Role of matrix metalloproteinases in the inflammatory response in human airway cell-based assays and in rodent models of airway disease.
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 are 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 preclinical rat models of airway inflammation. Therefore, the aim of this study was to characterize the role of MMPs in these models by profiling the impact of a broad-spectrum MMP inhibitor. In lipopolysaccharide (LPS)-stimulated THP-1 cells and primary human lung tissue macrophages, the MMP inhibitor had no significant effect on the release of tumor necrosis factor-alpha, interleukin (IL)-8, IL-1 beta, growth-regulated oncogene-alpha, macrophage inflammatory protein-1 alpha, or IL-6 whereas dexamethasone has a significant impact 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 have an 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, these data demonstrate for the first time that MMPs do not play a role in the increase in inflammatory mediators or cellular burden observed in these preclinical 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.
Birrell
Mark A
MA
Respiratory Pharmacology Section, Airway Disease Department, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
Wong
Sissie
S
Dekkak
Abdel
A
De Alba
Jorge
J
Haj-Yahia
Saleem
S
Belvisi
Maria G
MG
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008070:Lipopolysaccharides; D008168:Lung / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000502:physiology*; D010179:Pancreas / Q000201:enzymology; D010196:Pancreatic Elastase; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012140:Respiratory Tract Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D013552:Swine
D015415:Biomarkers; D016207:Cytokines; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D010196:Pancreatic Elastase; D020782:Matrix Metalloproteinases