Access the full text.
Sign up today, get DeepDyve free for 14 days.
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;email@example.com 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.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. C motif) ligand (CCL) 21 . 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- . 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.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. 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.ComparedtoVEGFR-2,VEGFR-1hasahigher lymphangiogenesis. 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. 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 , 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 , and K14 (keratin14) VEGF-A transgenic mice  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). 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.Several studiesintheseK14-VEGF-Atrans- genicmicebyourlaboratoryandothershavevalidatedthese IL-1 [72–74] miceasavaluablemodelforchroniccutaneousin�ammation IL-6  with a relevant involvement of vascular remodeling. In IL-8(CXCL18) [75,76] this model, the small molecular VEGFR inhibitor NVP- IL-15  �A�2881 showed strong anti-in�ammatory actions with a IL-17  reduction in in�ammation-induced angiogenesis and lym- IL-18 [79–82] phangiogenesis . 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  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.Consideringthesubstantialdiﬀerences forced expiratory volume, a measure for airway obstruction between mouse and human skin, however, most of these . 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 . 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. 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 .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 . 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 . Surprisingly, VEGF blood vessels are increased in asthmatic patients compared receptor blocking studies showed that this pathological to healthy subjects (reviewed in ). In mild asthma cases, angiogenesis might not be driven by VEGF-A . 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. unknown etiology with an insidious onset, leading to venti- latoryrestrictionandrespiratoryfailure. In the M. pulmonis driven mouse model of chronic 8.LymphaticVesselsinChronicAirwayDisease airway in�ammation, there is also a dramatic remodeling of lymphatic vessels . 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.However, onlypartially,comparedtothealmostcompleteregressionof knowledge of lymphatic involvement in edema formation in D2-40 vWF 6 JournalofAllergy blood vessels . 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. Blockade of VEGFR-3 signaling via soluble VEGFR-3-Fc or by an anti-VEGFR-3 antibody  V.MumprechtandM.Detmar,“Lymphangiogenesisandcancer almost completely prevented lymphangiogenesis in tracheas metastasis,”JournalofCellularandMolecularMedicine,vol.13, ofinfectedmice.Incontrast,adenoviraloverexpressionof no.8,pp.1405–1416,2009. VEGF-Cinthemurinetrachealeadstoenhancedlymphatic  M.Detmar,L.F.Brown,K.P.Claﬀeyetal.,“Overexpressionof �lopodiaformationandtosproutssimilartothoseseeninthe vascularpermeabilityfactor/vascularendothelialgrowthfactor M. pulmonis infected mice. Immuno�uorescence stainings anditsreceptorsinpsoriasis,”JournalofExperimentalMedicine, showedthatmucosalin�ammatorycells,inparticularF4/80� vol.180,no.3,pp.1141–1146,1994. macrophages, are a major source of VEGF-C in this model.  S. Danese, M. Sans, C. de la Motte et al., “Angiogenesis as a ReducedlymphangiogenesisaerinfectionwithM.pulmonis novelcomponentofin�ammatoryboweldiseasepathogenesis,” was also observed aer inhibition of TNF signaling by a Gastroenterology,vol.130,no.7,pp.2060–2073,2006. blockingantibodyandinTNFR-1komice.  