title: Negative impact of tissue inhibitor of metalloproteinase-3 null mutation on lung structure and function in response to sepsis.
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.
authors.affiliation: Department of Physiology, Lawson Health Research Institute, H417, 268 Grosvenor St., The University of Western Ontario, London, ON, Canada, N6A 4V2. emartin3@uwo.ca
authors.forename: Erica L
authors.initials: EL
authors.lastname: Martin
authors.forename: Brent Z
authors.initials: BZ
authors.lastname: Moyer
authors.forename: M Cynthia
authors.initials: MC
authors.lastname: Pape
authors.forename: Barry
authors.initials: B
authors.lastname: Starcher
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Leco
authors.forename: Ruud A W
authors.initials: RA
authors.lastname: Veldhuizen
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D008170:Lung Compliance / Q000502:physiology; D008171:Lung Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D011663:Pulmonary Surfactants / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D005353:Fibronectins; D015850:Interleukin-6; D011663:Pulmonary Surfactants; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D004549:Elastin