Protein tyrosine phosphatase-N13 promotes myofibroblast resistance to apoptosis in idiopathic pulmonary fibrosis
A Bamberg, EF Redente, SD Groshong… - American journal of …, 2018 - atsjournals.org
A Bamberg, EF Redente, SD Groshong, RM Tuder, CD Cool, RC Keith, BL Edelman…
American journal of respiratory and critical care medicine, 2018•atsjournals.orgRationale: Idiopathic 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. Objectives: To 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 …
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. Objectives: To 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 …
Rationale: Idiopathic 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.
Objectives: To 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.
Methods: PTPN13 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 Results: PTPN13 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.
Conclusions: These 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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