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

Departments of 1 Physiology and Pharmacology and 2 Medicine, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada Submitted 10 February 2005 ; accepted in final form 24 March 2005 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 null susceptibility to compliance changes correlated with increased MMPs. In conclusion, this study provides insight into the role of TIMP-3 in response to various lung insults, specifically its importance in regulating MMPs to maintain compliance during a sepsis. tissue inhibitor of metalloproteinases; matrix metalloproteinases; compliance; cytokines; lipopolysaccharide; inflammation Address for reprint requests and other correspondence: E. L. Martin, Lawson Health Research Inst. H417, 268 Grosvenor St., London, ON, Canada, N6A 4V2 (e-mail: emartin3{at}uwo.ca )