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- Copyright © 2013 Silvana Zgraggen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract
HindawiPublishingCorporation JournalofAllergy Volume2013,ArticleID672381,9pages http://dx.doi.org/10.1155/2013/672381 ReviewArticle AnImportantRoleofBloodandLymphaticVesselsin In�ammationandAllergy SilvanaZgraggen,AlexandraM.Ochsenbein,andMichaelDetmar InstituteofPharmaceuticalSciences,SwissFederalInstituteofTechnology,ETHZurich,WolfgangPauli-Strasse10, HCIH303,8093Zurich,Switzerland CorrespondenceshouldbeaddressedtoMichaelDetmar;michael.detmar@pharma.ethz.ch Received9September2012;Revised4December2012;Accepted19December2012 AcademicEditor:Alisonorburn Copyright©2013SilvanaZgraggenetal. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Angiogenesisandlymphangiogenesis,thegrowthofnewvesselsfrompreexistingones,havereceivedincreasinginterestduetotheir roleintumorgrowthandmetastaticspread.However,vascularremodeling,associatedwithvascularhyperpermeability,isalsoakey featureofmanychronicin�ammatorydiseasesincludingasthma,atopicdermatitis,psoriasis,andrheumatoidarthritis.ema�or driversofangiogenesisandlymphangiogenesisarevascularendothelialgrowthfactor-�VE�F-�AandVE�F-C,activatingspeci�c VE�Freceptorsonthelymphaticandbloodvascularendothelium.Recentexperimentalstudiesfoundpotentanti-in�ammatory responsesa�ertargetedinhibitionofactivatedbloodvesselsinmodelsofchronicin�ammatorydiseases.Importantly,ourrecent resultsindicatethatspeci�cactivationoflymphaticvesselsreducesbothacuteandchronicskinin�ammation.us,antiangiogenic andprolymphangiogenictherapiesmightrepresentanewapproachtotreatchronicin�ammatorydisorders,includingthosedue tochronicallergicin�ammation. 1.Introduction metastatic spread [2–5]. Angiogenesis and lymphangiogen- esis also occur in several chronic in�ammatory conditions, According to the World Allergy Organization, allergic dis- includingrheumatoidarthritis,in�ammatoryboweldisease, orders affect 30–40% of the world’s population, and the asthma,chronicairwayin�ammation,atopicdermatitis,and prevalence is escalating to epidemic proportions. Much of psoriasis[6–9]. the pathology of chronic allergic disorders such as atopic Eventhoughbloodandlymphaticvesselsarekeyplayers dermatitis and asthma is the long-term result of chronic inacuteandchronicin�ammatoryprocesses,andthusmight allergic in�ammation at the site of allergen exposure [ 1]. serveasnewtherapeutictargetsinin�ammatoryandallergic us,toexploreadditionalpossibilitiestotreatchronicaller- diseases, there is currently no clinically approved treatment gic disorders, it is of importance to understand the distinct tospeci�callymodulatethevasculature. pathomechanismsandpropertiesofchronicin�ammation. In�ammation in general is the response of tissues to 2.TheFunctionofBloodVesselsandLymphatic harmful stimuli such as infectious agents, antigens, or phys- VesselsinTissueHomeostasis ical and chemical damage. �esides the increased in�amma- tory cell in�ltration into the in�amed tissue, it has become In vertebrates, there are two vascular systems: the cardio- clearintherecentyearsthatacuteandchronicin�ammatory vascular and the lymphatic system. To exert their functions, processes are associated with pronounced vascular remod- bothvascularsystemsbuildhighlybranched,tree-liketubular eling. Angiogenesis and lymphangiogenesis, the growth of structures. In the cardiovascular system, the heart pumps new blood vessels and of lymphatic vessels from preexisting the blood through arteries into smaller arterioles and into ones, are involved in a number of physiological and patho- capillary beds. From there, the blood returns via venules logicalconditionssuchaswoundhealing,tumorgrowth,and andveinstotheheart toproceed tothelungsfornew 2 JournalofAllergy oxygen loading. Under physiological conditions, the major 4.TheRoleofBloodandLymphaticVessels functions of blood vessels include the supply of gases, �uid, in�n�ammation nutrition, and signaling molecules to the tissues with the Boththebloodandthelymphaticvascularsystemcontribute capillaries as the actual sites of exchange. At these