Mechanisms of bradykinin-induced contraction in human fetal lung fibroblasts

Eur Respir J. 2010 Sep;36(3):655-64. doi: 10.1183/09031936.00112209. Epub 2010 Mar 29.

Abstract

Bradykinin (BK) induces fibroblast contraction but the structural changes and intracellular mechanisms involved have not been completely explored. We stimulated HFL-1 fibroblasts with BK to assess: 1) fibroblast contractility; 2) the role of α-smooth muscle actin (SMA) in contraction by small interfering RNA (siRNA); 3) α-SMA protein expression; 4) α-SMA and F-actin structure; 5) intracellular calcium concentration ([Ca(2+)](i)); and 6) phosphorylated myosin light-chain (pMLC) and MLC kinase (MLCK) expression. BK triggered concentration- and time-dependent fibroblast gel contraction in conjunction with α-SMA over expression, but not in α-SMA-siRNA-treated cells. BK also increased α-SMA(+) and F-actin(+) cell number and stress fibre polymerisation (detectable at 5-60 min). These BK-induced changes were associated with an increase in [Ca(2+)](i), which peaked within 15 s, and activation of pMLC, which was detectable at 5-60 min. No MLCK content modification was observed. The different manifestations of the BK-induced fibroblast activation were downregulated at different levels (25-100%) by HOE140, a specific BK B2 receptor (B2R) antagonist and by the Ca(2+) chelator, EGTA. Thus, BK-induced fibroblast contraction, associated with differentiation into α-SMA(+) myofibroblasts, is mediated through the activation of the B2R and involves the Ca(2+)/calmodulin pMLC-dependent pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Bradykinin / pharmacology*
  • Cell Differentiation
  • Collagen / chemistry
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • Lung / drug effects*
  • Lung / embryology*
  • Microscopy, Fluorescence / methods
  • Muscle, Smooth / cytology
  • Myosins / chemistry
  • Phosphorylation
  • RNA, Small Interfering / metabolism
  • Time Factors
  • Vasodilator Agents / pharmacology*

Substances

  • Actins
  • RNA, Small Interfering
  • Vasodilator Agents
  • Collagen
  • Myosins
  • Bradykinin