thank Ravi Sitapara for the excel- that TLR4 activation protects against hyperoxia-mediated lent technical assistance in constucting the g fi ures in this lung injury via up-regulation of anti-apoptotic molecules. manuscript. Contradictory to these observations, Ogawa et al. (2007) showed that TLR4-dependent NF-κB activation signic fi antly contributed to hyperoxic lung injury. e Th y showed that TLR4 Declaration of interest played a critical role in up-regulation of pro-ina fl mmatory i Th s work was supported by grants from the National Heart mediators and neutrophil accumulation into the lung in and Blood Institute (HL093708, LLM), St. John’s University hyperoxia. Exposure to hyperoxia for 96 h caused an NF-κB and the Feinstein Institute for Medical Research at the North translocation in the wild-type mice (C3H/HeN); in contrast, Shore-Long Island Jewish Health System. e Th authors are this response was significantly attenuated in the TLR4 mutant alone responsible for the content and writing of the paper. mice (C3H/HeJ). The lack of TLR4 signaling also suppressed any expected hyperoxia-mediated elevations of TNFα and IL-6 in the bronchoalveolar lavage fluid (Ogawa et al., 2007). In References conclusion, the data from this 2007 study indicated that TLR4- Abraham, E. 2003. Neutrophils and acute lung injury. Crit. Care Med. dependent NF-κB activation might promote up-regulation of 31:S195–S199. pro-inflammatory mediators and consequent neutrophil infil- Aderem, A. and Ulevitch, R.J. 2000. Toll-like receptors in the induction of the innate immune response. Nature 406:782–787. tration leading to HALI. 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Journal

Journal of ImmunotoxicologyTaylor & Francis

Published: Dec 1, 2010

Keywords: Hyperoxia; inflammation; sensing; apoptosis; cell death; signaling; acute lung injury; ROS

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