Carbon monoxide inhibits human airway smooth muscle cell proliferation via mitogen-activated protein kinase pathway. Academic Article uri icon

Overview

MeSH

  • Cell Cycle
  • Cell Division
  • Cells, Cultured
  • Cyclic GMP
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Activation
  • Enzyme Inhibitors
  • Guanylate Cyclase
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases

MeSH Major

  • Bronchi
  • Carbon Monoxide
  • MAP Kinase Signaling System
  • Muscle, Smooth

abstract

  • The gaseous molecule carbon monoxide (CO) is elevated in the breath of individuals with asthma. The physiologic function of CO in asthma is poorly understood. Here we demonstrate that CO (250 ppm) markedly inhibits human airway smooth muscle cell (HASMC) proliferation, arresting cells at the G0/G1 phase. This CO-induced cell growth arrest of HASMC was associated with upregulation of p21 and downregulation of cyclin D1 expression. It is generally believed that the signaling pathway by which CO affects biologic processes is primarily mediated via the guanylyl cyclase/3',5'-Guanylate cyclic monophosphate (cGMP) pathway. To examine whether guanylyl cyclase/cGMP was involved in CO-induced growth arrest of HASMC, Rp-8-Br-cGMP, a selective inhibitor of cGMP-dependent protein kinase and ODQ, a selective inhibitor of soluble guanylate cyclase, were administered to HASMC in the presence of CO. Interestingly, CO-induced cell growth arrest was not reversed by these inhibitors. We next examined whether the extracellular signal-regulated kinase (ERK) 1/ERK2 mitogen-activated protein kinase (MAPK) signaling pathway may regulate the antiproliferative effect of CO. We first showed time-dependent activation of the various MAPKs in HASMC in response to serum, including phosphorylated ERK1/ERK2, p38, and JNK and then demonstrated that CO exerted negligible effect on activated p38 and JNK; however, ERK activation was significantly attenuated in the presence of CO. These data suggest that CO can inhibit HASMC proliferation via the ERK1/ERK2 MAPK pathway, independent of a guanylyl cyclase/cGMP independent pathway. CO may act as an important mediator of remodeling of human airways in asthma via its ability to regulate cell growth of airway smooth muscle cells.

publication date

  • November 2002

has subject area

  • Bronchi
  • Carbon Monoxide
  • Cell Cycle
  • Cell Division
  • Cells, Cultured
  • Cyclic GMP
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Activation
  • Enzyme Inhibitors
  • Guanylate Cyclase
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Muscle, Smooth

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1165/rcmb.4851

PubMed ID

  • 12397020

Additional Document Info

start page

  • 603

end page

  • 610

volume

  • 27

number

  • 5