title: Ubiquitous protective effects of cyclosporine A in preventing cardiac arrest-induced multiple organ failure.
abstract: Opening of the mitochondrial permeability transition pore (mPTP) appears to be a pivotal event in myocardial ischemia-reperfusion (I/R) injury. Resuscitated cardiac arrest (CA) leads to the post-CA syndrome that encompasses, not only myocardial dysfunction, but also brain injury, failure of other organs (kidney, liver, or lung), and systemic response to I/R. We aimed to determine whether cyclosporine A (CsA) might prevent multiple organ failure following CA through a ubiquitous mPTP inhibition in each distant vital organ. Anesthetized New Zealand White rabbits were subjected to 15 min of CA and 120 min of reperfusion. At the onset of resuscitation, the rabbits received CsA, its non-immunosuppressive derivative NIM811, or vehicle (controls). Survival, hemodynamics, brain damage, organ injuries, and systemic I/R response were analyzed. Fresh mitochondria were isolated from the brain, heart, kidney, liver, and lung to assess both oxidative phosphorylation and permeability transition. CsA analogs significantly improved short-term survival and prevented multiple organ failure, including brain damage and myocardial dysfunction (P < 0.05 vs. controls). Susceptibility of mPTP opening was significantly increased in heart, brain, kidney, and liver mitochondria isolated from controls, while mitochondrial respiration was impaired (P < 0.05 vs. sham). CsA analogs prevented these mitochondrial dysfunctions (P < 0.05 vs. controls). These results suggest that CsA and NIM811 can prevent the post-CA syndrome through a ubiquitous mitochondrial protective effect at the level of each major distant organ.
authors.affiliation: Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Service de Réanimation Médicale, Lyon, France; Faculté de Médecine Lyon-Est, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France; INSERM UMR 1060, CarMeN, Lyon, France;
authors.forename: Martin
authors.initials: M
authors.lastname: Cour
authors.affiliation: INSERM UMR 1060, CarMeN, Lyon, France;
authors.forename: Maryline
authors.initials: M
authors.lastname: Abrial
authors.affiliation: Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Service de Réanimation Médicale, Lyon, France; Faculté de Médecine Lyon-Est, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France; INSERM UMR 1060, CarMeN, Lyon, France;
authors.forename: Vincent
authors.initials: V
authors.lastname: Jahandiez
authors.affiliation: INSERM UMR 1060, CarMeN, Lyon, France;
authors.forename: Joseph
authors.initials: J
authors.lastname: Loufouat
authors.affiliation: INSERM UMR 1060, CarMeN, Lyon, France;
authors.forename: Elise
authors.initials: E
authors.lastname: Belaïdi
authors.affiliation: INSERM UMR 1060, CarMeN, Lyon, France;
authors.forename: Abdallah
authors.initials: A
authors.lastname: Gharib
authors.affiliation: Laboratoire de Biochimie, Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Lyon, France;
authors.forename: Annie
authors.initials: A
authors.lastname: Varennes
authors.affiliation: Laboratoire d'Immunologie Clinique, Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Lyon, France; and.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Monneret
authors.affiliation: INSERM UMR 1060, CarMeN, Lyon, France; Explorations Fonctionnelles Cardiovasculaires & Centre d'Investigations Cliniques de Lyon, Hospices Civils de Lyon, Groupement Hospitalier Est, Lyon, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Thibault
authors.affiliation: INSERM UMR 1060, CarMeN, Lyon, France; Explorations Fonctionnelles Cardiovasculaires & Centre d'Investigations Cliniques de Lyon, Hospices Civils de Lyon, Groupement Hospitalier Est, Lyon, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Ovize
authors.affiliation: Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Service de Réanimation Médicale, Lyon, France; Faculté de Médecine Lyon-Est, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France; INSERM UMR 1060, CarMeN, Lyon, France; laurent.argaud@chu-lyon.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Argaud
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D006323:Heart Arrest / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009102:Multiple Organ Failure / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011817:Rabbits
chemical_list: D002316:Cardiotonic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine
keywords: cardiopulmonary resuscitation; ischemia; mitochondria; reperfusion