Protein Tyrosine Phosphatase-Alpha (ptpa) Promotes Profibrotic Responses In Lung Fibroblasts

Pulmonary fibrosis encompases a group progressive, often fatal lung diseases including Idiopathic Pulmonary Fibrosis (IPF) for which treatment is suboptimal. Several cytokines, including TGF-β, are critical to the pathogenesis of pulmonary fibrosis. We have reported that mice genetically deficient in PTPα (Ptpra-/-) were protected from pulmonary fibrosis in experimental models. Herein, we sought to determine the mechanisms by which PTPα drives pulmonary fibrosis. To achieve cell-type specific deletion of Ptpra in fibroblasts or alveolar type (AT)II cells, we crossed mice harboring a floxed Ptpra allele (Ptpraf/f) with mice expressing Cre recombinase in fibroblasts (Dermo1-Cre) or in ATII cells (Sftpc-Cre.ERT2). Mice genetically deficient in Ptpra in fibroblasts (Dermo1-Cre/Ptpraf/f) were protected from bleomycin-induced pulmonary fibrosis as determined by physiological (Cstat), histological, and biochemical assays. In contrast, bleomycin-induced pulmonary fibrosis was equivalent in mice genetically deficient in Ptpra in ATII cells (Sftpc-Cre.ERT2/Ptpraf/f) compared to WT controls. In human IPF lungs, PTPα was expressed in mesenchymal cells in fibroblastic foci as determined by immunohistochemistry. In isolated lung fibroblasts, TGF-β-induced phosphorylation of Smad 2/3 was attenuated in Ptpra-/- compared to WT fibroblasts. By contrast, no differences in PDGF-induced phosphorylation of AKT were observed in WT compared to Ptpra-/- fibroblasts. We conclude that PTPα promotes TGF-β-induced pro-fibrotic signaling in fibroblasts.