Pulmonary fibrosis is one of the important causes of morbidity and mortality in fibroproliferative disorders such as systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Lysyl oxidase (LOX) is a copper-dependent amine oxidase whose primary function is the covalent crosslinking of collagens in the extracellular matrix (ECM). We investigated the role of LOX in the pathophysiology of SSc. LOX mRNA and protein levels were increased in lung fibroblasts of SSc patients compared to healthy controls and IPF patients. In vivo, bleomycin induced LOX mRNA expression in lung tissues, and LOX activity increased in the circulation of mice with pulmonary fibrosis, suggesting that circulating LOX parallels levels in lung tissues. Circulating levels of LOX were reduced upon amelioration of fibrosis with an anti-fibrotic peptide. LOX induced ECM production at the transcriptional levels in lung fibroblasts, in human lungs and human skin maintained in organ culture. In vivo, LOX synergistically exacerbated fibrosis in bleomycin-treated mice. Further, LOX increased the production of IL-6, and the increase was mediated by LOX-induced c-Fos expression, the nuclear localization of c-Fos, and its engagement with the IL-6 promoter region. Our findings demonstrate that LOX expression and activity correlated with fibrosis in vitro, ex vivo, and in vivo. LOX induced ECM production via upregulation of IL-6 and nuclear localization of c-Fos. Our findings suggest that measuring circulating LOX levels and activity can be used for monitoring response to anti-fibrotic therapy. Thus, LOX has a direct pathogenic role in SSc-associated fibrosis that is independent of its crosslinking function.

中文翻译：

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赖氨酰氧化酶直接导致系统性硬化症中的细胞外基质产生和纤维化。

肺纤维化是导致系统性硬化症 (SSc) 和特发性肺纤维化 (IPF) 等纤维增生性疾病发病率和死亡率的重要原因之一。赖氨酰氧化酶 (LOX) 是一种铜依赖性胺氧化酶，其主要功能是细胞外基质 (ECM) 中胶原蛋白的共价交联。我们研究了 LOX 在 SSc 病理生理学中的作用。与健康对照和 IPF 患者相比，SSc 患者的肺成纤维细胞中 LOX mRNA 和蛋白质水平增加。在体内，博莱霉素诱导肺组织中 LOX mRNA 表达，肺纤维化小鼠循环中 LOX 活性增加，表明循环 LOX 与肺组织中的水平平行。用抗纤维化肽改善纤维化后，LOX 的循环水平降低。LOX 在器官培养中维持的肺成纤维细胞、人肺和人皮肤中以转录水平诱导 ECM 产生。在体内，LOX 协同加剧了博莱霉素治疗小鼠的纤维化。此外，LOX 增加了 IL-6 的产生，这种增加是由 LOX 诱导的 c-Fos 表达、c-Fos 的核定位及其与 IL-6 启动子区域的结合介导的。我们的研究结果表明，LOX 表达和活性与体外、离体和体内纤维化相关。LOX 通过上调 IL-6 和 c-Fos 的核定位诱导 ECM 产生。我们的研究结果表明，测量循环 LOX 水平和活性可用于监测对抗纤维化治疗的反应。因此，