Critical Care Medicine  |   February 2017
Transient Receptor Potential Vanilloid 4 and Serum Glucocorticoid–regulated Kinase 1 Are Critical Mediators of Lung Injury in Overventilated Mice In Vivo
Author Notes
  • From the Institute of Physiology (L.M., L.E., U.W., W.M.K.) and Department of Nephrology, Medizinische Klinik (M.v.d.G.), Charité—Universitaetsmedizin Berlin, Berlin, Germany; Departments of Medicine, Neurology, and Neurobiology, Duke University, Durham, North Carolina (W.L.); Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Ontario, Canada (W.M.K.); Departments of Surgery and Physiology, University of Toronto, Toronto, Ontario, Canada (W.M.K.); and German Heart Institute, Berlin, Germany (W.M.K.).
  • Submitted for publication February 19, 2016. Accepted for publication October 19, 2016.
    Submitted for publication February 19, 2016. Accepted for publication October 19, 2016.×
  • Address correspondence to Dr. Kuebler: Institute of Physiology, Charité—Universitätsmedizin Berlin, Charitéplatz 1 10117 Berlin, Germany. wolfgang.kuebler@charite.de. 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 / Respiratory System
Critical Care Medicine   |   February 2017
Transient Receptor Potential Vanilloid 4 and Serum Glucocorticoid–regulated Kinase 1 Are Critical Mediators of Lung Injury in Overventilated Mice In Vivo
Anesthesiology 2 2017, Vol.126, 300-311. doi:10.1097/ALN.0000000000001443
Anesthesiology 2 2017, Vol.126, 300-311. doi:10.1097/ALN.0000000000001443
Abstract

Background: Mechanical ventilation can cause lung endothelial barrier failure and inflammation cumulating in ventilator-induced lung injury. Yet, underlying mechanotransduction mechanisms remain unclear. Here, the authors tested the hypothesis that activation of the mechanosensitive Ca2+ channel transient receptor potential vanilloid (TRPV4) by serum glucocorticoid–regulated kinase (SGK) 1 may drive the development of ventilator-induced lung injury.

Methods: Mice (total n = 54) were ventilated for 2 h with low (7 ml/kg) or high (20 ml/kg) tidal volumes and assessed for signs of ventilator-induced lung injury. Isolated-perfused lungs were inflated with continuous positive airway pressures of 5 or 15 cm H2O (n = 7 each), and endothelial calcium concentration was quantified by real-time imaging.

Results: Genetic deficiency or pharmacologic inhibition of TRPV4 or SGK1 protected mice from overventilation-induced vascular leakage (reduction in alveolar protein concentration from 0.84 ± 0.18 [mean ± SD] to 0.46 ± 0.16 mg/ml by TRPV4 antagonization), reduced lung inflammation (macrophage inflammatory protein 2 levels of 193 ± 163 in Trpv4−/− vs. 544 ± 358 pmol/ml in wild-type mice), and attenuated endothelial calcium responses to lung overdistension. Functional coupling of TRPV4 and SGK1 in lung endothelial mechanotransduction was confirmed by proximity ligation assay demonstrating enhanced TRPV4 phosphorylation at serine 824 at 18% as compared to 5% cyclic stretch, which was prevented by SGK1 inhibition.

Conclusions: Lung overventilation promotes endothelial calcium influx and barrier failure through a mechanism that involves activation of TRPV4, presumably due to phosphorylation at its serine 824 residue by SGK1. TRPV4 and SGK1 may present promising new targets for prevention or treatment of ventilator-induced lung injury.