Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL.
Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
J Exp Med. 2021 May 3;218(5). doi: 10.1084/jem.20202033.
Aging is a strong risk factor and an independent prognostic factor for progressive human idiopathic pulmonary fibrosis (IPF). Aged mice develop nonresolving pulmonary fibrosis following lung injury. In this study, we found that mouse double minute 4 homolog (MDM4) is highly expressed in the fibrotic lesions of human IPF and experimental pulmonary fibrosis in aged mice. We identified MDM4 as a matrix stiffness-regulated endogenous inhibitor of p53. Reducing matrix stiffness down-regulates MDM4 expression, resulting in p53 activation in primary lung myofibroblasts isolated from IPF patients. Gain of p53 function activates a gene program that sensitizes lung myofibroblasts to apoptosis and promotes the clearance of apoptotic myofibroblasts by macrophages. Destiffening of the fibrotic lung matrix by targeting nonenzymatic cross-linking or genetic ablation of Mdm4 in lung (myo)fibroblasts activates the Mdm4-p53 pathway and promotes lung fibrosis resolution in aged mice. These findings suggest that mechanosensitive MDM4 is a molecular target with promising therapeutic potential against persistent lung fibrosis associated with aging.
衰老是进行性特发性肺纤维化（IPF）的一个强烈风险因素和独立预后因素。年老的小鼠在肺损伤后会发展为不可缓解的肺纤维化。在这项研究中，我们发现鼠双微体 4 同源物（MDM4）在人特发性肺纤维化和年老小鼠的实验性肺纤维化的纤维化病变中高度表达。我们确定 MDM4 是一种基质刚度调节的 p53 内源性抑制剂。降低基质刚度会下调 MDM4 的表达，导致从 IPF 患者中分离的原代肺肌成纤维细胞中 p53 的激活。获得性 p53 功能激活了一个基因程序，使肺肌成纤维细胞对细胞凋亡敏感，并促进巨噬细胞清除凋亡的肌成纤维细胞。通过靶向非酶交联或肺（肌）成纤维细胞中 Mdm4 的基因消融来使纤维化的肺基质去 stiffness，可激活 Mdm4-p53 通路，并促进年老小鼠的肺纤维化消退。这些发现表明，机械敏感的 MDM4 是一种有前途的治疗靶点，可用于对抗与衰老相关的持续性肺纤维化。
