MAP kinase phosphatase-1 inhibition of p38α within lung myofibroblasts is essential for spontaneous fibrosis resolution.
MAP kinase phosphatase-1 inhibition of p38α within lung myofibroblasts is essential for spontaneous fibrosis resolution.
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肺肌成纤维细胞内 p38α 的 MAP 激酶磷酸酶 1 抑制对于自发性纤维化消退至关重要。
DOI：
10.1172/jci172826
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Peters-Golden,Marc
中科院分区：
文献类型：
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作者：
Fortier,SeanM;Walker,NatalieM;Penke,LokaR;Baas,JaredD;Shen,Qinxue;Speth,JenniferM;Huang,StevenK;Zemans,RachelL;Bennett,AntonM;Peters-Golden,Marc
组织损伤后的纤维化与正常修复的区别在于致病性和抗增生性肌成纤维细胞（MF）的积累，其主要通过从常驻成纤维细胞分化而产生。在实验性肺纤维化自发消退过程中促进MF去分化和清除的内源性分子制动器可能提供可以告知和改善患者进行性肺纤维化治疗的见解。MAPK磷酸酶1（MKP 1）通过精确和及时地调节各种细胞类型和组织中的MAPK活性来影响细胞表型和命运，但其在肺成纤维细胞和肺纤维化中的作用尚未被探索。通过功能获得和功能丧失研究，我们发现MKP 1促进肺MF去分化并恢复这些细胞对凋亡的敏感性-这种作用主要依赖于MKP 1对p38α MAPK（p38α）的去磷酸化。博莱霉素诱导的肺纤维化峰值后成纤维细胞特异性MKP 1缺失在很大程度上消除了其随后的自发消退。通过用p38α抑制剂VX-702处理这些转基因小鼠，恢复了这种消退。我们的结论是，MKP 1是一个关键的抗纤维化制动器，其抑制肺成纤维细胞中的致病性p38α是肺损伤后纤维化消退所必需的。
Fibrosis following tissue injury is distinguished from normal repair by the accumulation of pathogenic and apoptosis-resistant myofibroblasts (MFs), which arise primarily by differentiation from resident fibroblasts. Endogenous molecular brakes that promote MF dedifferentiation and clearance during spontaneous resolution of experimental lung fibrosis may provide insights that could inform and improve the treatment of progressive pulmonary fibrosis in patients. MAPK phosphatase 1 (MKP1) influences the cellular phenotype and fate through precise and timely regulation of MAPK activity within various cell types and tissues, yet its role in lung fibroblasts and pulmonary fibrosis has not been explored. Using gain- and loss-of-function studies, we found that MKP1 promoted lung MF dedifferentiation and restored the sensitivity of these cells to apoptosis — effects determined to be mainly dependent on MKP1’s dephosphorylation of p38α MAPK (p38α). Fibroblast-specific deletion of MKP1 following peak bleomycin-induced lung fibrosis largely abrogated its subsequent spontaneous resolution. Such resolution was restored by treating these transgenic mice with the p38α inhibitor VX-702. We conclude that MKP1 is a critical antifibrotic brake whose inhibition of pathogenic p38α in lung fibroblasts is necessary for fibrosis resolution following lung injury.