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This Article Full Text Full Text (PDF) All Versions of this Article: 285/6/L1222    most recent 00141.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Martin, E. L. Articles by Veldhuizen, R. A. W. Search for Related Content PubMed PubMed Citation Articles by Martin, E. L. Articles by Veldhuizen, R. A. W.

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

Departments of ¹Physiology and Pharmacology and ²Medicine, Lawson Health Research Institute, The University of Western Ontario, London, Ontario, Canada N6A 5C1; and ³Department of Biochemistry, University of Texas Health Center at Tyler, Tyler, Texas 75708-3154

Submitted 7 May 2003 ; accepted in final form 30 July 2003

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.

compliance; collagen; fibronectin; surfactant; cecal ligation and perforation

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