MMP/TIMP expression profiles in distinct lung disease models: implications for possible future therapies.
BACKGROUND
There is currently a vast amount of evidence in the literature suggesting that matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in the pathogenesis of inflammatory airways diseases, such as asthma and COPD. Despite this, the majority of reports only focus on single MMPs, often only in one model system. This study aimed to investigate the profile of an extensive range of MMP/TIMP levels in three different pre-clinical models of airways disease. These models each have a different and very distinct inflammatory profile, each exhibiting inflammatory characteristics that are similar to that observed in asthma or COPD. Since these models have their own characteristic pathophysiological phenotype, one would speculate that the MMP/TIMP expression profile would also be different.


METHODS
With the use of designed and purchased MMP/TIMP assays, investigation of rat MMP-2, 3, 714 and TIMP-14 mRNA expression was undertaken by Real Time PCR. The three rodent models of airways disease investigated were the endotoxin model, elastase model, and the antigen model.


RESULTS
Intriguingly, we demonstrated that despite the distinct inflammatory profile observed by each model, the MMP/TIMP expression profile is similar between the models, in that the same MMPs/TIMPs were observed to be generally increased or decreased in all three models. It could therefore be speculated that in a particular disease, it may be a complex network of MMPs, rather than an individual MMP, together with inflammatory cytokines and other mediators, that results in the distinct phenotype of inflammatory diseases, such as asthma and COPD.


CONCLUSIONS
We believe our data may provide key information necessary to understand the role of various MMPs/TIMPs in different inflammatory airway diseases, and aid the development of more selective therapeutics without the side effect profile of current broad-spectrum MMP inhibitors.
Wong
Sissie
S
Respiratory Pharmacology Group, Airways Disease Section, Imperial College London, Faculty of Medicine, National Heart and Lung Institute, 1st Floor Room 102, Sir Alexander Fleming Building, South Kensington Campus, Exhibition Road, London SW72AZ, UK. sissie.wong@imperial.ac.uk
Belvisi
Maria G
MG
Birrell
Mark A
MA
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D010196:Pancreatic Elastase / Q000633:toxicity; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D010196:Pancreatic Elastase; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2