title: Neuromuscular Blocking Agent Cisatracurium Attenuates Lung Injury by Inhibition of Nicotinic Acetylcholine Receptor-α1.
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.
authors.affiliation: 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.).
authors.forename: Vito
authors.initials: V
authors.lastname: Fanelli
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Morita
authors.forename: Paola
authors.initials: P
authors.lastname: Cappello
authors.forename: Mirna
authors.initials: M
authors.lastname: Ghazarian
authors.forename: Bina
authors.initials: B
authors.lastname: Sugumar
authors.forename: Luisa
authors.initials: L
authors.lastname: Delsedime
authors.forename: Jane
authors.initials: J
authors.lastname: Batt
authors.forename: V Marco
authors.initials: VM
authors.lastname: Ranieri
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001279:Atracurium / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D007249:Inflammation / Q000150:complications / Q000517:prevention & control*; D055370:Lung Injury / Q000150:complications / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*
chemical_list: D009466:Neuromuscular Blocking Agents; D011978:Receptors, Nicotinic; D001279:Atracurium; C101584:cisatracurium