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TRPV4 通道对于肺泡上皮屏障功能至关重要，可防止肺水肿。

TRPV4 channels are essential for alveolar epithelial barrier function as protection from lung edema.

机构信息

Walther Straub Institute of Pharmacology and Toxicology, a member of the German Center for Lung Research (DZL), Ludwig Maximilian University of Munich, Munich Germany.

Institute of Anatomy and Cell Biology, School of Medicine, Saarland University, Homburg, Germany.

出版信息

JCI Insight. 2020 Oct 15;5(20):134464. doi: 10.1172/jci.insight.134464.

DOI:10.1172/jci.insight.134464
PMID:32931478
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7605532/
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.

摘要

缺血再灌注诱导的水肿（IRE）是肺移植后导致患者死亡的最主要原因之一，可以在离体灌流的小鼠肺（IPL）中模拟。瞬时受体电位香草醛 4 型（TRPV4）是一种在血管内皮中研究的非选择性阳离子通道，但其在肺上皮细胞中的作用仍不清楚。在这里，我们发现与 WT 对照组相比，TRPV4 缺陷型（TRPV4-/-）的 IPL 中的 IRE 增强，这表明 TRPV4 在维持肺泡上皮屏障方面具有保护作用。通过免疫组织化学、mRNA 谱分析和电生理特性分析，我们在支气管上皮细胞、肺泡上皮细胞 I 型（ATI）和肺泡上皮细胞 II 型（ATII）中检测到 TRPV4。TRPV4 的基因缺失导致 ATI 细胞中水通道蛋白-5（AQP-5）通道的表达减少。TRPV4-/-ATI 细胞的迁移减少，细胞屏障功能受损。对分离的原代 TRPV4-/-ATII 细胞的分析表明，表面活性蛋白 C 的表达减少，而 TRPV4 激活剂 GSK1016790A 仅在 WT ATII 细胞中诱导电流密度增加。此外，与 WT 肺相比，成年小鼠的 TRPV4-/-肺表现出更大的平均弦长和改变的肺功能。因此，我们的数据说明了 TRPV4 通道在肺泡上皮细胞中的重要功能及其在防止水肿形成中的保护作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/5d3371b70c43/jciinsight-5-134464-g161.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/909e391b3ab3/jciinsight-5-134464-g156.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/f00233e0b977/jciinsight-5-134464-g157.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/93021cc17b8d/jciinsight-5-134464-g158.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/af48130b0b0e/jciinsight-5-134464-g159.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/f4c775b0198c/jciinsight-5-134464-g160.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/5d3371b70c43/jciinsight-5-134464-g161.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/909e391b3ab3/jciinsight-5-134464-g156.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/f00233e0b977/jciinsight-5-134464-g157.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/93021cc17b8d/jciinsight-5-134464-g158.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/af48130b0b0e/jciinsight-5-134464-g159.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/f4c775b0198c/jciinsight-5-134464-g160.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1695/7605532/5d3371b70c43/jciinsight-5-134464-g161.jpg

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