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.
Highlights
The alveolar epithelium has multiple functions in the lung
These results clearly contrast with observations on TRPC6-deficient lungs, which are protected from IR-induced edema due to reduced endothelial permeability [37]
Lung edema formation in Transient receptor potential vanilloid 4 (TRPV4)–/– lungs was clearly visible by the naked eye (Figure 1C), and, consistently, the wet-to-dry weight ratio increase doubled in TRPV4–/– lungs but only slightly increased in TRPV4/ TRPC6–/– lungs (Figure 1D)
Summary
The alveolar epithelium has multiple functions in the lung. On the one hand, the epithelial layer forms a natural barrier to the external environment, protecting the body from invading microorganisms and toxicants, while, on the other hand, alveolar epithelial cells facilitate gas exchange. The alveolar epithelium consists of 2 epithelial cell types that are crucial to maintain lung homeostasis and tissue repair [1]. Alveolar epithelial type I (ATI) cells are elongated with a large surface area and high barrier function, which facilitates gas exchange in close proximity to endothelial cells of the alveolar capillaries [1]. ATI cells are highly water permeable, allowing for ion transport and maintenance of lung fluid balance [2]. The latter cells cover the largest surface area of the lung [3], alveolar epithelial type II (ATII) cells, which exhibit a cubic morphology, by far outnumber ATI cells [4]. Alveolar epithelial cells express a wide variety of ion transporters and channels [8], the exact roles of these proteins for specialized alveolar cell functions have remained elusive
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