Neuromuscular Blocking Agent Cisatracurium Attenuates Lung Injury by Inhibition of Nicotinic Acetylcholine Receptor-α1.

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.

Wiskott-Aldrich syndrome proteins in the nucleus: aWASH with possibilities.

Actin and proteins that regulate its dynamics or interactions have well-established roles in the cytoplasm where they function as key components of the cytoskeleton to control diverse processes, including cellular infrastructure, cellular motility, cell signaling, and vesicle transport. Recent work has also uncovered roles for actin and its regulatory proteins in the nucleus, primarily in mechanisms governing gene expression. The Wiskott Aldrich Syndrome (WAS) family of proteins, comprising the WASP/N-WASP, SCAR/WAVE, WHAMM/JMY/WHAMY, and WASH subfamilies, function in the cytoplasm where they activate the Arp2/3 complex to form branched actin filaments. WAS proteins are present in the nucleus and have been implicated as transcriptional regulators. We found that Drosophila Wash, in addition to transcriptional effects, is involved in global nuclear architecture. Here we summarize the regulation and function of nuclear WAS proteins, and highlight how our work with Wash expands the possibilities for the functions of these proteins in the nucleus.