Differential response of TIMP-3 null mice to the lung insults of sepsis, mechanical ventilation, and hyperoxia

作者：Erica L. Martin, Lynda McCaig, Brent Z. Moyer, M. Cynthia Pape, Kevin J. Leco, James F. Lewis, Ruud A. W. Veldhuizen · 发表于：American Journal of Physiology-Lung Cellular and Molecular Physiology · 年份：2005 · DOI：10.1152/ajplung.00070.2005 · 被引用次数：23 · 研究领域：Protease and Inhibitor Mechanisms、Blood Coagulation and Thrombosis Mechanisms、Neonatal and Maternal Infections

An imbalance in matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) leads to excessive or insufficient tissue breakdown, which is associated with many disease processes. The TIMP-3 null mouse is a model of MMP/TIMP imbalance, which develops air space enlargement and decreased lung function. These mice responded differently to cecal ligation and perforation (CLP)-induced septic lung injury than wild-type controls. The current study addresses whether the TIMP-3 knockout lung is susceptible to different types of insults or only those involving sepsis, by examining its response to lipopolysaccharide (LPS)-induced sepsis, mechanical ventilation (MV), and hyperoxia. TIMP-3 null noninjured controls of each insult consistently demonstrated significantly higher compliance vs. wild-type mice. Null mice treated with LPS had a further significantly increased compliance compared with untreated controls. Conversely, MV and hyperoxia did not alter compliance in the null lung. MMP abundance and activity increased in response to LPS but were generally unaltered following MV or hyperoxia, correlating with compliance alterations. All three insults produced inflammatory cytokines; however, the response of the null vs. wild-type lung was dependent on the type of insult. Overall, this study demonstrated that 1) LPS-induced sepsis produced a similar response in null mice to CLP-induced sepsis, 2) the null lung responded differently to various insults, and 3) the...