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Am J Physiol Lung Cell Mol Physiol. 2003 Dec;285(6):L1222-32. Epub 2003 Aug 8.

Negative impact of tissue inhibitor of metalloproteinase-3 null mutation on lung structure and function in response to sepsis.

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  • 1Department of Physiology, Lawson Health Research Institute, H417, 268 Grosvenor St., The University of Western Ontario, London, ON, Canada, N6A 4V2. emartin3@uwo.ca

Abstract

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 air space enlargement. The objectives of this study were to determine the effects of a septic lung stress induced by cecal ligation and perforation (CLP) on lung function, structure, pulmonary surfactant, and inflammation in TIMP-3 null mice. Knockout and wild-type animals were randomized to either sham or CLP surgery, allowed to recover for 6 h, and then euthanized. TIMP-3 null animals exposed to sham surgery had a significant increase in lung compliance when compared with 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.

PMID:
12909586
DOI:
10.1152/ajplung.00141.2003
[PubMed - indexed for MEDLINE]
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