title: δV1-1 Reduces Pulmonary Ischemia Reperfusion-Induced Lung Injury by Inhibiting Necrosis and Mitochondrial Localization of PKCδ and p53.
abstract: Ischemia-reperfusion (IR)-induced lung injury is one of the major contributing factors of morbidity and mortality after lung transplantation. To determine the IR-induced molecular changes in lung epithelial cells, we developed a cell-culture model that simulates lung preservation and transplantation. Six hours of cold ischemic time (CIT) and reperfusion elicited production of multiple inflammatory cytokines and chemokines and increased expression of endoplasmic reticulum (ER) proteins. Prolonged hypothermic condition (18 h CIT) reduced ER stress protein levels, and induced apoptosis and necrosis (via mechanisms related to mitochondrial permeability transition pore opening). Protein kinase C (PKCδ) was activated during CIT, and its downregulation via small interference (si) (in siRNA) RNA reduced IR-induced cytokine production and apoptotic cell death. δV1-1, a PKCδ peptide inhibitor, reduced translocation of PKCδ and p53 to the mitochondria after 18 h CIT, rescued ER stress protein expression, and converted the major mode of cell death from necrosis to apoptosis. Administration of δV1-1 effectively reduced lung transplantation and IR-induced pulmonary injury in rats. Therefore, inhibition of PKCδ by δV1-1 could be an effective strategy to ameliorate IR-induced lung injury by inhibiting the signaling pathways leading to necrosis.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute University Health Network, Toronto, Ontario, Canada.|Department of Physiology, Toronto, Ontario, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute University Health Network, Toronto, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute University Health Network, Toronto, Ontario, Canada.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute University Health Network, Toronto, Ontario, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute University Health Network, Toronto, Ontario, Canada.|Institute of Medical Science, Toronto, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Lee
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute University Health Network, Toronto, Ontario, Canada.
authors.forename: X
authors.initials: X
authors.lastname: Bai
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute University Health Network, Toronto, Ontario, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Turrell
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute University Health Network, Toronto, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute University Health Network, Toronto, Ontario, Canada.|Department of Physiology, Toronto, Ontario, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Gao
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute University Health Network, Toronto, Ontario, Canada.|Institute of Medical Science, Toronto, Ontario, Canada.|Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Keshavjee
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute University Health Network, Toronto, Ontario, Canada.|Department of Physiology, Toronto, Ontario, Canada.|Institute of Medical Science, Toronto, Ontario, Canada.|Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Liu
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D055370:Lung Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D009842:Oligopeptides / Q000494:pharmacology*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015427:Reperfusion Injury / Q000503:physiopathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D009842:Oligopeptides; D034741:RNA, Small Interfering; C477270:Ser-Phe-Asn-Ser-Tyr-Glu-Leu-Gly-Glu-Ser-Leu; D016159:Tumor Suppressor Protein p53; D051745:Protein Kinase C-delta
keywords: Basic (laboratory) research/science; cell death; cellular biology; cytokines/cytokine receptors; ischemia reperfusion injury (IRI); lung failure/injury; lung transplantation/pulmonology; signal transduction; translational research/science