Ischemia-reperfusion-induced edema (IRE) one of the most significant causes of mortality after lung transplantation can be mimicked ex-vivo in isolated perfused mouse lungs (IPL). Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel studied in endothelium, while its role in the lung epithelium remains elusive. Here we show enhanced IRE in TRPV4-deficient (TRPV4–/–) IPL compared to wild-type (WT) controls, indicating a protective role of TRPV4 to maintain the alveolar epithelial barrier. By immunohistochemistry, mRNA profiling and electrophysiological characterization, we detected TRPV4 in bronchial epithelium, alveolar type I (ATI) and alveolar type II (ATII) cells. Genetic ablation of TRPV4 resulted in reduced expression of the water conducting aquaporin-5 (AQP-5) channel in ATI cells. Migration of TRPV4–/– ATI cells was reduced and cell barrier function was impaired. Analysis of isolated primary TRPV4-deficient ATII cells revealed a reduced expression of surfactant protein C (SP-C) and the TRPV4 activator GSK1016790A induced increases in current densities only in WT ATII cells. Moreover, TRPV4–/– lungs of adult mice developed significantly larger mean chord lengths and altered lung function compared to WT lungs. Therefore, our data discover essential functions of TRPV4 channels in alveolar epithelial cells and in the protection from edema formation.
Jonas Weber, Suhasini Rajan, Christian Schremmer, Yu-Kai Chao, Gabriela Krasteva-Christ, Martina Kannler, Ali Önder Yildirim, Monika Brosien, Johann Schredelseker, Norbert Weissmann, Christian Grimm, Thomas Gudermann, Alexander Dietrich
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