sites, tothebody�sin�ammatoryresponse.Inacutein�ammation, plasmaleaksfromthecapillariesintotheinterstitium,driven by blood pressure and osmotic gradients. e lymphatic blood vascular endothelial cells are activated by several in�ammatory mediators (e.g., vascular endothelial growth capillariestakeupthisprotein-rich�uid,therebymaintaining factor- (VEGF-)A, tumor necrosis factor (TNF-)𝛼𝛼 , inter- not only tissue �uid homeostasis but also exerting immune leukin (IL)-6, and IL-1𝛽𝛽), leading to the typical signs of surveillance. e lymphatic network is composed of blind- in�ammation, increased blood �ow as a conse�uence of beginning thin-walled capillaries without pericyte coverage vesseldilationandedemaformationduetoincreasedperme- and with incomplete basal lamina as well as of collecting ability of the blood vessels. Furthermore, the expression of lymphaticvesselswithasmoothmusclecelllayer,abasement adhesionmolecules,suchasintercellularadhesionmolecule- membrane, and valves, which prevent back �ow of lymph. (ICAM-)1, vascular cell adhesion molecule- (VCAM-)1, elargestcollectinglymphaticvessel,thethoracicduct,con- and E-selectin on activated blood vascular endothelial cells, nects the lymphatic system with the cardiovascular system. enables the interaction between leukocytes and endothe- Inadults,physiologicalangiogenesisandlymphangiogenesis lium, a major event in the in�ammatory process [20, 21]. are uncommon. However, new lymphatic and blood vessels In chronic in�ammation, the blood vasculature remains formduringthefemalereproductivecycle,thehaircycle,and enlarged, hyperpermeable, and activated with high expres- inhealingwounds[10,11]. sionofadhesionmolecules,leadingtocontinuousextravasa- tionofin�ammatorycellsand�uidintothein�amedtissue. A number of in�ammatory conditions such as rheuma- 3.AnatomyoftheCutaneousandPulmonary toid arthritis, in�ammatory bowel disease, asthma, atopic VascularSystems dermatitis, and psoriasis are characterized by pronounced angiogenesis[7,9,22,23]. e epidermal layer of the skin is free of blood and lym- Besides the blood vasculature, also the lymphatic vascu- phatic vessels. In the dermis, the blood vascular system is lature plays an important role in in�ammation. Lymphatic organized into a deep and a super�cial horizontal plexus vessels regulate the in�ammatory response by the transport with capillaries arising from the latter one [12, 13]. e of �uid, extravasated leukocytes, and antigen-presenting lymphatic vasculature also forms two plexuses in vicinity to cells from the in�amed tissue to the lymph nodes and the blood vessels. Branches from the super�cial lymphatic to other secondary lymphoid organs, thereby contributing vessel plexus extend into the dermal papillae and descend to the decrease of in�ammation-induced edema and to intothelargerlymphaticvesselsinthelowerdermis[14].e the initiation of a speci�c immune response. e C-C bulk of blood microvascular vessels is located immediately chemokine receptor type (CCR) 7 expressed by dendritic below the epidermis, whereas the lymphatic vessels reside cells is important for their migration into afferent lymphatic vessels which secrete the respective ligand chemokine (C- moredistanttotheepidermis[15]. C motif) ligand (CCL) 21 [24]. Lymphangiogenesis occurs Pulmonarybloodvesselstransportthelow-oxygenblood in several chronic in�ammatory conditions such as human from the heart to the lung, whereas the bronchial vessels psoriasis and mouse models of chronic skin in�amma- supply the lung with nutrients and oxygen. e bronchial tion,chronicairwayin�ammation,andrheumatoidarthritis blood vessels arise from the aorta or intercostal arteries and [8,25–27]. enterthelungatthehilum.Atthemainstembronchus,they branchanddescendtothelowertracheaandextrapulmonary 5.MediatorsofAngiogenesisand airways. ey cover the whole lung from the bronchial tree Lymphangiogenesisin�n�ammation to the terminal bronchioles, where the bronchial vessels anastomosewitheachotheraswellaswithpulmonaryvessels In recent years, the understanding of in�ammatory angio- [16]. Studies of lymphatic vessels in normal human lung are genic and lymphangiogenic