Chymase mediates paraquat-induced collagen production in human lung fibroblasts.

Survivors of paraquat poisoning may be left with pulmonary fibrosis and a restrictive type of pulmonary dysfunction. Chymase converts angiotensin (Ang) I to Ang II, which is closely involved with lung fibrosis. The role played by chymase in paraquat-induced lung fibrosis is unclear. We examined the effects of paraquat on chymase, renin-angiotensin system components, and collagen expression in mice and human lung fibroblasts (MRC-5). Lung chymase and collagen type I mRNA and protein expressions were significantly increased and angiotensin-converting enzyme (ACE) mRNA and protein expressions were comparable between the control and paraquat-treated mice 1 and 3 weeks after administration. Paraquat significantly upregulated angiotensinogen mRNA expression in a dose-dependent manner while ACE activity and protein expression were similar in MRC-5 cells. Furthermore, paraquat enhanced Ang II and collagen type I mRNA and protein expressions, α-smooth muscle actin, chymase protein and chymase activity and chymostatin or chymase small interfering RNA inhibited these effects. The cDNA sequence of MRC-5 cells is identical to that of human mast cells. This study found increased chymase expression in paraqaut-treated human lung fibroblasts and confirmed in vitro and in an in vivo paraquat model of lung fibrosis that chymase generates Ang II and enhances collagen expression. These data suggest a role for chymase in the pathogenesis of paraquat-induced lung fibrosis.