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Negative impact of tissue inhibitor of metalloproteinase-3 null mutation on lung structure and function in response
Erica L Martin1, Brent Z Moyer, M Cynthia Pape
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.
Insights
Mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3) showed worsened lung function and increased matrix metalloproteinase (MMP) activity when exposed to sepsis. This suggests TIMP-3 is crucial for maintaining lung health during infection.
Area of Science:
- Biochemistry
- Pulmonary Medicine
- Pathology
Background:
- Matrix metalloproteinases (MMPs) remodel tissues, with their activity regulated by tissue inhibitors of metalloproteinases (TIMPs).
- An imbalance between MMP degradation and TIMP inhibition is linked to diseases like sepsis.
- TIMP-3 knockout animals exhibit spontaneous air space enlargement, indicating a role for TIMP-3 in lung integrity.
Purpose of the Study:
- To investigate the impact of sepsis, induced by cecal ligation and perforation (CLP), on lung function, structure, pulmonary surfactant, and inflammation in TIMP-3 null mice.
- To elucidate the role of TIMP-3 in the lung's response to septic stress.
Main Methods:
- Wild-type and TIMP-3 knockout mice underwent either sham or CLP surgery.
- Animals were euthanized 6 hours post-surgery for analysis.
- Lung function (compliance), collagen and fibronectin levels, and gelatinase (MMP-2 and -9) activity were assessed.
- In situ zymography was used to evaluate airway-associated gelatinase activity.
Main Results:
- TIMP-3 null mice exhibited increased lung compliance even without sepsis (sham surgery) compared to wild-type controls.
- Septic stress (CLP) further increased lung compliance in TIMP-3 knockout mice.
- These functional changes correlated with decreased collagen and fibronectin, and increased MMP-2 and MMP-9 activity and activation.
- Enhanced gelatinase activity was observed in the airways of TIMP-3 knockout mice, particularly after CLP.
Conclusions:
- Sepsis rapidly exacerbates pre-existing lung abnormalities in TIMP-3 deficient mice.
- Increased matrix metalloproteinase activity, triggered by the septic insult, is the underlying mechanism driving these enhanced abnormalities.