processes such as endothelial rare, not only because for a long time lymphatic speci�c cell growth, migration, and survival has increased, and a markers were notknown,butalsobecausein the lungthe variety of involved mediators have been identi�ed. e commonlyusedlymphaticmarkerlymphaticvesselendothe- mostimportantmoleculethatcontrolsin�ammation-driven lialhyaluronanreceptor-(LYVE-)1stainsbothlymphaticand angiogenesisisVEGF-A,amemberofafamilyofangiogenic bloodvascularendothelialcells[17].Recentstudiesusingthe and lymphangiogenic drivers such as VEGF-C, VEGF-D, speci�c lymphatic endothelium marker podoplanin showed and placenta growth factor (PlGF) [6, 28]. VEGF-A signals that in human lung, lymphatic vessels extend beyond the via its receptor tyrosine kinases VEGFR-1 and VEGFR-2 respiratory bronchioles, accompanying intralobular arteries and thereby induces angiogenesis and lymphangiogenesis deepinsidethelobule,thesmallestunitofthelung[18,19].In (Figure1). Expression of VEGF-A and VEGFR-2 is induced themurinetrachea,thelymphaticnetworkishighlyordered, by cytokines such as TNF-𝛼𝛼, thereby linking angiogen- and vessels are restricted to the mucosa located between the esis with in�ammatory conditions [14, 29]. VEGFR-1 is cartilagerings[8]. expressed on blood vessels, whereas VEGFR-2 is expressed JournalofAllergy 3 Lymphatic endothelial cells Blood vascular endothelial cells PIGF VEGF-A VEGF-C VEGF-D VEGFR-2 VEGFR-2 VEGFR-1 VEGFR-3 Lymphangiogenesis Angiogenesis F1:VEGF-bindingpropertiesanddistinctVEGFreceptorexpressiononlymphatic andbloodvascularendothelium.VEGFs bindto thethreeVEGFreceptortyrosinekinases,leadingtotheformationofVEGFRdimers.BloodvascularendothelialcellsexpressVEGFR-1and VEGFR-2,whereaslymphaticendothelialcellsexpressVEGFR-2andVEGFR-3.VEGF-A—whichbindsbothVEGFR-1andVEGFR-2—can directlyinducebloodandlymphaticvascularremodeling.VEGF-Cand-DbindVEGFR-3and,aerproteolyticprocessing,alsoVEGFR-2, thusinducingangiogenesisandlymphangiogenesis. onbothbloodandlymphaticvesselswithhighexpressionon 40]. TNF-𝛼𝛼 might also contribute to in�ammatory airway tipcells[30].ComparedtoVEGFR-2,VEGFR-1hasahigher lymphangiogenesis[39]. affinity for VEGF-A but a lower kinase activity. VEGFR- 1 has been reported to trap VEGF-A to prevent excess 6.BloodandLymphaticVesselsinChronic signaling via VEGFR-2 during embryogenesis, whereas in ��in�n�ammation the adult the function of VEGFR-1 remains more elusive [31, 32]. Several cytokines and chemokines such asIL-1,IL- Several skin diseases such as atopic dermatitis, contact der- 8, IL-18, chemokine (C-X-C motif) ligand (CXCL) 3, and matitis, UV damage, and psoriasis are associated with CXCL12havealsobeenreportedtoexertproangiogenicand increased vascular remodeling (Figure 2)[25, 41, 42]. In lymphangiogenicactivities(Table1). the lesional skin of atopic dermatitis and psoriasis, levels of the angiogenic growth factor VEGF-A are elevated [27, 43, In�ammatory lymphangiogenesis, as lymphangiogenesis 44], and in psoriasis patients, the plasma levels of VEGF-A in general, is mainly driven by VEGFR-2 and -3 signal- correlatepositivelywiththediseaseseverity[45]. ing. us, VEGF-A-induced VEGFR-2 signaling plays not In recent years, a number of mouse models have been only a role in angiogenesis but also in lymphangiogenesis. developed to study vascular remodeling in chronic skin VEGFR-3,whichisexpressedonlymphaticendothelialcells, bindsVEGF-CandVEGF-D(Figure1).However,aerprote- in�ammation, for example, the epidermal speci�c JunB�C- olyticcleavage,VEGF-CcanalsoinduceVEGFR-2signaling Jun knockout mice [46], human psoriatic skin transplanta- [33–35]. VEGFR-2 and -3 signaling have been shown to tionontoseverecombinedimmunode�ciency-(SCID-)mice be involved in in�ammatory lymphangiogenesis in mouse [47], and K14 (keratin14) VEGF-A transgenic mice [48] models of skin in�ammation and of airway in�ammation whichhavebeendevelopedinourlaboratory.Inthesemice, [8,36,37].esemodelswillbediscussedinmoredetaillater murine VEGF-A164 is continuously expressed in epidermal on.eexpressionofthelymphangiogenicfactorVEGF-Cis keratinocytes under the control of the K14 