Activation of Nicotinic Cholinergic Receptors Prevents Ventilator-Induced Lung Injury in Rats

Fabienne Brégeon,Nicolas Andreotti,Antoine Roch,Francois Xeridat,Jean-Guillaume Steinberg,Yves Jammes,Stéphane Delpierre,Hubert Lepidi,Sylvie Ravailhe,Martin R.J Kolb

doi:10.1371/journal.pone.0022386

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-cmH2O 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.

Highlights

Mechanical ventilation is the main life-sustaining tool in Acute Respiratory Distress Syndrome (ARDS), but even low tidal volume strategies may cause the undesirable side-effects of cyclic hyperinflation of some lung areas [1]
Ventilator-induced lung injury In animals exposed to high stretch mechanical ventilation (HV), the average tidal volume indexed to the body weight was 24.3360.21 mL/kg, with no significant difference between groups
At the fixed stroke volume, the HV25-sham group showed a progressive increase in Paw with time and a decrease in blood oxygenation while the PaCO2 was maintained in the normal range for all groups throughout the study period

Summary

Introduction

Mechanical ventilation is the main life-sustaining tool in Acute Respiratory Distress Syndrome (ARDS), but even low tidal volume strategies may cause the undesirable side-effects of cyclic hyperinflation of some lung areas [1]. As for VILI, we found only one in vivo report which supposes the existence of an interaction between stretch-induced lung cytokine release (20 mL/kg tidal volume) and the vagal anti-inflammatory pathway [14]. In this above mentioned report, additional in vitro experiments have shown that specific agonist or antagonist of the a7-nAChR acts on the intracellular mediators involved in cell inflammatory response to stretch such as pJNK (pro-inflammatory) and Fas, Daxx, pJNK and Bad (pro-apoptotic) [14]. The protective effect of a7-nAChR activation against VILI still remains to be assessed in vivo

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