Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury

Aims: Exposure to irritant gases, such as bromine (Br-2), poses an environmental and occupational hazard that results in severe lung and systemic injury. However, the mechanism(s) of Br-2 toxicity and the therapeutic responses required to mitigate lung damage are not known. Previously, it was demonstrated that Br-2 upregulates the heme degrading enzyme, heme oxygenase-1 (HO-1). Since heme is a major inducer of HO-1, we determined whether an increase in heme and heme-dependent oxidative injury underlies the pathogenesis of Br-2 toxicity. Results: C57BL/6 mice were exposed to Br-2 gas (600ppm, 30min) and returned to room air. Thirty minutes postexposure, mice were injected intraperitoneally with a single dose of the heme scavenging protein, hemopexin (Hx) (3g/gm body weight), or saline. Twenty-four hours postexposure, saline-treated mice had elevated total heme in bronchoalveolar lavage fluid (BALF) and plasma and acute lung injury (ALI) culminating in 80% mortality after 10 days. Hx treatment significantly lowered heme, decreased evidence of ALI (lower protein and inflammatory cells in BALF, lower lung wet-to-dry weight ratios, and decreased airway hyperreactivity to methacholine), and reduced mortality. In addition, Br-2 caused more severe ALI and mortality in mice with HO-1 gene deletion (HO-1(-/-)) compared to wild-type controls, while transgenic mice overexpressing the human HO-1 gene (hHO-1) showed significant protection. Innovation: This is the first study delineating the role of heme in ALI caused by Br-2. Conclusion: The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI. Antioxid. Redox Signal. 24, 99-112.