P.Baluk,T.Tammela,E.Atoretal.,“Pathogenesisofpersistent lymphatic vessel hyperplasia in chronic airway in�ammation,” 9.ConclusionsandOutlook Journal of Clinical Investigation, vol. 115, no. 2, pp. 247–257, ere is clear evidence that in humans, vascular remodeling  N. airu, S. Kiriakidis, P. Dawson et al., “Angiogenesis as a occursinmanychronicin�ammatorydisorders.Eventhough therapeutic target in arthritis in 2011: learning the lessons of diﬀerent anti-in�ammatory drugs are on the market, there the colorectal cancer experience,” Angiogenesis, vol. 14, no. 3, is no speci�c therapy that interferes with the pathological pp.223–234,2011. vascular changes that occur during in�ammation. Angio-  M. J. Karkkainen and T. V. Petrova, “Vascular endothelial genesis and lymphangiogenesis are tightly linked to chronic growth factor receptors in the regulation of angiogenesis and in�ammation,andtargetingthebloodvesselsandlymphatic lymphangiogenesis,” Oncogene, vol. 19, no. 49, pp. 5598–5605, vesselshasbeenshowntobeaneﬀectivestrategyindiﬀerent experimental mouse models of chronic in�ammation. One  C.Norrmén,T.Tammela,T.V.Petrova,andK.Alitalo,“Biolog- has to keep in mind, however, that in most conditions the ical basis of therapeutic lymphangiogenesis,” Circulation, vol. vascularactivationlikelyrepresentsadownstreameventthat 123,no.12,pp.1335–1351,2011. maintainsthein�ammatoryprocess,butnotthepathogenetic  I. M. Braverman, “Ultrastructure and organization of the cause of the respective disease, which oen has remained cutaneous microvasculature in normal and pathologic states,” unknown. Nonetheless, antiangiogenic and prolymphangio- Journal of Investigative Dermatology, vol. 93, supplement2, pp. genic therapies might represent new approaches to treat 2S–9S,1989. chronic in�ammatory disorders, including those due to  M. Detmar and S. Hirakawa, “Vascular Biology,” in Dermatol- chronicallergicin�ammation. ogy,pp.1679–1689,3rdedition,2012.  R. Huggenberger and M. Detmar, “e cutaneous vascular system in chronic skin in�ammation,” Journal of Investigative Authors’Contribution Dermatology,vol.15,no.1,pp.24–32,2011. S.ZgraggenandA.M.Ochsenbeinequallycontributedtothis  M. Skobe and M. Detmar, “Structure, function, and molecular control of the skin lymphatic system,” Journal of Investigative work. Dermatology Symposium Proceedings, vol. 5, no. 1, pp. 14–19, Acknowledgments  A. Zanini, A. Chetta, A. S. Imperatori, A. Spanevello, and D. Olivieri, “e role of the bronchial microvasculature in Work intheauthors’ laboratorywassupportedbythe the airway remodelling in asthma and COPD,” Respiratory NationalInstitutesofHealthGrantCA69184,SwissNational Research,vol.11,article132,2010. Science Foundation Grants 3100A0-108207 and 31003A-  E. J. Gordon, N. W. Gale, and N. L. Harvey, “Expression 130627, European Research Council Grant LYVICAM, of the hyaluronan receptor LYVE-1 is not restricted to the Oncosuisse,KrebsligaZurich,andtheLeducqFoundation. lymphaticvasculature;LYVE-1isalsoexpressedonembryonic blood vessels,” Developmental Dynamics, vol. 237, no. 7, pp. 1901–1909,2008. References  M.KambouchnerandJ.F.Bernaudin,“Intralobularpulmonary  S. J. Galli, M. Tsai, and A. M. Piliponsky, “e development of lymphatic distribution in normal human lung using D2-40 allergicin�ammation,”Nature,vol.454,no.7203,pp.445–454, antipodoplanin immunostaining,” Journal of Histochemistry andCytochemistry,vol.57,no.7,pp.643–648,2009.  P. Carmeliet, “Angiogenesis in health and disease,” Nature  F. Sozio, A. Rossi, E. Weber et al., “Morphometric analysis Medicine,vol.9,no.6,pp.653–660,2003. of intralobular, interlobular and pleural lymphatics in normal  T. Karpanen and K. Alitalo, “Molecular biology and pathology human lung,” Journal of Anatomy, vol. 220, no. 4, pp. 396–404, of lymphangiogenesis,” AnnualReviewofPathology, vol. 3, pp. 367–397,2008.  