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. CONCLUSION: 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.
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. CONCLUSION: 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.
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