Heme oxygenase-1-mediated autophagy protects against pulmonary endothelial cell death and development of emphysema in cadmium-treated mice

Academic Article

Abstract

  • © 2015 the American Physiological Society. 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 exhibi-/-d 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 apo-ptotic marker (cleaved caspase 3) suggested induction of au-tophagy 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 rapa-mycin 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.
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    Author List

  • Surolia R; Karki S; Kim H; Yu Z; Kulkarni T; Mirov SB; Carter AB; Rowe SM; Matalon S; Thannickal VJ
  • Start Page

  • L280
  • End Page

  • L292
  • Volume

  • 309
  • Issue

  • 3