J. S. Pober and W. C. Sessa, “Evolving functions of endothelial  S. Hirakawa, S. Kodama, R. Kunstfeld, K. Kajiya, L. F. Brown, cells in in�ammation,” Nature Reviews Immunology,vol.7,no. and M. Detmar, “VEGF-A induces tumor and sentinel lymph 10,pp.803–815,2007. JournalofAllergy 7  J. R. Jackson, M. P. Seed, C. H. Kircher, D. A. Willoughby, and  R. Huggenberger, S. Ullmann, S. T. Proulx, B. Pytowski, K. J. D. Winkler, “e codependence of angiogenesis and chronic Alitalo, and M. Detmar, “Stimulation of lymphangiogenesis in�ammation,” e FASEB Journal, vol. 11, no. 6, pp. 457–465, via VEGFR-3 inhibits chronic skin in�ammation,” Journal of 1997. ExperimentalMedicine,vol.207,no.10,pp.2255–2269,2010.  A. Ristimäki, K. Narko, B. Enholm, V. Joukov, and K. Ali-  D. Ribatti, I. Puxeddu, E. Crivellato, B. Nico, A. Vacca, and F. talo, “Proin�ammatory cytokines regulate expression of the Levi-Schaﬀer, “Angiogenesis in asthma,” Clinical and Experi- lymphatic endothelial mitogen vascular endothelial growth mentalAllergy,vol.39,no.12,pp.1815–1821,2009. factor-C,” Journal of Biological Chemistry, vol. 273, no. 14, pp.  Y. Zhang, H. Matsuo, and E. Morita, “Increased production 8413–8418,1998. of vascular endothelial growth factor in the lesions of atopic  P. Baluk, L. C. Yao, J. Feng et al., “TNF-𝛼𝛼 drives remodeling of dermatitis,” Archives of Dermatological Research, vol. 297, no. bloodvesselsandlymphaticsinsustainedairwayin�ammation 9,pp.425–429,2006. in mice,” Journal of Clinical Investigation, vol. 119, no. 10, pp.  L. Ohl, M. Mohaupt, N. Czeloth et al., “CCR7 governs skin 2954–2964,2009. dendritic cell migration under in�ammatory and steady-state  C. Cursiefen, L. Chen, L. P. Borges et al., “VEGF-A stimulates conditions,”Immunity,vol.21,no.2,pp.279–288,2004. lymphangiogenesisandhemangiogenesisinin�ammatoryneo-  R. Kunstfeld, S. Hirakawa, Y. K. Hong et al., “Induction of vascularizationviamacrophagerecruitment,”JournalofClinical cutaneous delayed-type hypersensitivity reactions in VEGF-A Investigation,vol.113,no.7,pp.1040–1050,2004. transgenicmiceresultsinchronicskinin�ammationassociated  L. S. Chan, “Atopic dermatitis in 2008,” Current Directions in withpersistentlymphatichyperplasia,”Blood,vol.104,no.4,pp. Autoimmunity,vol.10,pp.76–118,2008. 1048–1057,2004.  K.Yano,H.Oura,andM.Detmar,“Targetedoverexpressionof  K. Kajiya and M. Detmar, “An important role of lymphatic theangiogenesisinhibitorthrombospondin-1intheepidermis vessels in the control of UVB-induced edema formation and oftransgenicmicepreventsultraviolet-B-inducedangiogenesis in�ammation,” Journal of Investigative Dermatology, vol. 126, and cutaneous photo-damage,” Journal of Investigative Derma- no.4,pp.920–922,2006. tology,vol.118,no.5,pp.800–805,2002.  Q. Zhang, Y. Lu, S. T. Proulx et al., “Increased lymphangio-  L.F.Brown,T.J.Harrist,K.T.Yeoetal.,“Increasedexpression genesis in joints of mice with in�ammatory arthritis,” Arthritis of vascular permeability factor (vascular endothelial growth Researchanderapy,vol.9,no.6,articleR118,2007. factor) in bullous pemphigoid, dermatitis herpetiformis, and  N.Ferrara,H.P.Gerber,andJ.LeCouter,“ebiologyofVEGF erythema multiforme,” Journal of Investigative Dermatology, vol.104,no.5,pp.744–749,1995. and its receptors,” Nature Medicine, vol. 9, no. 6, pp. 669–676,  M. Detmar, “e role of VEGF and thrombospondins in skin angiogenesis,” Journal of Dermatological Science, vol. 24,  A. Hoeben, B. Landuyt, M. S. Highley, H. Wildiers, A. T. van supplement1,pp.S78–S84,2000. Oosterom, and E. A. de Bruijn, “Vascular endothelial growth factor and angiogenesis,” Pharmacological Reviews, vol. 56, no.  