Matrix proteins from smoke-exposed fibroblasts are pro-proliferative

Am J Respir Cell Mol Biol. 2012 Jan;46(1):34-9. doi: 10.1165/rcmb.2010-0426OC.

Abstract

Airway remodeling decreases lung function in chronic obstructive pulmonary disease (COPD). Extracellular matrix (ECM) deposition is increased in remodeled airways and drives cellular processes of proliferation, migration, and inflammation. We investigated the role of cigarette smoke in altering the ECM deposited from human lung fibroblasts. Lung fibroblasts isolated from patients with COPD or other lung disease were exposed to cigarette smoke extract (CSE) and 5 ng/ml transforming growth factor-β1 for 72 hours; in some experiments, inhibitors of signaling molecules were added. Deposition of perlecan, fibronectin, and elastin were measured by ELISA, as was release of IL-8 and IL-13. Unstimulated fibroblast cells were reseeded onto deposited matrix and assessed for proliferation and cytokine release. CSE (5%) increased deposition of fibronectin and perlecan from only COPD fibroblasts. Fibronectin and perlecan deposition was attenuated by addition of the NF-κB inhibitor, BMS-345541, and the signal transduction and activator of transcription-1/3 inhibitor, pyridone 6, respectively. CSE (5%) increased IL-8 release from COPD fibroblasts more than non-COPD fibroblasts. This increase was attenuated by BMS-345541. Matrix deposited after 5% CSE stimulation increased proliferation of fibroblasts, but did not alter cytokine release. ECM produced from COPD fibroblasts after CSE exposure has proproliferative effects. Thus, the ECM in patients with COPD may create an environment that promotes airway remodeling.

MeSH terms

  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Elastin / metabolism
  • Extracellular Matrix / metabolism
  • Extracellular Matrix Proteins / metabolism*
  • Female
  • Fibrillar Collagens / metabolism
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Fibronectins / metabolism
  • Heparan Sulfate Proteoglycans / metabolism
  • Humans
  • Interleukin-13 / metabolism
  • Interleukin-8 / metabolism
  • Janus Kinases / metabolism
  • Lung / drug effects*
  • Lung / metabolism*
  • Lung / pathology
  • Male
  • Middle Aged
  • NF-kappa B / metabolism
  • STAT Transcription Factors / metabolism
  • Signal Transduction / drug effects
  • Smoke / adverse effects*
  • Tobacco / chemistry*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Extracellular Matrix Proteins
  • Fibrillar Collagens
  • Fibronectins
  • Heparan Sulfate Proteoglycans
  • Interleukin-13
  • Interleukin-8
  • NF-kappa B
  • STAT Transcription Factors
  • Smoke
  • perlecan
  • Elastin
  • Janus Kinases