RRC ID 60990
Author Weber J, Rajan S, Schremmer C, Chao YK, Krasteva-Christ G, Kannler M, Yildirim AÖ, Brosien M, Schredelseker J, Weissmann N, Grimm C, Gudermann T, Dietrich A.
Title TRPV4 channels are essential for alveolar epithelial barrier function as protection from lung edema.
Journal JCI Insight
Abstract 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 nonselective cation channel studied in endothelium; however, its role in the lung epithelium remains elusive. Here, we show enhanced IRE in TRPV4-deficient (TRPV4-/-) IPL compared with that of WT controls, indicating a protective role of TRPV4 in maintenance of the alveolar epithelial barrier. By immunohistochemistry, mRNA profiling, and electrophysiological characterization, we detected TRPV4 in bronchial epithelium, alveolar epithelial type I (ATI), and alveolar epithelial 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-/- ATII cells revealed a reduced expression of surfactant protein 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 with WT lungs. Therefore, our data illustrate essential functions of TRPV4 channels in alveolar epithelial cells and in protection from edema formation.
Volume 5(20)
Published 2020-10-15
DOI 10.1172/jci.insight.134464
PII 134464
PMID 32931478
PMC PMC7605532
MeSH Alveolar Epithelial Cells / pathology Animals Aquaporin 5 / genetics* Bronchi / metabolism Bronchi / pathology Cell Movement / genetics Disease Models, Animal Edema / etiology Edema / genetics* Edema / pathology Humans Leucine / analogs & derivatives Leucine / pharmacology Lung Diseases / etiology Lung Diseases / genetics* Lung Diseases / pathology Lung Transplantation / adverse effects Mice Mice, Knockout Reperfusion Injury / complications Reperfusion Injury / genetics* Reperfusion Injury / pathology Sulfonamides / pharmacology TRPV Cation Channels / genetics*
IF 6.205
Mice RBRC01939