M.Bhushan,B.McLaughlin,J.B.Weiss,andC.E.M.Griﬃths, “Levels of endothelial cell stimulating angiogenesis factor and 4,pp.549–580,2004. vascular endothelial growth factor are elevated in psoriasis,”  R. H. Adams and K. Alitalo, “Molecular regulation of angio- British Journal of Dermatology, vol. 141, no. 6, pp. 1054–1060, genesisandlymphangiogenesis,”NatureReviewsMolecularCell Biology,vol.8,no.6,pp.464–478,2007.  R. Zenz, R. Eferl, L. Kenner et al., “Psoriasis-like skin disease  G. H. Fong, J. Rossant, M. Gertsenstein, and M. L. Breitman, and arthritis caused by inducible epidermal deletion of Jun “Role of the Flt-1 receptor tyrosine kinase in regulating the proteins,”Nature,vol.437,no.7057,pp.369–375,2005. assembly of vascular endothelium,” Nature, vol. 376, no. 6535,  S. P. Raychaudhuri, M. Sanyal, S. K. Raychaudhuri, S. Dutt, pp.66–70,1995. andE.M.Farber,“Severecombinedimmunode�ciencymouse-  S. Hiratsuka, O. Minowa, J. Kuno, T. Noda, and M. Shibuya, human skin chimeras: a unique animal model for the study “Flt-1 lacking the tyrosine kinase domain is suﬃcient for of psoriasis and cutaneous in�ammation,” British Journal of normal development and angiogenesis in mice,” Proceedings of Dermatology,vol.144,no.5,pp.931–939,2001. theNationalAcademyofSciencesoftheUnitedStatesofAmerica,  Y.P.Xia,B.Li,D.Hylton,M.Detmar,G.D.Yancopoulos,andJ. vol.95,no.16,pp.9349–9354,1998. S.Rudge,“TransgenicdeliveryofVEGFtomouseskinleadsto  V. Joukov, T. Sorsa, V. Kumar et al., “Proteolytic processing anin�ammatoryconditionresemblinghumanpsoriasis,”Blood, regulates receptor speci�city and activity of VEGF-C,” e vol.102,no.1,pp.161–168,2003. EMBOJournal,vol.16,no.13,pp.3898–3911,1997.  C. Halin, H. Fahrngruber, J. G. Meingassner et al., “Inhibition  T. Mäkinen, T. Veikkola, S. Mustjoki et al., “Isolated lymphatic of chronic and acute skin in�ammation by treatment with endothelial cells transduce growth, survival and migratory a vascular endothelial growth factor receptor tyrosine kinase signals via the VEGF-C/D receptor VEGFR-3,” e EMBO inhibitor,” American Journal of Pathology, vol. 173, no. 1, pp. Journal,vol.20,no.17,pp.4762–4773,2001. 265–277,2008.  E.Kriehuber,S.Breiteneder-Geleﬀ,M.Groegeretal.,“Isolation  M. P. Schön, “Animal models of psoriasis: a critical appraisal,” andcharacterizationofdermallymphaticandbloodendothelial ExperimentalDermatology,vol.17,no.8,pp.703–712,2008. cells reveal stable and functionally specialized cell lineages,”  L.vanderFits,S.Mourits,J.S.A.Voermanetal.,“Imiquimod- Journal of Experimental Medicine, vol. 194, no. 6, pp. 797–808, induced psoriasis-like skin in�ammation in mice is mediated viatheIL-23/IL-17axis,”JournalofImmunology,vol.182,no.9, pp.5836–5845,2009.  R. Huggenberger, S. S. Siddiqui, D. Brander et al., “An impor- tantroleoflymphaticvesselactivationinlimitingacutein�am-  C. E. Brewster, P. H. Howarth, R. Djukanovic, J. Wilson, S. T. mation,”Blood,vol.117,no.17,pp.4667–4678,2011. Holgate, and W. R. Roche, “Myo�broblasts and subepithelial 8 JournalofAllergy �brosis in bronchial asthma,” American Journal of Respiratory  S.El-Chemaly,G.Pacheco-Rodriguez,Y.Ikeda,D.Malide,and CellandMolecularBiology,vol.3,no.5,pp.507–511,1990. J. Moss, “Lymphatics in idiopathic pulmonary �brosis: new insights into an old disease,” Lymphatic Research and Biology,  W. R. Roche, R. Beasley, J. H. Williams, and S. T. Holgate, vol.7,no.4,pp.197–203,2009. “Subepithelial�brosisinthebronchiofasthmatics,”eLancet, vol.1,no.8637,pp.520–524,1989.  