Heme oxygenase-1-mediated autophagy protects against pulmonary endothelial cell death and development of emphysema in cadmium-treated mice
Year: 2015
Type: article
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.
Institutions: University of Alabama at Birmingham, UAB Medicine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Human Heme Oxygenase-1 Gene Regulation in Renal Injury, G1966007161, Prevention and Treatment of Chlorine Gas Induced Injury to the Pulmonary System, Bromine Inhalation Induced Lung Injury: Novel Mechanisms and Treatment Strategies, G3753295308, Central Role of Heme Oxygenase in Reversing Bromine Morbidity and Mortality, Mitochondrial Bioenergetic Dysfunction and Chlorine Toxicity, Lung Macrophage Metabolic Reprogramming in Asbestos-Induced Toxicity, UAB-UCSD O'Brien Center for Acute Kidney Injury Research, Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease, UAB CF Research and Translation Core Center, G941714095
OpenAlex ID: W1942970747