title: Heme oxygenase-1-mediated autophagy protects against pulmonary endothelial cell death and development of emphysema in cadmium-treated mice.
abstract: Pulmonary exposure to cadmium, a major component of cigarette smoke, has a dramatic impact on lung function and the development of emphysema. Cigarette smoke exposure induces heme oxygenase-1 (HO-1), a cytoprotective enzyme. In this study, we employed a truncated mouse model of emphysema by intratracheal instillation of cadmium (CdCl2) solution (0.025% per 1 mg/kg body wt) in HO-1(+/+), HO-1(-/-), and overexpressing humanized HO-1 bacterial artificial chromosome (hHO-1BAC) mice. We evaluated the role of HO-1 in cadmium-induced emphysema in mice by analyzing histopathology, micro-computed tomography scans, and lung function tests. CdCl2-exposed HO-1(-/-) mice exhibited more severe emphysema compared with HO-1(+/+) or hHO-1BAC mice. Loss of pulmonary endothelial cells (PECs) from the alveolar capillary membrane is recognized to be a target in emphysema. PECs from HO-1(+/+), HO-1(-/-), and hHO-1BAC were employed to define the underlying molecular mechanism for the protection from emphysema by HO-1. Electron microscopy, expression of autophagic markers (microtubule-associated protein 1B-light chain 3 II, autophagy protein 5, and Beclin1) and apoptotic marker (cleaved caspase 3) suggested induction of autophagy and apoptosis in PECs after CdCl2 treatment. CdCl2-treated HO-1(-/-) PECs exhibited downregulation of autophagic markers and significantly increased cleaved caspase 3 expression and activity (∼4-fold higher). Moreover, hHO-1BAC PECs demonstrated upregulated autophagy and absence of cleaved caspase 3 expression or activity. Pretreatment of HO-1(+/+) PECs with rapamycin induced autophagy and resulted in reduced cell death upon cadmium treatment. Induction of autophagy following CdCl2 treatment was found to be protective from apoptotic cell death. HO-1 induced protective autophagy in PECs and mitigated cadmium-induced emphysema.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Alabama;
authors.forename: Ranu
authors.identifier: http://orcid.org/0000-0001-5389-3584
authors.initials: R
authors.lastname: Surolia
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Alabama;
authors.forename: Suman
authors.initials: S
authors.lastname: Karki
authors.affiliation: Department of Radiology, University of Alabama at Birmingham, Alabama;
authors.forename: Hyunki
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Alabama;
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Alabama;
authors.forename: Tejaswini
authors.initials: T
authors.lastname: Kulkarni
authors.affiliation: Department of Physics, University of Alabama at Birmingham, Alabama;
authors.forename: Sergey B
authors.initials: SB
authors.lastname: Mirov
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Alabama; Veterans Affairs Medical Center, University of Alabama at Birmingham, Alabama;
authors.forename: A Brent
authors.initials: AB
authors.lastname: Carter
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Alabama; Department of Pediatrics, University of Alabama at Birmingham, Alabama; Department of Cell Development and Integrative Biology, University of Alabama at Birmingham, Alabama.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Alabama;
authors.forename: Sadis
authors.initials: S
authors.lastname: Matalon
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Alabama;
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: Division of Nephrology Department of Medicine, University of Alabama at Birmingham, Alabama; Veterans Affairs Medical Center, University of Alabama at Birmingham, Alabama;
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Alabama; vantony@uab.edu.
authors.forename: Veena B
authors.initials: VB
authors.lastname: Antony
mesh_terms: D000818:Animals; D001343:Autophagy; D002104:Cadmium; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology*; D051547:Heme Oxygenase-1 / Q000502:physiology*; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000201:enzymology*
chemical_list: D008565:Membrane Proteins; D002104:Cadmium; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: autophagy; cadmium-induced emphysema; heme oxygenase 1; pulmonary endothelial cells