promoter. Mice induced in response to different proin�ammatory cytokines homozygous for this transgene develop a chronic cutaneous such as TNF-𝛼𝛼 and IL-1𝛽𝛽, most likely via the activation of in�ammationattheageofapproximately5-6months,which the nuclear factor of kappa light polypeptide gene enhancer has most of the features of human psoriasis, namely epi- in B-cells (NF-𝜅𝜅 B) pathway [38, 39]. Furthermore, in�am- dermal hyperplasia and abnormal terminal differentiation matory cells such as macrophages promote the formation of epidermal keratinocytes, typical leukocyte in�ltration of lymphatic vessels by secreting VEGF-C and VEGF-D [8, including dermal CD4+ T cell and epidermal CD8+ T-cell 4 JournalofAllergy accumulationaswellasapronouncedincreaseinthenumber T1:Proangiogeniccytokinesandchemokines. and size of blood and lymphatic vessels (Figure3)[48]. In Name References hemizygousK14-VEGF-A transgenic mice, the chronic skin Cytokines in�ammation is inducible by applying the contact sensitizer TNF-𝛼𝛼 [69–71] oxazolone[25].Several studiesintheseK14-VEGF-Atrans- genicmicebyourlaboratoryandothershavevalidatedthese IL-1 [72–74] miceasavaluablemodelforchroniccutaneousin�ammation IL-6 [41] with a relevant involvement of vascular remodeling. In IL-8(CXCL18) [75,76] this model, the small molecular VEGFR inhibitor NVP- IL-15 [77] �A�2881 showed strong anti-in�ammatory actions with a IL-17 [78] reduction in in�ammation-induced angiogenesis and lym- IL-18 [79–82] phangiogenesis [49]. Furthermore, treatment with the spe- Chemokines ci�c anti-VEGFR-2 antibody DC101 inhibited skin in�am- CXCL1 [83,84] mation,in�ammatorycellin�ltration,andangiogenesis37[], CXCL2 [83,84] indicating that angiogenesis plays an important role for CXCL3 [83–86] disease maintenance and progression. e importance of CXCL5 [83,84] the lymphatic vasculature in in�ammation was also studied in these mice. Surprisingly, blockade of VEGFR-3 signaling CXCL6 [83,84] increased the severity of skin in�ammation. Conversely, CXCL7 [83,84] speci�c activation of the lymphatic vasculature by intracu- CXCL9 [83] taneous injections of recombinant VEGF-C156S, a speci�c CXCL12(SDF-1) [87,88] ligandofVEGFR-3,reducedchronicskinin�ammation37[ ]. CCL2(MCP-1) [89,90] Takentogether,hemizygousK14-VEGF-Atgmicerepresent Alsoantiangiogenicactivityhasbeenreported. a reliable model to study in�ammation-induced vascular remodeling in the skin and to test the potential effective- ness of new anti-in�ammatory drugs. However, psoriasis is a human-speci�c disease that is not naturally observed in the increased submucosal vascularity in the inner area of animals. us, different genetic and xenotransplant mouse the medium airway might contribute to air�ow limitation, models have been developed to mimic some features of as indicated by the inverse correlation of vascularity and humanpsoriasis[50].Consideringthesubstantialdifferences forced expiratory volume, a measure for airway obstruction between mouse and human skin, however, most of these [56]. VEGF-A, the major driver of angiogenesis, was also models do not fully recapitulate all characteristics of the increased in sputum samples of patients with mild asthma human disease. erefore, for speci�c pathogenetic studies, compared to healthy controls [58]. VEGF-A and VEGFR-1 the evaluation of different psoriasis mouse models might be mRNA levels were increased in lung biopsy specimens from advantageous. In this regard, it has been recently reported patientswithmild-to-moderateasthmacomparedtohealthy thattopicaltreatmentwith Imiquimod,a toll-likereceptor7 controls.ereportedcolocalizationofVEGF-AwithCD68, and 8 agonist, triggers psoriasis-like skin lesions in humans majorbasicproteinandChymase-positivecellssuggeststhat and in mice, with an involvement of the IL23/IL17 axis, macrophages, eosinophils, and mast cells are a major source knowntoplayacrucialroleinhumanpsoriasis[51]. of VEGF-A in the lung [59, 60], which thus may contribute toangiogenesisinasthma.Conversely,ithasbeenshown—in differentinvitroandinvivosettings—thateosinophils,mast 7.BloodVesselsinAsthma cells, and macrophages are also in�uenced