Effect of World Trade Center Dust Exposure and Chronic Intermittent Hypoxia on Macrophage Matrix Metalloproteinase-12 Expression in Mice

Abstract

RATIONALE: The pathophysiologic mechanisms by which World Trade Center (WTC) dust exposure leads to pulmonary disease have not been established. Matrix metalloproteinase-12 (MMP-12) is involved in the development of pulmonary fibrosis and chronic obstructive pulmonary disease. We have previously shown that exposure of mice to WTC dust results in increased expression of matrix metalloproteinase 12 by alveolar macrophages. Matrix metalloproteinase 12 expression is regulated, in part, by oxidative stress, which is also increased after WTC dust exposure. A significant percentage of WTC dust-exposed individuals have concomitant obstructive sleep apnea, which is an added source of oxidative stress, through chronic intermittent hypoxia (CIH). OBJECTIVES: To determine if combined exposures of mice to WTC dust and CIH exacerbated matrix metalloproteinase 12 expression in alveolar macrophages. METHODS: Male Balbc/J mice (12-24 wk) were treated intratracheally with phosphate-buffered saline (PBS) or WTC dust suspended in PBS, followed by CIH (cycles of 21 to 5% fraction of inspired oxygen, 2-min cycles) (CIH groups) or chronic intermittent air (CIA; cycles of 21 to 19% fraction of inspired oxygen, 2-min cycles) (CIA groups) 12 hours per day for 28 days. Histologic sections were then examined for macrophage expression of matrix metalloproteinase 12 by immunohistochemistry. RESULTS: The mean number of positively stained alveolar macrophages from five fields per lobe was quantified. Mice exposed to WTC dust or CIH displayed increased macrophage expression of matrix metalloproteinase 12 compared with the control group. Exposure to WTC dust plus CIH was additive in effect (mean ± SD, PBS/CIA: 20.8 ± 5.2; PBS/CIH: 43.3 ± 19.8; WTC/CIA: 43.3 ± 12.5; WTC/CIH: 77.8 ± 12.2). CONCLUSIONS: To our knowledge, this is the first study to suggest CIH increases macrophage matrix metalloproteinase 12 expression in mice. Combined exposures to WTC dust and CIH further increased macrophage matrix metalloproteinase 12 expression. Given the role of matrix metalloproteinase 12 in pulmonary fibrosis and chronic obstructive pulmonary disease pathogenesis, patients with obstructive sleep apnea who have been exposed to WTC dust may have added risk for pulmonary parenchymal disease.