title: Regulation of pulmonary inflammation and fibrosis through expression of integrins alphaVbeta3 and alphaVbeta5 on pulmonary T lymphocytes.
abstract: OBJECTIVE
  Pulmonary diseases associated with fibrosis, including scleroderma lung disease, are characterized by the accumulation of T cells in the lungs. These cells are thought to facilitate lung fibrosis, but the exact mechanisms of their profibrotic action are not clear. Several alphaV-containing integrins, including alphaVbeta3 and alphaVbeta5, have been shown to directly activate transforming growth factor beta (TGFbeta) and promote collagen accumulation. The aim of this study was to investigate whether pulmonary T cells express profibrotic integrins and regulate collagen accumulation.
  
  
  METHODS
  Expression of integrins was assessed by immunohistochemical analysis of lung tissue, by flow cytometry using bronchoalveolar lavage fluid from patients with systemic sclerosis (SSc), and in a CCL18 overexpression animal model of pulmonary T cell infiltration. Experiments in cell cultures were performed to determine whether integrin-expressing T cells are profibrotic in cocultures with pulmonary fibroblasts and, if so, through what possible mechanism.
  
  
  RESULTS
  Lymphocytes and integrin-positive cells were present in the lungs, and pulmonary T cells expressed integrins alphaVbeta3 and alphaVbeta5 in patients with SSc and in the animal model. Systemic administration of neutralizing anti-integrin alphaV antibody or a genetic deficiency of integrin beta3 in the CCL18 overexpression model significantly attenuated CCL18-driven pulmonary lymphocytic infiltration and collagen accumulation. Jurkat T cells overexpressing integrin alphaVbeta3 or integrin alphaVbeta5 in cocultures with primary pulmonary fibroblasts stimulated collagen accumulation and Smad2 nuclear translocation. Neutralizing anti-TGFbeta antibody attenuated the profibrotic effect of integrin-expressing T cells.
  
  
  CONCLUSIONS
  Pulmonary infiltrating T lymphocytes may express integrins alphaVbeta3 and alphaVbeta5 that are necessary for lymphocytic infiltration and T cell-associated TGFbeta activation and collagen accumulation.
authors.affiliation: University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Luzina
authors.forename: Nevins W
authors.initials: NW
authors.lastname: Todd
authors.forename: Natalia
authors.initials: N
authors.lastname: Nacu
authors.forename: Virginia
authors.initials: V
authors.lastname: Lockatell
authors.forename: Jung
authors.initials: J
authors.lastname: Choi
authors.forename: Laura K
authors.initials: LK
authors.lastname: Hummers
authors.forename: Sergei P
authors.initials: SP
authors.lastname: Atamas
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D039564:Integrin alphaV / Q000276:immunology; D039302:Integrin alphaVbeta3 / Q000032:analysis*; D019169:Jurkat Cells; D008168:Lung / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000628:therapy*; D019030:Receptors, Vitronectin / Q000032:analysis*; D012595:Scleroderma, Systemic / Q000378:metabolism / Q000628:therapy*; D013601:T-Lymphocytes / Q000737:chemistry*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000906:Antibodies; D039564:Integrin alphaV; D039302:Integrin alphaVbeta3; D019030:Receptors, Vitronectin; D016212:Transforming Growth Factor beta; C064660:integrin alphaVbeta5; D003094:Collagen