Saurabh Aggarwal1,2, Adam Lam1, Subhashini Bolisetty3,4, Matthew A Carlisle1, Amie Traylor3,4, Anupam Agarwal3,4, Sadis Matalon1,2. 1. 1 Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama. 2. 2 Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama. 3. 3 Division of Nephrology, Department of Medicine, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama. 4. 4 Nephrology Research and Training Center, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.
Abstract
AIMS: 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. INNOVATION: This is the first study delineating the role of heme in ALI caused by Br2. CONCLUSION: The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI.
AIMS: 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 Br2toxicity 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 Br2toxicity. 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 humanHO-1 gene (hHO-1) showed significant protection. INNOVATION: This is the first study delineating the role of heme in ALI caused by Br2. CONCLUSION: The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI.
Authors: Juan Xavier Masjoan Juncos; Shazia Shakil; Aamir Ahmad; Duha Aishah; Charity J Morgan; Louis J Dell'Italia; David A Ford; Aftab Ahmad; Shama Ahmad Journal: Ann N Y Acad Sci Date: 2020-07-09 Impact factor: 5.691
Authors: Dylan R Addis; Saurabh Aggarwal; Stephen F Doran; Ming-Yuan Jian; Israr Ahmad; Kyoko Kojima; David A Ford; Sadis Matalon; James A Mobley Journal: Am J Physiol Lung Cell Mol Physiol Date: 2020-06-24 Impact factor: 5.464
Authors: Mark A Duerr; Elisa N D Palladino; Celine L Hartman; James A Lambert; Jacob D Franke; Carolyn J Albert; Sadis Matalon; Rakesh P Patel; Arne Slungaard; David A Ford Journal: J Lipid Res Date: 2018-02-14 Impact factor: 5.922
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