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Small airway remodeling in mice : analysis of growth factor gene expression following exposure to cigarette smoke Coulthard, Tonya

Abstract

Chronic obstructive pulmonary disease (COPD) results in progressive airflow obstruction, characterized by shortness of breath and chronic cough, and is most commonly caused by exposure to cigarette smoke. Small airway remodelling (SAR) is a key pathological event in COPD affecting mainly the respiratory and membranous bronchioles, resulting in irregularly shaped lumens as well as thickened airway walls. Analyses of human and animal samples has shown that smoke exposure causes increased fibrosis, a feature of SAR; additional experiments have shown upregulation of many growth factors in various pulmonary fibrosis diseases and models. Further research into the pathogenesis of COPD is necessary as current treatments have not been overwhelmingly successful; a better understanding of the pathological processes involved in the development of SAR could lead to new and innovative therapies. This project examined the fibrotic response induced by cigarette smoke in the small airways of mice; laser capture microdisection was used to selectively dissect the airways from the remainder of the lung tissue. Real-time PCR was used to determine the gene expression levels of procollagen and the growth factors TGFβ, CTGF, PDGF-A, and PDGF-B, which have been previously implicated in a number of fibrotic diseases. Following a single smoke exposure a peak in all gene expression levels occurred at 2 hours, which resolved by 6 hours for all growth factors. Procollagen expression levels declined much slower, and at 24 hours the apparent increase in expression was no longer statistically significant due to variability. Repeated smoke exposures resulted in a significant increase in procollagen and all growth factors at 1 week, 1 month, and 6 months, with the exception of TGFβl at 6 months, and PDGF-A at 1 month. These data indicate that chronic exposure of C57B1/6 mice to cigarette smoke does induce a sustained fibrotic response as indicated by the procollagen data, and that several growth factors are important in this response.

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