Grant-in-Aid for Scientific Research (C)
|Allocation Type||Single-year Grants |
|Research Institution||Keio University |
AKIBA Yasutada Keio University, School of Medicine, Instructor, 医学部, 助手 (50286449)
NAGATA Hiroshi Keio University, School of Medicine, Associate Professor, 医学部, 助教授 (00146599)
NAKAMURA Masahiko Center for Basic Research, The Kitasato Institute, Researcher, 基礎研究所, 研究員 (30155858)
高木 珠子 慶應義塾大学, 医学部, 助手 (90286469)
|Project Period (FY)
2001 – 2002
Completed (Fiscal Year 2002)
|Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2001: ¥2,600,000 (Direct Cost: ¥2,600,000)
|Keywords||murosal defense / ion transport / acid-sensing pathway / capsaicin-sensitive afferent nerves / luminal pH / intravital microscopy / sodium bicarbonate cotransporter / CFTR chloride channel / ion transport / sodium bicarbonate cotransporter|
1 Establishment of the integrated intravital microscopy for gastrointestinal tract
As the our previous method for rat duodenum, we have established the intravital microscopic system for rat jejunum and colon, in which intracetlular pH of the epithelial cells, injured cells and blood flow are simultaneously measured.
2 Mucosal defense mechanisms to luminal acid and acid-induced epithelial injury
Using the system above, we found that duodenal mucosal defenses in response to luminal acid are regulated by capsaicin- and COX-pathways. We also demonstrated that cellular bicarbonate uptake via sodium bicarbonate cotransporter (NBC) protects the epithelial cells from acid-induced injury arid that indomethacin increases susceptibility to acid-induced injury. Furthermore, the in vivo system enabled us to show that luminal acid and taurocholic acid (TCA) acidify jejunal epithelium and TCA under the ischemia injures the cells with intracellular acidification, and that colonic mucosal blood flow i
ncreases in response to luminal acid ranging pH 6.0 or lower through the activation of vanilloid receptor (VR).
3 Localization of ion transporter in rat gastrointestinal tract
Immunohistochemistry showed that NBC localizes on the basolateral membrane and CFTR localizes on the apical membrane of the duodenal epithelial cells, suggesting that NBC uptakes bicarbonate to enhance the cellular buffering power and CFTR secretes bicarbonate, resulting in mucosal defense.
1 Roles of afferent nerves in mucosal defense mechanisms
We found that acid-sensing pathway in mucosal defense involves VR on capsaicin-sensitive afferents in rat duodenum. VR-1 localizes in the mucosa, submucosa and myenteric plexus in gastrointestinal tract, and is related with the short chain fatty acid absorption in colon. Acid-sensing pathway in hyperemia involves vagal afferents and intrinsic afferents in duodenum.
2 Jejunal mucosal defense mechanisms
We found that TCA is absorbed by DIDS-inhibitable organic anion transporter (Oatp3) in rat jejunal epithelia and the inhibition of TCA absorption under ischemia attenuates the mucosal injury. Furthermore, P2Y receptor is involves in the regulation of jejunal mucosal defense via bicarbonate secretion.
3 Expressions of ion transport in human duodenal epithelium
Because of ethics unsolved problem, we could not prepare and sample the human duodenal biopsy specimens enough to assess. Less