title: Role of semaphorin 7a signaling in transforming growth factor β1-induced lung fibrosis and scleroderma-related interstitial lung disease.
abstract: OBJECTIVE
  Semaphorin 7a regulates transforming growth factor β1 (TGFβ1)-induced fibrosis. This study was undertaken to test the hypothesis that semaphorin 7a exerts its profibrotic effects in part by promoting the tissue accumulation of CD45+ fibrocytes.
  
  
  METHODS
  A murine model of pulmonary fibrosis in which an inducible, bioactive form of the human TGFβ1 gene is overexpressed in the lung was used. Fibrosis and fibrocytes were evaluated in TGFβ1-transgenic mice in which the semaphorin 7a locus had been disrupted. The effect of replacement or deletion of semaphorin 7a on bone marrow-derived cells was ascertained using bone marrow transplantation. The role of the semaphorin 7a receptor β1 integrin was assessed using neutralizing antibodies. The applicability of these findings to TGFβ1-driven fibrosis in humans was examined in patients with scleroderma-related interstitial lung disease (ILD).
  
  
  RESULTS
  The appearance of fibrocytes in the lungs of TGFβ1-transgenic mice required semaphorin 7a. Replacement of semaphorin 7a on bone marrow-derived cells restored lung fibrosis and fibrocytes. Immunoneutralization of β1 integrin reduced pulmonary fibrocytes and fibrosis. Peripheral blood mononuclear cells (PBMCs) from patients with scleroderma-related ILD showed increased levels of messenger RNA for semaphorin 7a and its receptors, with semaphorin 7a located on collagen-producing fibrocytes and CD19+ lymphocytes. Peripheral blood fibrocyte outgrowth was enhanced in these patients. Stimulation of normal human PBMCs with recombinant semaphorin 7a enhanced fibrocyte differentiation; these effects were attenuated by β1 integrin neutralization.
  
  
  CONCLUSIONS
  Our findings indicate that interventions that reduce semaphorin 7a expression or prevent the semaphorin 7a-β1 integrin interaction may ameliorate TGFβ1-driven or fibrocyte-associated autoimmune fibroses.
authors.affiliation: Central South University, Changsha, Hunan, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Gan
authors.forename: Ronald
authors.initials: R
authors.lastname: Reilkoff
authors.forename: Xueyan
authors.initials: X
authors.lastname: Peng
authors.forename: Thomas
authors.initials: T
authors.lastname: Russell
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Chen
authors.forename: Susan K
authors.initials: SK
authors.lastname: Mathai
authors.forename: Robert
authors.initials: R
authors.lastname: Homer
authors.forename: Mridu
authors.initials: M
authors.lastname: Gulati
authors.forename: Jonathan
authors.initials: J
authors.lastname: Siner
authors.forename: Jack
authors.initials: J
authors.lastname: Elias
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Erica
authors.initials: E
authors.lastname: Herzog
mesh_terms: D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D017563:Lung Diseases, Interstitial / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000150:complications / Q000378:metabolism*; D039961:Semaphorins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019012:Integrin beta1; D039961:Semaphorins; D053773:Transforming Growth Factor beta1