| First Author | Aschner Y | Year | 2022 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 323 |
| Issue | 1 | Pages | L69-L83 |
| PubMed ID | 35670474 | Mgi Jnum | J:330035 |
| Mgi Id | MGI:7355174 | Doi | 10.1152/ajplung.00436.2021 |
| Citation | Aschner Y, et al. (2022) PTPalpha promotes fibroproliferative responses after acute lung injury. Am J Physiol Lung Cell Mol Physiol 323(1):L69-L83 |
| abstractText | The acute respiratory distress syndrome (ARDS) is a major healthcare problem, accounting for significant mortality and long-term disability. Approximately 25% of patients with ARDS will develop an overexuberant fibrotic response, termed fibroproliferative ARDS (FP-ARDS) that portends a poor prognosis and increased mortality. The cellular pathological processes that drive FP-ARDS remain incompletely understood. We have previously shown that the transmembrane receptor-type tyrosine phosphatase protein tyrosine phosphatase-alpha (PTPalpha) promotes pulmonary fibrosis in preclinical murine models through regulation of transforming growth factor-beta (TGF-beta) signaling. In this study, we examine the role of PTPalpha in the pathogenesis of FP-ARDS in a preclinical murine model of acid (HCl)-induced acute lung injury. We demonstrate that although mice genetically deficient in PTPalpha (Ptpra(-/-)) are susceptible to early HCl-induced lung injury, they exhibit markedly attenuated fibroproliferative responses. In addition, early profibrotic gene expression is reduced in lung tissue after acute lung injury in Ptpra(-/-) mice, and stimulation of naive lung fibroblasts with the BAL fluid from these mice results in attenuated fibrotic outcomes compared with wild-type littermate controls. Transcriptomic analyses demonstrate reduced extracellular matrix (ECM) deposition and remodeling in mice genetically deficient in PTPalpha. Importantly, human lung fibroblasts modified with a CRISPR-targeted deletion of PTPRA exhibit reduced expression of profibrotic genes in response to TGF-beta stimulation, demonstrating the importance of PTPalpha in human lung fibroblasts. Together, these findings demonstrate that PTPalpha is a key regulator of fibroproliferative processes following acute lung injury and could serve as a therapeutic target for patients at risk for poor long-term outcomes in ARDS. |
