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Role of transient receptor potential vanilloid 4 activation in indomethacin-induced intestinal damage.
- Source :
-
American Journal of Physiology: Gastrointestinal & Liver Physiology . Jul2014, Vol. 307 Issue 1, pG33-G40. 8p. - Publication Year :
- 2014
-
Abstract
- Gastrointestinal ulcers and bleeding are serious complications of nonsteroidal anti-inflammatory drug (NSAID) use. Although administration of antibiotics and Toll-like receptor 4 knockdown mitigate NSAID-induced enteropathy, the molecular mechanism of these effects is poorly understood. Intestinal hyperpermeability is speculated to trigger the initial damage due to NSAID use. Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel expressed throughout the gastrointestinal tract epithelium that is activated by temperature, extension, and chemicals such as 5,6-epoxyeicosatrienoic acid (5,6-EET). The aim of this study was to investigate the possible role of TRPV4 in NSAID-induced intestinal damage. TRPV4 mRNA and protein expression was confirmed by RT-PCR and immunochemistry, respectively, in mouse and human tissues while TRPV4 channel activity of the intestinal cell line IEC-6 was assessed by Ca2+-imaging analysis. TRPV4 activators or the NSAID indomethacin significantly decreased transepithelial resistance (TER) in IEC-6 cells, and indomethacin-induced TER decreases were inhibited by specific TRPV4 inhibitors or small-interfering RNA TRPV4 knockdown, as well as by the epoxygenase inhibitor N-(methylsulfonyl)- 2-(2-propynyloxy)-benzenehexanamide, which decreased 5,6- EET levels. In TRPV4 knockout mice, indomethacin-induced intestinal damage was significantly reduced compared with WT mice. Taken together, these results show that TRPV4 activation in the intestinal epithelium caused epithelial hyperpermeability in response to NSAID-induced arachidonic acid metabolites and contributed to NSAID-induced intestinal damage. Thus, TRPV4 could be a promising new therapeutic target for the prevention of NSAID-induced intestinal damage. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01931857
- Volume :
- 307
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- American Journal of Physiology: Gastrointestinal & Liver Physiology
- Publication Type :
- Academic Journal
- Accession number :
- 98541865
- Full Text :
- https://doi.org/10.1152/ajpgi.00105.2013