Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado.
Department of Medicine, National Jewish Health, Denver, Colorado.
Am J Physiol Lung Cell Mol Physiol. 2022 Jul 1;323(1):L69-L83. doi: 10.1152/ajplung.00436.2021. Epub 2022 Jun 7.
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-α (PTPα) promotes pulmonary fibrosis in preclinical murine models through regulation of transforming growth factor-β (TGF-β) signaling. In this study, we examine the role of PTPα 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 PTPα () 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 mice, and stimulation of naïve 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 PTPα. Importantly, human lung fibroblasts modified with a CRISPR-targeted deletion of exhibit reduced expression of profibrotic genes in response to TGF-β stimulation, demonstrating the importance of PTPα in human lung fibroblasts. Together, these findings demonstrate that PTPα 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.
急性呼吸窘迫综合征（ARDS）是一个主要的医疗保健问题，其死亡率和长期残疾率都很高。大约 25%的 ARDS 患者会出现过度活跃的纤维化反应，称为纤维增生性 ARDS（FP-ARDS），这预示着预后不良和死亡率增加。导致 FP-ARDS 的细胞病理过程仍不完全清楚。我们之前已经表明，跨膜受体型酪氨酸磷酸酶蛋白酪氨酸磷酸酶-α（PTPα）通过调节转化生长因子-β（TGF-β）信号通路，在临床前的小鼠模型中促进肺纤维化。在这项研究中，我们在酸（HCl）诱导的急性肺损伤的临床前小鼠模型中研究了 PTPα 在 FP-ARDS 发病机制中的作用。我们证明，尽管缺乏 PTPα 的基因敲除小鼠 () 易受早期 HCl 诱导的肺损伤影响，但它们表现出明显减弱的纤维增生反应。此外，在 小鼠急性肺损伤后肺组织中的早期致纤维化基因表达减少，并且与野生型同窝对照相比，用来自这些小鼠的 BAL 液刺激幼稚肺成纤维细胞会导致纤维化结果减弱。转录组分析表明，缺乏 PTPα 的小鼠的细胞外基质（ECM）沉积和重塑减少。重要的是，用 CRISPR 靶向缺失修饰的人肺成纤维细胞在 TGF-β刺激下表现出致纤维化基因表达减少，证明了 PTPα 在人肺成纤维细胞中的重要性。总之，这些发现表明 PTPα 是急性肺损伤后纤维增生过程的关键调节剂，可作为 ARDS 患者长期预后不良风险的治疗靶点。
