Abstract：
Arsenic exposure is connected with lung toxicity and is related to lung fibrotic changes. Idiopathic pulmonary fibrosis (IPF) is characterized by extracellular matrix (ECM) deposition. Various genetic mechanisms and environmental factors induce or exacerbate pulmonary fibrosis. Collagen synthesis induced by sodium arsenite (NaAsO2) is closely associated with IPF. Fibroblasts tend to fine-tune their metabolic networks to support their synthetic requirements in response to environmental stimuli. Alterations in metabolism have an influential role in the pathogenesis of IPF. However, it is unclear how arsenic affects the metabolism in IPF. The urea cycle (UC) is needed for collagen formation, which provides adequate levels of proline (Pro) for biosynthesis of collagen. Carbamoyl phosphate synthetase 1 (CPS1) converts the ammonia to carbamoyl phosphate, which controls the first reaction of the UC. We show that, in arsenite-exposed mice, high amounts of ammonia in the lung microenvironment promotes the expression levels of CPS1 and the Pro metabolism. Reduction of ammonia and CPS1 ablation inhibit collagen synthesis and ameliorate IPF phenotypes induced by arsenite. This work takes advantage of multi-omics data to enhance understanding of the underlying pathogenic mechanisms, the key molecules and the complicated cellular responses to this pollutant, which provide a target for the prevention of pulmonary fibrosis caused by arsenic.
摘要：
砷暴露与肺毒性有关，并与肺纤维化变化有关。特发性肺纤维化（IPF）的特征是细胞外基质（ECM）沉积。各种遗传机制和环境因素诱发或加剧肺纤维化。亚砷酸盐（NaAsO2）诱导的胶原蛋白合成与IPF密切相关。成纤维细胞倾向于微调其代谢网络，以支持其对环境刺激的合成要求。代谢的改变在IPF的发病机制中具有影响作用。然而,目前尚不清楚砷如何影响IPF的代谢。尿素循环（UC）是胶原蛋白形成所需要的，它为胶原蛋白的生物合成提供了足够水平的脯氨酸（Pro）。氨基甲酰磷酸合成酶1（CPS1）将氨转化为氨基甲酰磷酸，控制UC的第一反应。我们证明,在暴露于亚砷酸盐的小鼠中，肺微环境中大量的氨促进CPS1的表达水平和Pro代谢。氨的减少和CPS1消融抑制胶原合成并改善亚砷酸盐诱导的IPF表型。这项工作利用了多组学数据来增强对潜在致病机制的理解，关键分子和细胞对这种污染物的复杂反应，为预防砷引起的肺纤维化提供了靶点。
