Peng Lan, Sun Wenqing, Cheng Demin, Jia Xinying, Lian Wenxiu, Li Ziwei, Xiong Haojie, Wang Ting, Liu Yi, Ni Chunhui
Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi Center for Disease Control and Prevention, Wuxi Medical Center, Nanjing medical university, Wuxi, China.
Ecotoxicol Environ Saf. 2025 Jan 15;290:117572. doi: 10.1016/j.ecoenv.2024.117572. Epub 2024 Dec 18.
Silicosis is a disease caused by prolonged exposure to silica dust. It is the most typical, rapidly progressive, and fatal form of pneumoconiosis. Currently, there is no specific medication available for the treatment of silicosis. LOXL2 is a copper-dependent lysine oxidase whose main function is to catalyze the cross-linking of extracellular matrix components, particularly collagen and elastin. However, few researchers have investigated the role of LOXL2 in the pathogenesis of silicosis. In this study, we demonstrated that LOXL2 is upregulated in silica-inhaled mouse lung tissue and in a TGF-β-induced fibroblast model. In vitro, we confirmed that LOXL2 functions to promote ECM deposition by binding directly to collagen and elastin. We then used scavenger receptor cysteine-rich (SRCR) domains to show that LOXL2 can induce fibrosis independently of its enzymatic activity. Furthermore, we discovered that NUDT21, the LOXL2 upstream regulatory mechanism of LOXL2, alters LOXL2's 3'UTR usage by substituting alternative polyadenylation (APA), thereby modulating LOXL2 expression. By injecting LOXL2 siRNA-loaded liposomes into the tail vein of mice in the silica dust-treated mouse pulmonary fibrosis model, the severity of lung fibrosis was significantly reduced. In this context, LOXL2 is regulated by NUDT21 and may affect pulmonary fibrosis by influencing the cross-linking of ECM proteins. Our research provides a scientific basis for the development of new anti-fibrosis treatment strategies.
矽肺是一种因长期接触二氧化硅粉尘而引发的疾病。它是尘肺病最典型、进展迅速且致命的形式。目前，尚无特效药物可用于治疗矽肺。赖氨酰氧化酶2（LOXL2）是一种依赖铜的赖氨酸氧化酶，其主要功能是催化细胞外基质成分的交联，尤其是胶原蛋白和弹性蛋白。然而，很少有研究人员探究过LOXL2在矽肺发病机制中的作用。在本研究中，我们证明了LOXL2在吸入二氧化硅的小鼠肺组织以及转化生长因子-β（TGF-β）诱导的成纤维细胞模型中表达上调。在体外，我们证实LOXL2通过直接与胶原蛋白和弹性蛋白结合来促进细胞外基质（ECM）沉积。然后我们利用富含半胱氨酸的清道夫受体（SRCR）结构域表明，LOXL2可独立于其酶活性诱导纤维化。此外，我们发现LOXL2的上游调控机制——NUDT21，通过替代可变聚腺苷酸化（APA）改变LOXL2的3'非翻译区（UTR）使用情况，从而调节LOXL2的表达。通过将负载LOXL2小干扰RNA（siRNA）的脂质体注射到二氧化硅粉尘处理的小鼠肺纤维化模型小鼠的尾静脉中，肺纤维化的严重程度显著降低。在此背景下，LOXL2受NUDT21调控，并可能通过影响ECM蛋白的交联来影响肺纤维化。我们的研究为开发新的抗纤维化治疗策略提供了科学依据。