S. J. Leibovich, P. J. Polverini, H. M. Shepard, D. M. Wiseman, V. Shively, and N. Nuseir, “Macrophage-induced angiogenesis  B. E. Orsida, X. Li, B. Hickey, F. ien, J. W. Wilson, and E. H. is mediated by tumour necrosis factor-𝛼𝛼,” Nature, vol. 329, no. Walters, “Vascularity in asthmatic airways: relation to inhaled 6140,pp.630–632,1987. steroiddose,”orax,vol.54,no.4,pp.289–295,1999.  M.Frater-Schroder,W.Risau,andR.Hallmann,“Tumornecro-  A. Chetta, A. Zanini, O. Torre, and D. Olivieri, “Vascu- sis factor type 𝛼𝛼, a potent inhibitor of endothelial cell growth lar remodelling and angiogenesis in asthma: Morphological in vitro, is angiogenic in vivo,” Proceedings of the National aspects and pharmacological modulation,” In�ammation and AcademyofSciencesoftheUnitedStatesofAmerica,vol.84,no. Allergy,vol.6,no.1,pp.41–45,2007. 15,pp.5277–5281,1987.  M. Hashimoto, H. Tanaka, and S. Abe, “Quantitative analysis  L. F. Fajardo, H. H. Kwan, J. Kowalski, S. D. Prionas, and A. C. of bronchial wall vascularity in the medium and small airways Allison,“Dualroleoftumornecrosisfactor-𝛼𝛼 inangiogenesis,” of patients with asthma and COPD,” Chest, vol. 127, no. 3, pp. American Journal of Pathology, vol. 140, no. 3, pp. 539–544, 965–972,2005.  M.S.Dunill,“epathologyofasthma,withspecialreferenceto  J. Jagielska, P. R. Kapopara, G. Salguero et al., “Interleukin- changesinthebronchialmucosa,”JournalofClinicalPathology, 1 assembles a proangiogenic signaling module consisting of vol.13,pp.27–33,1960. caveolin-1, tumor necrosis factor receptor-associated factor 6,  K. Asai, H. Kanazawa, K. Otani, S. Shiraishi, K. Hirata, and p38-mitogen-activated protein kinase (MAPK), and MAPK- J. Yoshikawa, “Imbalance between vascular endothelial growth activated protein kinase 2 in endothelial cells,” Arteriosclerosis, factorandendostatinlevelsininducedsputumfromasthmatic rombosisandVascularBiology,vol.32,no.5,pp.1280–1288, subjects,” Journal of Allergy and Clinical Immunology, vol. 110, no.4,pp.571–575,2002.  D. BenEzra, I. Hemo, and G. Mazir, “In vivo angiogenic  M.Hoshino,Y.Nakamura,andQ.A.Hamid,“Geneexpression activityofinterleukins,”ArchivesofOphthalmology,vol.108,no. of vascular endothelial growth factor and its receptors and 4,pp.573–576,1990. angiogenesis in bronchial asthma,” Journal of Allergy and  F. Cozzolino, M. Torcia, D. Aldinucci et al., “Interleukin 1 ClinicalImmunology,vol.107,no.6,pp.1034–1038,2001. is an autocrine regulator of human endothelial cell growth,”  A. Zanini, A. Chetta, M. Saetta et al., “Chymase-positive mast Proceedings of the National Academy of Sciences of the United cellsplayaroleinthevascularcomponentofairwayremodeling StatesofAmerica,vol.87,no.17,pp.6487–6491,1990. inasthma,”JournalofAllergyandClinicalImmunology,vol.120,  A. E. Koch, P. J. Polverini, S. L. Kunkel et al., “Interleukin-8 as no.2,pp.329–333,2007. a macrophage-derived mediator of angiogenesis,” Science, vol.  B. L. Gruber, M. J. Marchese, and R. Kew, “Angiogenic 258,no.5089,pp.1798–1801,1992. factorsstimulatemast-cellmigration,”Blood,vol.86,no.7,pp.  C. L. Addison, T. O. Daniel, M. D. Burdick et al., “e CXC 2488–2493,1995. chemokine receptor 2, CXCR2, is the putative receptor for  M. Detmar, L. F. Brown, M. P. Schön et al., “Increased mic- ELR+CXCchemokine-inducedangiogenicactivity,”Journalof rovascular density and enhanced leukocyte rolling and adhe- Immunology,vol.165,no.9,pp.5269–5277,2000. sionintheskinofVEGFtransgenicmice,”JournalofInvestiga-  A. L. Angiolillo, H. Kanegane, C. Sgadari, G. H. Reaman, tiveDermatology,vol.111,no.1,pp.1–6,1998. andG.Tosato,“Interleukin-15promotesangiogenesisinvivo,”  B. Barleon, S. Sozzani, D. Zhou, H. A. Weich, A. Mantovani, Biochemical and Biophysical Research Communications, vol. andD.Marmé,“Migrationofhumanmonocytesinresponseto 233,no.1,pp.231–237,1997. vascular endothelial growth factor (VEGF) is mediated via the  M. Numasaki, J. I. Fukushi, M. Ono et al., “Interleukin-17 VEGFreceptor�t-1,”Blood,vol.87,no.8,pp.3336–3343,1996. promotesangiogenesisandtumorgrowth,”Blood,vol.101,no.  