Critical Care Medicine  |   January 2016
Neuromuscular Blocking Agent Cisatracurium Attenuates Lung Injury by Inhibition of Nicotinic Acetylcholine Receptor-α1
Author Notes
  • From the Department of Anesthesia and Critical Care, University of Turin, AOU Città della Salute e della Scienza di Torino – Ospedale Molinette, Torino, Italy (V.F., V.M.R.); Critical Care Program, The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Ontario, Canada (Y.M., M.G., B.S., J.B., H.Z., A.S.S.); Department of Molecular Biotechnologies and Health Sciences, University of Turin, Turin, Italy (P.C.); Department of Pathology, AOU Città della Salute e della Scienza di Torino – Ospedale Molinette, Torino, Italy (L.D.); Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada (H.Z., A.S.S.); and Departments of Anesthesia and Physiology, University of Toronto, Toronto, Ontario, Canada (H.Z.).
  • Submitted for publication November 20, 2014. Accepted for publication August 26, 2015.
    Submitted for publication November 20, 2014. Accepted for publication August 26, 2015.×
  • Address correspondence to Dr. Zhang: Room 619, LKSKI, 209 Victoria Street, Toronto, Ontario, Canada M5B 1W8. zhangh@smh.ca. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Basic Science / Critical Care / Neuromuscular Diseases and Drugs / Respiratory System
Critical Care Medicine   |   January 2016
Neuromuscular Blocking Agent Cisatracurium Attenuates Lung Injury by Inhibition of Nicotinic Acetylcholine Receptor-α1
Anesthesiology 1 2016, Vol.124, 132-140. doi:10.1097/ALN.0000000000000907
Anesthesiology 1 2016, Vol.124, 132-140. doi:10.1097/ALN.0000000000000907
Abstract

Background: Neuromuscular blocking agents (NMBAs) bind the nicotinic acetylcholine receptor α1 (nAChRα1) that also contributes to inflammatory signaling. Thus, the author hypothesized that the use of NMBA mitigates lung injury by improving ventilator synchrony and decreasing inflammatory responses.

Methods: Lung injury was induced by intratracheal instillation of hydrogen chloride in rats that were randomized to receive no NMBA with evidence of asynchronous ventilation (noNMBA/aSYNC, n = 10); no NMBA with synchronous ventilation (noNMBA/SYNC, n = 10); cisatracurium (CIS, n = 10); or pancuronium (PAN, n = 10). Mechanical ventilation was set at a tidal volume of 6 ml/kg and positive end-expiratory pressure 8 cm H2O for 3 h. Human lung epithelial, endothelial, and CD14+ cells were challenged with mechanical stretch, lipopolysaccharide, lung lavage fluids (bronchoalveolar lavage fluid), or plasma obtained from patients (n = 5) with acute respiratory distress syndrome, in the presence or absence of CIS or small-interfering RNA and small hairpin RNA to attenuate the cell expression of nAChRα1.

Results: The use of CIS and PAN improved respiratory compliance (7.2 ± 0.7 in noNMBA/aSYNC, 6.6 ± 0.5 in noNMBA/SYNC, 5.9 ± 0.3 in CIS, and 5.8 ± 0.4 cm H2O/l in PAN; P < 0.05), increased Pao2 (140 ± 54, 209 ± 46, 269 ± 31, and 269 ± 54 mmHg, respectively, P < 0.05), and decreased the plasma levels of tumor necrosis factor-α (509 ± 252 in noNMBA, 200 ± 74 in CIS, and 175 ± 84 pg/ml in PAN; P < 0.05) and interleukin-6 (5789 ± 79, 1608 ± 534, and 2290 ± 315 pg/ml, respectively; P < 0.05). The use of CIS and PAN or silencing the receptor nAChRα1 resulted in decreased cytokine release in the human cells in response to a variety of stimuli mentioned earlier.

Conclusions: The use of NMBA is lung protective through its antiinflammatory properties by blocking the nAChRα1.

Abstract

In rodent models of acute lung injury, neuromuscular blocking agents protected against ventilator-induced lung injury through their antiinflammatory properties mediated by blockade of the nicotinic acetylcholine receptor α1. This protective effect was not due to improved ventilator synchrony, and the reduced cytokine release could be mimicked ex vivo through knockdown of nicotinic acetylcholine receptor α1 expression.