• Mei Li, Juliana Roeder, Jorge Blázquez-Prieto, Sabrina Schulz, Julia Naujox, Juliana Falivene, Lasti Erfinanda, Wolfgang Liedtke, Guillermo M Albaiceta, Wolfgang M Kuebler, and Laura Michalick.
• Institute of Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of the Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany; Department of Pathology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
• Anesthesiology. 2024 Nov 1; 141 (5): 913928913-928.

BackgroundAs a mechanosensitive cation channel and key regulator of vascular barrier function, endothelial transient receptor potential vanilloid type 4 (TRPV4) contributes critically to ventilator-induced lung injury and edema formation. Ca2+ influx via TRPV4 can activate Ca2+-activated potassium (KCa) channels, categorized into small (SK1-3), intermediate (IK1), and big (BK) KCa, which may in turn amplify Ca2+ influx by increasing the electrochemical Ca2+ gradient and thus promote lung injury. The authors therefore hypothesized that endothelial KCa channels may contribute to the progression of TRPV4-mediated ventilator-induced lung injury.MethodsMale C57Bl/6J mice were ventilated for 2 h with low or high tidal volumes in the presence or absence of the nonselective KCa antagonists apamin and charybdotoxin or the selective IK1 antagonist TRAM34. Lung injury was similarly assessed in overventilated, endothelial-specific TRPV4-deficient mice or TRAM34-treated C57Bl/6J mice challenged with intratracheal acid installation. Changes in intracellular calcium Ca2+ concentration ([Ca2+]i) were monitored by real-time imaging in isolated-perfused lungs in response to airway pressure elevation or in human pulmonary microvascular endothelial cells in response to TRPV4 activation with or without inhibition of KCa channels. Analogously, changes in intracellular potassium concentration ([K+]i) and membrane potential were imaged in vitro.ResultsEndothelial TRPV4 deficiency or inhibition of KCa channels, and most prominently inhibition of IK1 by TRAM34, attenuated ventilator-induced lung injury as demonstrated by reduced lung edema, protein leak, and quantitative lung histology. All KCa antagonists reduced the [Ca2+]i response to mechanical stimulation or direct TRPV4 activation in isolated lungs. TRAM34 and charybdotoxin yet not apamin prevented TRPV4-induced potassium efflux and membrane hyperpolarization in human pulmonary microvascular endothelial cells. TRAM34 also attenuated the TRPV4 agonist-induced Ca2+ influx in vitro and reduced acid-induced lung injury in vivo.ConclusionsKCa channels, specifically IK1, act as amplifiers of TRPV4-mediated Ca2+ influx and establish a detrimental feedback that promotes barrier failure and drives the progression of ventilator-induced lung injury.Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.

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