Chymase mediates paraquat-induced collagen production in human lung fibroblasts

Toxicol Lett. 2010 Mar 1;193(1):19-25. doi: 10.1016/j.toxlet.2009.12.001. Epub 2009 Dec 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Angiotensin II / metabolism
  • Animals
  • Blotting, Western
  • Cell Line
  • Chymases / metabolism*
  • Collagen Type I / biosynthesis*
  • DNA, Complementary / biosynthesis
  • DNA, Complementary / genetics
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Herbicides / toxicity*
  • Humans
  • Lung / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Paraquat / toxicity*
  • Peptidyl-Dipeptidase A / metabolism
  • RNA, Small Interfering / genetics
  • Renin-Angiotensin System / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Actins
  • Collagen Type I
  • DNA, Complementary
  • Herbicides
  • RNA, Small Interfering
  • Transforming Growth Factor beta1
  • alpha-smooth muscle actin, mouse
  • Angiotensin II
  • Peptidyl-Dipeptidase A
  • Chymases
  • Paraquat