Smad gene expression in pulmonary fibroblasts: indications for defective ECM repair in COPD.
BACKGROUND
Chronic Obstructive Pulmonary Disease (COPD) is characterized by defective extracellular matrix (ECM) turnover as a result of prolonged cigarette smoking. Fibroblasts have a central role in ECM turnover. The TGFbeta induced Smad pathway provides intracellular signals to regulate ECM production. We address the following hypothesis: fibroblasts have abnormal expression of genes in the Smad pathway in COPD, resulting in abnormal proteoglycan modulation, the ground substance of ECM.


METHODS
We compared gene expression of the Smad pathway at different time points after stimulation with TGFbeta, TNF or cigarette smoke extract (CSE) in pulmonary fibroblasts of GOLD stage II and IV COPD patients, and controls.


RESULTS
Without stimulation, all genes were similarly expressed in control and COPD fibroblasts. TGFbeta stimulation: downregulation of Smad3 and upregulation of Smad7 occurred in COPD and control fibroblasts, indicating a negative feedback loop upon TGFbeta stimulation. CSE hardly influenced gene expression of the TGFbeta-Smad pathway in control fibroblasts, whereas it reduced Smad3 and enhanced Smad7 gene expression in COPD fibroblasts. Furthermore, decorin gene expression decreased by all stimulations in COPD but not in control fibroblasts.


CONCLUSIONS
Fibroblasts of COPD patients and controls differ in their regulation of the Smad pathway, the contrast being most pronounced under CSE exposure. This aberrant responsiveness of COPD fibroblasts to CSE might result in an impaired tissue repair capability and is likely important with regard to the question why only a subset of smokers demonstrates an excess ECM destruction under influence of cigarette smoking.
Zandvoort
Andre
A
Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. a.zandvoort@med.umcg.nl
Postma
Dirkje S
DS
Jonker
Marnix R
MR
Noordhoek
Jacobien A
JA
Vos
Johannes T W M
JT
Timens
Wim
W
D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D011509:Proteoglycans / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000473:pathology*; D051785:Smad Proteins / Q000378:metabolism*
D011509:Proteoglycans; D051785:Smad Proteins