by angiogenic Asthma is a chronic in�ammatory disease of the airways factors. Due to their expression of VEGFR-1, these cells are thatischaracterizedbyairwayhyperresponsiveness,episodic able to migrate towards VEGF-A gradients [61–65]. ere- air�ow limitations, and a decline in lung function. ese fore, increased VEGF-A levels at the site of in�ammation symptoms are caused by chronic in�ammation and airway contributetotherecruitmentofdifferentin�ammatorycells remodeling, including increased thickness of the lamina whichthemselvescansecreteproin�ammatorymediators. reticularis[52,53],smoothmusclehyperplasia/hypertrophy, McDonald and colleagues established the Mycoplasma andincreasedvascularity[54,55]insmallandlargeairways pulmonisinfectionmodelofchronicairwayin�ammationas [56].Inthe1960s,Dunilldemonstratedforthe�rsttimethe avaluabletoolforinvestigationofchronicin�ammatoryair- involvement of blood vessels in asthma by showing swollen waydiseasesinmice.ismodelshowsseveral—thoughnot bronchial mucosa with dilated and congested capillaries all—characteristic features of asthma such as in�ammatory in lung samples of subjects who died of acute asthmatic cell in�ux, angiogenesis, mucosal edema, epithelial changes, attacks [57]. Since then, increased airway vascularity was �brosis, and bronchial hyperreactivity8[, 66]. Shortly aer not only found in severe but also in mild asthmatic cases, M. pulmonis infection, mucosal blood vessels enlarge by and it is nowadays a well established �nding that the endothelial cell proliferation, and angiogenesis reaches a number of blood vessels and the tissue area covered by plateau at 14 days aer infection [8]. Surprisingly, VEGF blood vessels are increased in asthmatic patients compared receptor blocking studies showed that this pathological to healthy subjects (reviewed in [55]). In mild asthma cases, angiogenesis might not be driven by VEGF-A [8]. However, JournalofAllergy 5 Normal skin Psoriasis F2:Bloodandlymphaticvesselenlargementinhumanpsoriasis.enumberandsizeofvonWillebrandfactor(vWF)-positiveblood vesselsinlesionalpsoriaticskinareincreasedcomparedtonormalhealthyskin.AlsothesizeofD2-40positivelymphaticvesselsisincreased inlesionalpsoriaticskin.Bar=100𝜇𝜇m. Uninflamed Inflamed Lyve-1 Meca-32 Dapi F3:Bloodandlymphaticvesselenlargementinthein�amedskinof�14-�E�F-Atransgenicmice.enumberandsizeof�eca-32 positive blood vessels (red) and ���E-1 positive lymphatic vessels (green) are increased in the in�amed skin of �14-�E�F-A transgenic micecomparedtounin�amedskin.Bar=100𝜇𝜇 m. blocking of TNF-𝛼𝛼 signaling by an anti-TNF-𝛼𝛼 antibody asthma is remarkably sparse. Only recently, it was shown dramatically reduced blood vessel remodeling 14 days aer that lymphangiogenesis increased with advanced stages of M. pulmonis infection, suggesting that TNF-𝛼𝛼 signaling is idiopathic pulmonary �brosis, a chronic lung disease of involvedinthisangiogenicprocess[39]. unknown etiology with an insidious onset, leading to venti- latoryrestrictionandrespiratoryfailure[68]. In the M. pulmonis driven mouse model of chronic 8.LymphaticVesselsinChronicAirwayDisease airway in�ammation, there is also a dramatic remodeling of lymphatic vessels [8]. Robust lymphangiogenesis is most Edema formation results when the amount of leakage from abundant on the surface facing the cartilage rings that grow the blood vessels exceeds the capacity of lymphatic vessels towardstheoverlayingairwayepithelium.Interestingly,aer for drainage. Such edemas are a cardinal sign of chronic 4 weeks of treatment with antibiotics, lymphatic sprouting in�ammation, and indeed increased microvascular perme- was completely inhibited, but lymphatic vessels regressed abilityaswellasedemaarefeaturesofasthma[67].However, onlypartially,comparedtothealmostcompleteregressionof knowledge of lymphatic involvement in edema formation in D2-40 vWF 6 JournalofAllergy blood vessels [8]. VEGF-C, VEGF-D, and TNF-𝛼𝛼 are major node lymphangiogenesis and promotes lymphatic metastasis,” JournalofExperimentalMedicine,vol.201,no.7,pp.1089–1099, drivers of this remodeling. 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