Mice deficient in tissue inhibitor of metalloproteinase-3 (TIMP3) develop an emphysema-like phenotype involving increased pulmonary compliance, tissue degradation, and matrix metalloproteinase activity. Following a septic insult, they develop a further increase in compliance thought to be a result of heightened metalloproteinase activity produced by the alveolar macrophage; potentially modeling an emphysemic exacerbation. Therefore, we hypothesized that TIMP3 null mice lacking alveolar macrophages would not be susceptible to the altered lung function associated with a septic insult. TIMP3 null and wild-type mice were depleted of alveolar macrophages prior to the induction of a septic insult and assessed for alteration in lung mechanics, alveolar structure, metalloproteinase levels, and inflammation. The results showed that TIMP3 null mice lacking alveolar macrophages were protected from septic-induced alterations in lung mechanics, particularly pulmonary compliance, which was supported by changes in alveolar structure. Additionally, changes in lung mechanics involved primarily peripheral tissue versus central airways as determined using the flexiVentTM system. Investigation into possible molecules which could cause these alterations found that although several proteases and inflammatory mediators were increased during the septic response, only matrix metalloproteinase-7 was attenuated following macrophage depletion. In conclusion, the alveolar macrophage is essential for the TIMP3 null septic-induced compliance alterations. This response may be mediated in part by matrix metalloproteinase-7 activity, but occurs independently of inflammatory cytokine and/or chemokine concentrations.