title: Heme oxygenase-1 protects corexit 9500A-induced respiratory epithelial injury across species.
abstract: The effects of Corexit 9500A (CE) on respiratory epithelial surfaces of terrestrial mammals and marine animals are largely unknown. This study investigated the role of CE-induced heme oxygenase-1 (HO-1), a cytoprotective enzyme with anti-apoptotic and antioxidant activity, in human bronchial airway epithelium and the gills of exposed aquatic animals. We evaluated CE-mediated alterations in human airway epithelial cells, mice lungs and gills from zebrafish and blue crabs. Our results demonstrated that CE induced an increase in gill epithelial edema and human epithelial monolayer permeability, suggesting an acute injury caused by CE exposure. CE induced the expression of HO-1 as well as C-reactive protein (CRP) and NADPH oxidase 4 (NOX4), which are associated with ROS production. Importantly, CE induced caspase-3 activation and subsequent apoptosis of epithelial cells. The expression of the intercellular junctional proteins, such as tight junction proteins occludin, zonula occludens (ZO-1), ZO-2 and adherens junctional proteins E-cadherin and Focal Adhesion Kinase (FAK), were remarkably inhibited by CE, suggesting that these proteins are involved in CE-induced increased permeability and subsequent apoptosis. The cytoskeletal protein F-actin was also disrupted by CE. Treatment with carbon monoxide releasing molecule-2 (CORM-2) significantly inhibited CE-induced ROS production, while the addition of HO-1 inhibitor, significantly increased CE-induced ROS production and apoptosis, suggesting a protective role of HO-1 or its reaction product, CO, in CE-induced apoptosis. Using HO-1 knockout mice, we further demonstrated that HO-1 protected against CE-induced inflammation and cellular apoptosis and corrected CE-mediated inhibition of E-cadherin and FAK. These observations suggest that CE activates CRP and NOX4-mediated ROS production, alters permeability by inhibition of junctional proteins, and leads to caspase-3 dependent apoptosis of epithelial cells, while HO-1 and its reaction products protect against oxidative stress and apoptosis.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Fu Jun
authors.initials: FJ
authors.lastname: Li
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Ryan N
authors.initials: RN
authors.lastname: Duggal
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Octavio M
authors.initials: OM
authors.lastname: Oliva
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Suman
authors.initials: S
authors.lastname: Karki
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Ranu
authors.initials: R
authors.lastname: Surolia
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Watson
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Mickie
authors.initials: M
authors.lastname: Powell
authors.affiliation: Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Watts
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Tejaswini
authors.initials: T
authors.lastname: Kulkarni
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Batra
authors.affiliation: Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Subhashini
authors.initials: S
authors.lastname: Bolisetty
authors.affiliation: Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Veena B
authors.initials: VB
authors.lastname: Antony
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003386:Brachyura; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005880:Gills / Q000187:drug effects / Q000201:enzymology; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013501:Surface-Active Agents / Q000633:toxicity*; D015027:Zebrafish; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism; D062827:Zonula Occludens-2 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D015820:Cadherins; D008055:Lipids; C568985:OCLN protein, human; D062793:Occludin; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D013501:Surface-Active Agents; C569042:TJP1 protein, human; C569046:TJP2 protein, human; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; C470995:corexit 9500; C447082:tricarbonyldichlororuthenium (II) dimer; D002097:C-Reactive Protein; D051547:Heme Oxygenase-1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D053148:Caspase 3
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