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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/L779    most recent 00442.2006v1 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 (2) 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.

Contribution of alveolar macrophages to the response of the TIMP-3 null lung during a septic insult

Departments of ¹Physiology and Pharmacology and ²Medicine, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada

Submitted 8 November 2006 ; accepted in final form 16 June 2007

Mice deficient in tissue inhibitor of metalloproteinase-3 (TIMP-3) develop an emphysema-like phenotype involving increased pulmonary compliance, tissue degradation, and matrix metalloproteinase (MMP) activity. After a septic insult, they develop a further increase in compliance that is thought to be a result of heightened metalloproteinase activity produced by the alveolar macrophage, potentially modeling an emphysemic exacerbation. Therefore, we hypothesized that TIMP-3 null mice lacking alveolar macrophages would not be susceptible to the altered lung function associated with a septic insult. TIMP-3 null and wild-type (WT) mice were depleted of alveolar macrophages before the induction of a septic insult and assessed for alteration in lung mechanics, alveolar structure, metalloproteinase levels, and inflammation. The results showed that TIMP-3 null mice lacking alveolar macrophages were protected from sepsis-induced alterations in lung mechanics, particularly pulmonary compliance, a finding that was supported by changes in alveolar structure. Additionally, changes in lung mechanics involved primarily peripheral tissue vs. central airways as determined using the flexiVent system. From investigation into possible molecules that could cause these alterations, it was found that although several proteases and inflammatory mediators were increased during the septic response, only MMP-7 was attenuated after macrophage depletion. In conclusion, the alveolar macrophage is essential for the TIMP-3 null sepsis-induced compliance alterations. This response may be mediated in part by MMP-7 activity but occurs independently of inflammatory cytokine and/or chemokine concentrations.

compliance; chronic obstructive pulmonary disease; metalloproteinase; inflammation

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				Y.-C. T. Huang Lung compliance measurement in mice Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L815 - L815. [Full Text] [PDF]

				E. L. Martin and R. A. W. Veldhuizen Reply to Huang Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L816 - L816. [Full Text] [PDF]