• Alison Bamberg, Elizabeth F Redente, Steve D Groshong, Rubin M Tuder, Carlyne D Cool, Rebecca C Keith, Benjamin L Edelman, Bart P Black, Gregory P Cosgrove, Murry W Wynes, Douglas Curran-Everett, Stijn De Langhe, Luis A Ortiz, Andrew Thorburn, and RichesDavid W HDWH1 Program in Cell Biology, Department of Pediatrics.2 Department of Immunology and Microbiology.3 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, and.9 Department of Pharmacology, University of Colorado.
• 1 Program in Cell Biology, Department of Pediatrics.
• Am. J. Respir. Crit. Care Med. 2018 Oct 1; 198 (7): 914927914-927.

RationaleIdiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic interstitial lung disease characterized by (myo)fibroblast accumulation and collagen deposition. Resistance to Fas-induced apoptosis is thought to facilitate (myo)fibroblast persistence in fibrotic lung tissues by poorly understood mechanisms.ObjectivesTo test the hypothesis that PTPN13 (protein tyrosine phosphatase-N13) is expressed by IPF lung (myo)fibroblasts, promotes their resistance to Fas-induced apoptosis, and contributes to the development of pulmonary fibrosis.MethodsPTPN13 was localized in lung tissues from patients with IPF and control subjects by immunohistochemical staining. Inhibition of PTPN13 function in primary IPF and normal lung (myo)fibroblasts was accomplished by: 1) downregulation with TNF-α (tumor necrosis factor-α)/IFN-γ, 2) siRNA knockdown, or 3) a cell-permeable Fas/PTPN13 interaction inhibitory peptide. The role of PTPN13 in the development of pulmonary fibrosis was assessed in mice with genetic deficiency of PTP-BL, the murine ortholog of PTPN13.Measurements And Main ResultsPTPN13 was constitutively expressed by (myo)fibroblasts in the fibroblastic foci of patients with IPF. Human lung (myo)fibroblasts, which are resistant to Fas-induced apoptosis, basally expressed PTPN13 in vitro. TNF-α/IFN-γ or siRNA-mediated PTPN13 downregulation and peptide-mediated inhibition of the Fas/PTPN13 interaction in human lung (myo)fibroblasts promoted Fas-induced apoptosis. Bleomycin-challenged PTP-BL-/- mice, while developing inflammatory lung injury, exhibited reduced pulmonary fibrosis compared with wild-type mice.ConclusionsThese findings suggest that PTPN13 mediates the resistance of human lung (myo)fibroblasts to Fas-induced apoptosis and promotes pulmonary fibrosis in mice. Our results suggest that strategies aimed at interfering with PTPN13 expression or function may represent a novel strategy to reduce fibrosis in IPF.

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