title: Upregulation of autophagy decreases chlorine-induced mitochondrial injury and lung inflammation.
abstract: The mechanisms of toxicity during exposure of the airways to chlorinated biomolecules generated during the course of inflammation and to chlorine (Cl2) gas are poorly understood. We hypothesized that lung epithelial cell mitochondria are damaged by Cl2 exposure and activation of autophagy mitigates this injury. To address this, NCI-H441 (human lung adenocarcinoma epithelial) cells were exposed to Cl2 (100 ppm/15 min) and bioenergetics were assessed. One hour after Cl2, cellular bioenergetic function and mitochondrial membrane potential were decreased. These changes were associated with increased MitoSOX signal, and treatment with the mitochondrial redox modulator MitoQ attenuated these bioenergetic defects. At 6h postexposure, there was significant increase in autophagy, which was associated with an improvement of mitochondrial function. Pretreatment of H441 cells with trehalose (an autophagy activator) improved bioenergetic function, whereas 3-methyladenine (an autophagy inhibitor) resulted in increased bioenergetic dysfunction 1h after Cl2 exposure. These data indicate that Cl2 induces bioenergetic dysfunction, and autophagy plays a protective role in vitro. Addition of trehalose (2 vol%) to the drinking water of C57BL/6 mice for 6 weeks, but not 1 week, before Cl2 (400 ppm/30 min) decreased white blood cells in the bronchoalveolar lavage fluid at 6h after Cl2 by 70%. Acute administration of trehalose delivered through inhalation 24 and 1h before the exposure decreased alveolar permeability but not cell infiltration. These data indicate that Cl2 induces bioenergetic dysfunction associated with lung inflammation and suggests that autophagy plays a protective role.
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Pulmonary Injury and Repair Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Asta
authors.initials: A
authors.lastname: Jurkuvenaite
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294,USA; Center for Free Radical Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Benavides
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Komarova
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Doran
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294,USA; Center for Free Radical Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Pulmonary Injury and Repair Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Center for Free Radical Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294,USA; Center for Free Radical Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Veterans Administration Medical Center, Birmingham, AL 35233, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294,USA; Center for Free Radical Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Darley-Usmar
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Pulmonary Injury and Repair Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Center for Free Radical Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: sadis@uab.edu.
authors.forename: Sadis
authors.initials: S
authors.lastname: Matalon
mesh_terms: D000818:Animals; D001343:Autophagy; D001992:Bronchoalveolar Lavage Fluid; D002460:Cell Line; D002713:Chlorine / Q000633:toxicity*; D004734:Energy Metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced*; D008168:Lung / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002713:Chlorine
keywords: 3-Methyladenine; Autophagy; Bioenergetics; Chlorine; Free radicals; Lung injury; MitoQ; Mitochondrial dysfunction; Trehalose