Received for publication April 5, 2006.
Revised May 10, 2006.
Accepted for publication May 10, 2006.

Role of matrix metalloproteinases in the inflammatory response in human airway cell based assays and in rodent models of airway disease

Abstract

Since the discovery of the first matrix metalloproteinase (MMP), this ever growing family of proteinases has been the subject of intense research. Although it was initially believed that MMPs were solely involved in matrix turnover and degradation, there is now data suggesting MMPs are actively involved in the inflammatory process. In previous studies, we have demonstrated an increase in MMP expression in human cell based assays and in pre-clinical rat models of airway inflammation. Therefore, the aim of this study was to characterise the role of MMPs in these models by profiling the impact of a broad spectrum MMP inhibitor. In LPS stimulated THP-1 cells and primary human lung tissue macrophages, the MMP inhibitor had no significant effect on the release of TNF, IL-8, IL-1, GRO, MIP-1 or IL-6 whereas dexamethasone significantly impacted on all cytokines from both cell types. Similarly, in the more biologically complex LPS-driven rat model of airway inflammation the MMP inhibitor did not impact on mediator release and cellular burden. The compound did, however, significantly reduce levels of lung MMP-9. Furthermore, in a "disease" model the compound did not affect cellular inflammation but did significantly reduce elastase-induced experimental emphysema. In summary, this data demonstrates for the first time that MMPs do not play a role in the increase in inflammatory mediators or cellular burden observed in these pre-clinical models. However, they do appear to be involved in the elastase driven breakdown of airway structure, which is not due to a direct effect of the stimulus.

Key words: Cytokines, Emphysema, Inflammation, Lung, Neutrophil, Rat

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