A comparative study of matrix remodeling in chronic models for COPD; mechanistic insights into the role of TNF-α

Remodeling in COPD has at least two dimensions: small airway wall thickening and destruction of alveolar walls. The aim of this study was to characterize and assess similarities in alveolar and small airway wall matrix remodeling in chronic COPD models. From this comparative characterization of matrix remodeling we derived and elaborated underlying mechanisms to the matrix changes reported in COPD. Lung tissue sections of chronic models for COPD, either induced by exposure to cigarette smoke, chronic intratracheal LPS instillation or local TNF expression (SPC-TNFalpha mice), were stained for elastin, collagen and hyaluronan. Furthermore TNFalpha, MMP2, 9 and 12 mRNA expression was analyzed using qPCR and localized using immunohistochemistry. Both collagen and hyaluronan were increased in alveolar and small airway walls of all three models. Interestingly, elastin contents were differentially affected, with a decrease in both alveolar and airway walls in SPC-TNFalpha mice. Furthermore TNFalpha, and MMP2 and 9 mRNA and protein levels were found to be increased in alveolar walls and around airway walls only in SPC-TNFalpha mice. We show that only SPC-TNFalpha mice show changes in elastin remodeling which are comparable to what has been observed in COPD patients. This reveals that the SPC-TNFalpha model is a suitable model to study processes underlying matrix remodeling and in particular elastin breakdown as seen in COPD. Furthermore we indicate a possible role for MMP2 and MMP9 in the breakdown of elastin in airways and alveoli of SPC-TNFalpha mice