Protective Role of Matrix Metalloproteinase-9 in Ozone-Induced Airway Inflammation

BACKGROUND: Exposure to ozone causes airway inflammation, hyperreactivity, lung hyper-permeability, and epithelial cell injury. An early inflammatory response induced by inhaled O(3) is characterized primarily by release of inflammatory mediators such as cytokines, chemokines, and airway neutrophil accumulation. Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of oxidative lung disorders including acute lung injury, asthma, and chronic obstructive pulmonary disease. OBJECTIVE: We hypothesized that MMPs have an important role in the pathogenesis of O(3)-induced airway inflammation. METHODS: We compared the lung injury responses in either Mmp7- (Mmp7(−/−)) or Mmp9-deficient (Mmp9(−/−)) mice and their wild-type controls (Mmp7(+/+), Mmp9(+/+)) after exposure to 0.3 ppm O(3) or filtered air. RESULTS: Relative to air-exposed controls, MMP-9 activity in bronchoalveolar lavage fluid (BALF) was significantly increased by O(3) exposure in Mmp9(+/+) mice. O(3)-induced increases in the concentration of total protein (a marker of lung permeability) and the numbers of neutrophils and epithelial cells in BALF were significantly greater in Mmp9(−/−) mice compared with Mmp9(+/+) mice. Keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2 levels in BALF were also significantly higher in Mmp9(−/−) mice than in Mmp9(+/+) mice after O(3) exposure, although no differences in mRNA expression for these chemokines were found between genotypes. Mean BALF protein concentration and numbers of inflammatory cells were not significantly different between Mmp7(+/+) and Mmp7(−/−) mice after O(3) exposure. CONCLUSIONS: Results demonstrated a protective role of MMP-9 but not of MMP-7, in O(3)-induced lung neutrophilic inflammation and hyperpermeability. The mechanism through which Mmp9 limits O(3)-induced airway injury is not known but may be via posttranscriptional effects on proinflammatory CXC chemokines including KC and MIP-2.