title: Activation of nicotinic cholinergic receptors prevents ventilator-induced lung injury in rats.
abstract: Respiratory distress syndrome is responsible for 40 to 60 percent mortality. An over mortality of about 10 percent could result from additional lung injury and inflammation due to the life-support mechanical ventilation, which stretches the lung. It has been recently demonstrated, in vitro, that pharmacological activation of the alpha 7 nicotinic receptors (α7-nAChR) could down regulate intracellular mediators involved in lung cell inflammatory response to stretch. Our aim was to test in vivo the protective effect of the pharmacological activation of the α7-nAChR against ventilator-induced lung injury (VILI). Anesthetized rats were ventilated for two hours with a high stretch ventilation mode delivering a stroke volume large enough to generate 25-cmH(2)O airway pressure, and randomly assigned to four groups: pretreated with parenteral injection of saline or specific agonist of the α7-nAChR (PNU-282987), or submitted to bilateral vagus nerve electrostimulation while pre-treated or not with the α7-nAChR antagonist methyllycaconitine (MLA). Controls ventilated with a conventional stroke volume of 10 mL/kg gave reference data. Physiological indices (compliance of the respiratory system, lung weight, blood oxygenation, arterial blood pressure) and lung contents of inflammatory mediators (IL-6 measured by ELISA, substance P assessed using HPLC) were severely impaired after two hours of high stretch ventilation (sham group). Vagal stimulation was able to maintain the respiratory parameters close to those obtained in Controls and reduced lung inflammation except when associated to nicotinic receptor blockade (MLA), suggesting the involvement of α7-nAChR in vagally-mediated protection against VILI. Pharmacological pre-treatment with PNU-282987 strongly decreased lung injury and lung IL-6 and substance P contents, and nearly abolished the increase in plasmatic IL-6 levels. Pathological examination of the lungs confirmed the physiological differences observed between the groups. In conclusion, these data suggest that the stimulation of α7-nAChR is able to attenuate VILI in rats.
authors.affiliation: UMR MD2 P2COE, Institut Fédératif de Recherche Jean-Roche, Faculté de Médecine, Université de la Méditerranée Aix-Marseille II and Explorations Fonctionnelles Respiratoires de l' Hôpital Nord, Assistance Publique-Hôpitaux de Marseille, Marseille, France. fabienne.bregeon@ap-hm.fr
authors.forename: Fabienne
authors.initials: F
authors.lastname: Brégeon
authors.forename: Francois
authors.initials: F
authors.lastname: Xeridat
authors.forename: Nicolas
authors.initials: N
authors.lastname: Andreotti
authors.forename: Hubert
authors.initials: H
authors.lastname: Lepidi
authors.forename: Stéphane
authors.initials: S
authors.lastname: Delpierre
authors.forename: Antoine
authors.initials: A
authors.lastname: Roch
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ravailhe
authors.forename: Yves
authors.initials: Y
authors.lastname: Jammes
authors.forename: Jean-Guillaume
authors.initials: JG
authors.lastname: Steinberg
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001549:Benzamides; D001643:Bridged Bicyclo Compounds; C579165:Chrna7 protein, rat; D015850:Interleukin-6; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; C498513:PNU-282987; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine; D013373:Substance P; D000157:Aconitine