Urea cycle promotion via ammonia-upregulated CPS1 is involved in arsenite-induced pulmonary fibrosis through enhancing collagen synthesis

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. Arsenite exposure causes ammonia accumulation in the lung microenvironment, which elevates the levels of CPS1 in fibroblasts. CPS1 promotes the urea cycle and thus increases proline synthesis for collagen deposition in pulmonary fibrosis. [Display omitted] •Arsenite exposure causes ammonia accumulation in the lung microenvironment.•Ammonia-regulated CPS1 promotes the urea cycle, which provides proline for collagen synthesis.•Reduction of ammonia and CPS1 ablation block collagen synthesis by decreasing urea cycle.