C.Feistritzer,N.C.Kaneider,D.H.Sturn,B.A.Mosheimer,C. 7,pp.2620–2627,2003. M.Kähler,andC.J.Wiedermann,“Expressionandfunctionof thevascularendothelialgrowthfactorreceptorFLT-1inhuman  C. C. Park, J. C. M. Morel, M. A. Amin, M. A. Connors, L. A. Harlow, and A. E. Koch, “Evidence of IL-18 as a novel eosinophils,”AmericanJournalofRespiratoryCellandMolecular Biology,vol.30,no.5,pp.729–735,2004. angiogenic mediator,” Journal of Immunology, vol. 167, no. 3, pp.1644–1653,2001.  A.Detoraki,R.I.Staiano,F.Granataetal.,“Vascularendothelial growth factors synthesized by human lung mast cells exert  M. A. Amin, B. J. Rab�uer, P. J. Mans�eld et al., “Interleukin angiogeniceﬀects,”JournalofAllergyandClinicalImmunology, 18 induces angiogenesis in vitro and in vivo via Src and Jnk vol.123,no.5,pp.1142.e5–1149.e5,2009. kinases,” Annals of the Rheumatic Diseases, vol. 69, no. 12, pp. 2204–2212,2010.  D. M. McDonald, “Angiogenesis and remodeling of airway  C.M.Coughlin,K.E.Salhany,M.Wysockaetal.,“Interleukin- vasculature in chronic in�ammation,” American Journal of Respiratory and Critical Care Medicine, vol. 164, no. 10, pp. 12, and interleukin-18 synergistically induce murine tumor S39–S45,2001. regression which involves inhibition of angiogenesis,” Journal ofClinicalInvestigation,vol.101,no.6,pp.1441–1452,1998.  K. F. Chung, D. F. Rogers, P. J. Barnes, and T. W. Evans, “e roleofincreasedairwaymicrovascularpermeabilityandplasma  R. Cao, J. Farnebo, M. Kurimoto, and Y. Cao, “Interleukin- exudation in asthma,” European Respiratory Journal, vol. 3, no. 18 acts as an angiogenesis and tumor suppressor,” e FASEB 3,pp.329–337,1990. Journal,vol.13,no.15,pp.2195–2202,1999. JournalofAllergy 9  R.M.Strieter,P.J.Polverini,S.L.Kunkeletal.,“efunctional role of the ELR motif in CXC chemokine-mediated angio- genesis,” Journal of Biological Chemistry, vol. 270, no. 45, pp. 27348–27357,1995.  E. C. Keeley, B. Mehrad, and R. M. Strieter, “Chemokines as mediators of neovascularization,” Arteriosclerosis, rombosis, andVascularBiology,vol.28,no.11,pp.1928–1936,2008.  Y.Fan,J.Ye,F.Shenetal.,“Interleukin-6stimulatescirculating blood-derivedendothelialprogenitorcellangiogenesisinvitro,” JournalofCerebralBloodFlowandMetabolism,vol.28,no.1,pp. 90–98,2008.  M. V. Volin, J. M. Woods, M. A. Amin, M. A. Connors, L. A. Harlow, and A. E. Koch, “Fractalkine: a novel angio- genicchemokinein rheumatoidarthritis,” American Journal of Pathology,vol.159,no.4,pp.1521–1530,2001.  R. Salcedo, K. Wasserman, H. A. Young et al., “Vascular endothelial growth factor and basic �broblast growth factor induce expression of CXCR4 on human endothelial cells. In vivoneovascularizationinducedbystromal-derivedfactor-1𝛼𝛼 ,” American Journal of Pathology, vol. 154, no. 4, pp. 1125–1135,  I.Kryczek,N.Frydman,F.Gaudinetal.,“echemokineSDF- 1/CXCL12contributestoTlymphocyterecruitmentinhuman pre-ovulatory follicles and coordinates with lymphocytes to increasegranulosacellsurvivalandembryoquality,”American JournalofReproductiveImmunology,vol.54,no.5,pp.270–283,  R.Salcedo,M.L.Ponce,H.A.Youngetal.,“Humanendothelial cellsexpressCCR2andrespondtoMCP-1:directroleofMCP- 1inangiogenesisandtumorprogression,”Blood,vol.96,no.1, pp.34–40,2000.  K. Ebnet and D. Vestweber, “Molecular mechanisms that con- trolleukocyteextravasation:theselectinsandthechemokines,” HistochemistryandCellBiology,vol.112,no.1,pp.1–23,1999. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014
Journal of Allergy – Hindawi Publishing Corporation
Published: Jan 31, 2013
Access the full text.
Sign up today, get DeepDyve free for 14 days.