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1 Department of Physiology and Pharmacology, Lawson Health Research Institute, The University of Western Ontario, London, Ontario, Canada
2 Department of Biochemistry, University of Texas Health Center at Tyler, Tyler, Texas, USA
3 Department of Medicine, Lawson Health Research Institute, The University of Western Ontario, London, Ontario, Canada; Department of Physiology and Pharmacology, Lawson Health Research Institute, The University of Western Ontario, London, Ontario, Canada
* To whom correspondence should be addressed. E-mail: emartin3{at}uwo.ca.
Matrix metalloproteinases (MMPs) are degradative enzymes, which act to remodel tissue. Their activity is regulated by the tissue inhibitors of metalloproteinases (TIMPs). An imbalance in the degradation/inhibition activities has been associated with many diseases, including sepsis. We have previously shown that TIMP-3 knockout animals develop spontaneous, progressive airspace enlargement. The objectives of this study were to determine the effects of a septic lung stress induced by cecal ligation & perforation (CLP), on lung function, structure, pulmonary surfactant and inflammation in TIMP-3 null mice. Knockout and wild-type animals were randomized to either a sham or CLP surgery, allowed to recover for six hours and then euthanized. TIMP-3 null animals exposed to sham surgery had a significant increase in lung compliance when compared to sham wild-type mice. Additionally, the TIMP-3 knockout mice showed a significant increase in compliance following CLP. Rapid compliance changes were accompanied by significantly decreased collagen and fibronectin levels, and increased gelatinase (MMP-2 and -9) abundance and activation. Additionally, in situ zymography showed increased airway-associated gelatinase activity in the knockout animals, enhanced following CLP. In conclusion, exposing TIMP-3 null animals to sepsis rapidly enhances the phenotypic abnormalities of these mice, due to increased MMP activity induced by CLP.
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