Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of California, Davis, Davis, CA, USA; Division of Nephrology, Department of Internal Medicine, University of California, Davis, Davis, CA 95616, USA.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of California, Davis, Davis, CA, USA.
Mol Ther. 2021 Apr 7;29(4):1487-1500. doi: 10.1016/j.ymthe.2021.01.028. Epub 2021 Jan 26.
Argininosuccinate synthase 1 (ASS1) serves as a critical enzyme in arginine biosynthesis; however, its role in interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF), remains largely unknown. This study aims at characterization and targeting of ASS1 deficiency in pulmonary fibrosis. We find that ASS1 was significantly decreased and inversely correlated with fibrotic status. Transcriptional downregulation of ASS1 was noted in fibroblastic foci of primary lung fibroblasts isolated from IPF patients. Genetic manipulations of ASS1 studies confirm that ASS1 expression inhibited fibroblast cell proliferation, migration, and invasion. We further show that the hepatocyte growth factor receptor (Met) receptor was activated and acted upstream of the Src-STAT3 axis signaling in ASS1-knockdown fibroblasts. Interestingly, both arginine-free conditions and arginine deiminase treatment were demonstrated to kill fibrotic fibroblasts, attenuated bleomycin-induced pulmonary fibrosis in mice, as well as synergistically increased nintedanib efficacy. Our data suggest ASS1 deficiency as a druggable target and also provide a unique therapeutic strategy against pulmonary fibrosis.
精氨酸琥珀酸合成酶 1（ASS1）是精氨酸生物合成中的关键酶；然而，其在间质性肺疾病，特别是特发性肺纤维化（IPF）中的作用在很大程度上仍然未知。本研究旨在对肺纤维化中 ASS1 缺乏进行特征描述和靶向治疗。我们发现 ASS1 显著减少，并且与纤维化状态呈负相关。从 IPF 患者分离的原代肺成纤维细胞的成纤维细胞灶中观察到 ASS1 的转录下调。ASS1 表达的遗传操作研究证实，ASS1 表达抑制成纤维细胞的增殖、迁移和侵袭。我们进一步表明，在 ASS1 敲低的成纤维细胞中，肝细胞生长因子受体（Met）受体被激活，并作用于 Src-STAT3 轴信号的上游。有趣的是，无精氨酸条件和精氨酸脱氨酶处理均被证明可杀死纤维性成纤维细胞，减轻博来霉素诱导的小鼠肺纤维化，并协同增加尼达尼布的疗效。我们的数据表明 ASS1 缺乏是一个可治疗的靶点，并为治疗肺纤维化提供了一种独特的治疗策略。
