BACKGROUND & AIMS: Crohn's disease (CD) is a chronic inflammatory bowel disease. In this study, we have investigated sodium absorption via epithelial sodium channels (ENaC) in the macroscopically noninflamed colon in active CD. METHODS: Sodium transport via ENaC was investigated in Ussing chambers using biopsy specimens of sigmoid colon from controls and active CD limited to the small intestine. ENaC messenger RNA expression and subcellular localization were studied by real-time polymerase chain reaction and confocal microscopy. Effects of proinflammatory cytokines on ENaC and signaling via mitogen-activated protein kinases were investigated in rat distal colon. Therapeutic inhibition of mitogen-activated protein kinases was studied in CD biopsy specimens. RESULTS: Electrogenic sodium absorption via ENaC was strongly impaired in the macroscopically noninflamed CD colon because of reduced gamma-ENaC transcription, whereas subcellular localization of ENaC was not changed. In contrast to impaired epithelial sodium transport, epithelial barrier function was not altered in noninflamed CD colon, indicating that paracellular leak flux of ions did not contribute to decreased sodium absorption. Exposure of rat distal colon to tumor necrosis factor alpha led to reduced electrogenic sodium absorption because of impaired transcriptional gamma-ENaC induction, which resembled the changes found in CD. Tumor necrosis factor alpha effects were dependent on extracellular signal-regulated kinase 1/2 but not p38 or c-Jun-N-terminal kinase because inhibition of mitogen-activated protein kinase/extracellular regulated kinase (MEK)1/2 but not inhibition of p38 or c-Jun-N-terminal kinase prevented suppression of ENaC. Finally, therapeutic inhibition of MEK1/2 restored electrogenic sodium absorption in CD. CONCLUSIONS: In CD, macroscopically noninflamed colon contributes to diarrhea via impaired ENaC-mediated sodium absorption. Inhibition of extracellular signal-regulated kinase might serve as a potential therapeutic strategy for CD diarrhea.
BACKGROUND & AIMS:Crohn's disease (CD) is a chronic inflammatory bowel disease. In this study, we have investigated sodium absorption via epithelial sodium channels (ENaC) in the macroscopically noninflamed colon in active CD. METHODS:Sodium transport via ENaC was investigated in Ussing chambers using biopsy specimens of sigmoid colon from controls and active CD limited to the small intestine. ENaC messenger RNA expression and subcellular localization were studied by real-time polymerase chain reaction and confocal microscopy. Effects of proinflammatory cytokines on ENaC and signaling via mitogen-activated protein kinases were investigated in rat distal colon. Therapeutic inhibition of mitogen-activated protein kinases was studied in CD biopsy specimens. RESULTS: Electrogenic sodium absorption via ENaC was strongly impaired in the macroscopically noninflamed CD colon because of reduced gamma-ENaC transcription, whereas subcellular localization of ENaC was not changed. In contrast to impaired epithelial sodium transport, epithelial barrier function was not altered in noninflamed CD colon, indicating that paracellular leak flux of ions did not contribute to decreased sodium absorption. Exposure of rat distal colon to tumor necrosis factor alpha led to reduced electrogenic sodium absorption because of impaired transcriptional gamma-ENaC induction, which resembled the changes found in CD. Tumor necrosis factor alpha effects were dependent on extracellular signal-regulated kinase 1/2 but not p38 or c-Jun-N-terminal kinase because inhibition of mitogen-activated protein kinase/extracellular regulated kinase (MEK)1/2 but not inhibition of p38 or c-Jun-N-terminal kinase prevented suppression of ENaC. Finally, therapeutic inhibition of MEK1/2 restored electrogenic sodium absorption in CD. CONCLUSIONS: In CD, macroscopically noninflamed colon contributes to diarrhea via impaired ENaC-mediated sodium absorption. Inhibition of extracellular signal-regulated kinase might serve as a potential therapeutic strategy for CD diarrhea.
Authors: Cole B Enns; Brandon A Keith; Nitin Challa; John C S Harding; Matthew E Loewen Journal: Am J Physiol Gastrointest Liver Physiol Date: 2019-11-25 Impact factor: 4.052
Authors: Rebecca A Chanoux; Calla B Shubin; Amal Robay; Laurence Suaud; Ronald C Rubenstein Journal: Am J Physiol Cell Physiol Date: 2013-07-24 Impact factor: 4.249
Authors: Dorothea M Peters; István Vadász; Lukasz Wujak; Malgorzata Wygrecka; Andrea Olschewski; Christin Becker; Susanne Herold; Rita Papp; Konstantin Mayer; Sebastian Rummel; Ralph P Brandes; Andreas Günther; Siegfried Waldegger; Oliver Eickelberg; Werner Seeger; Rory E Morty Journal: Proc Natl Acad Sci U S A Date: 2013-12-09 Impact factor: 11.205