| Protective Role of Matrix Metalloproteinase-9 in Ozone-Induced Airway Inflammation Hyoung-Kyu Yoon,1,2 Hye-Youn Cho,1 and Steven R. Kleeberger1 1Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; 2Division of Pulmonary and Critical Care, Department of Internal Medicine, College of Medicine, Catholic University of Korea, Seoul, Korea Abstract
Background: Exposure to ozone causes airway inflammation, hyperreactivity, lung hyperpermeability, and epithelial cell injury. An early inflammatory response induced by inhaled O3 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 O3-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 O3 or filtered air. Results: Relative to air-exposed controls, MMP-9 activity in bronchoalveolar lavage fluid (BALF) was significantly increased by O3 exposure in Mmp9+/+ mice. O3-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 O3 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 O3 exposure. Conclusions: Results demonstrated a protective role of MMP-9 but not of MMP-7, in O3-induced lung neutrophilic inflammation and hyperpermeability. The mechanism through which Mmp9 limits O3-induced airway injury is not known but may be via posttranscriptional effects on proinflammatory CXC chemokines including KC and MIP-2. Key words: chemokine, knockout mice, lung, MMP-9, O3, oxidant. Environ Health Perspect 115:1557–1563 (2007) . doi:10.1289/ehp.10289 available via http://dx.doi.org/ [Online 24 August 2007]
Address correspondence to S.R. Kleeberger, Laboratory of Respiratory Biology, NIEHS, National Institutes of Health, 111 T.W. Alexander Dr., Bldg. 101, MD D-201, Research Triangle Park, NC 27709 USA. Telephone: (919) 541-3540. Fax: (919) 541-4133. E-mail: kleeber1@niehs. nih.gov The authors thank D. Morgan and H. Price for coordinating the inhalation exposures. D. Brass and D. Cook at the NIEHS provided excellent critical review of the manuscript. This research was supported by the Intramural Research Program of the NIH, and NIEHS. Ozone exposures were conducted at the NIEHS Inhalation Facility under contract to Alion Science and Technology, Inc. The authors declare they have no competing financial interests. Received 21 March 2007 ; accepted 24 August 2007.
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