title: Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury.
abstract: OBJECTIVE
  Exposure to irritant gases, such as bromine (Br2), poses an environmental and occupational hazard that results in severe lung and systemic injury. However, the mechanism(s) of Br2 toxicity and the therapeutic responses required to mitigate lung damage are not known. Previously, it was demonstrated that Br2 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 Br2 toxicity.
  
  
  RESULTS
  C57BL/6 mice were exposed to Br2 gas (600 ppm, 30 min) and returned to room air. Thirty minutes postexposure, mice were injected intraperitoneally with a single dose of the heme scavenging protein, hemopexin (Hx) (3 μg/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, Br2 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.
  
  
  METHODS
  This is the first study delineating the role of heme in ALI caused by Br2.
  
  
  CONCLUSIONS
  The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI.
authors.affiliation: 1 Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.|2 Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: 1 Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.
authors.forename: Adam
authors.initials: A
authors.lastname: Lam
authors.affiliation: 3 Division of Nephrology, Department of Medicine, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.|4 Nephrology Research and Training Center, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.
authors.forename: Subhashini
authors.initials: S
authors.lastname: Bolisetty
authors.affiliation: 1 Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Carlisle
authors.affiliation: 3 Division of Nephrology, Department of Medicine, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.|4 Nephrology Research and Training Center, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.
authors.forename: Amie
authors.initials: A
authors.lastname: Traylor
authors.affiliation: 3 Division of Nephrology, Department of Medicine, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.|4 Nephrology Research and Training Center, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: 1 Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.|2 Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.
authors.forename: Sadis
authors.initials: S
authors.lastname: Matalon
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001966:Bromine; D005260:Female; D006418:Heme / Q000378:metabolism*; D006466:Hemopexin / Q000494:pharmacology / Q000627:therapeutic use; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D006418:Heme; D006466:Hemopexin; D001966:Bromine