title: Chymase mediates paraquat-induced collagen production in human lung fibroblasts.
abstract: 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 murine and human lung fibroblasts (MRC-5). Lung chymase and collagen type I mRNA and protein expression were significantly increased and angiotensin-converting enzyme (ACE) mRNA and protein expression 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 expression, alpha-smooth muscle actin, and chymase protein and chymase small interfering RNA inhibited these effects. The cDNA sequence of chymase in MRC-5 cells is identical to that in human mast cells. This study found increased chymase expression in paraquat-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.
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Yaw-Dong
authors.initials: YD
authors.lastname: Lang
authors.forename: Shwu-Fen
authors.initials: SF
authors.lastname: Chang
authors.forename: Leng-Fang
authors.initials: LF
authors.lastname: Wang
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Chen
mesh_terms: D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D053818:Chymases / Q000378:metabolism*; D024042:Collagen Type I / Q000096:biosynthesis*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D008168:Lung / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010269:Paraquat / Q000633:toxicity*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D018076:DNA, Complementary; D006540:Herbicides; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; D053818:Chymases; D010269:Paraquat