A new drug delivery system targeting ileal epithelial cells induced electrogenic sodium absorption: Possible promotion of intestinal adaptation following total colectomy
Sho Haneda1, Kouhei Fukushima1, Yuji Funayama1, Chikashi Shibata1, Ken-ichi Takahashi1, Hitoshi Ogawa1, Yasuhiko Tabata2, Iwao Sasaki1; 1Surgery, Tohoku University, Graduate School of Medicine, Sendai, Japan; 2Institute for Frontier Medical Science, Kyoto University, Kyoto, Japan
Background: Patients undergoing total proctocolectomy (TPC) suffer from persistent postoperative diarrhea and frequent bowel movement. We investigated mechanisms of intestinal adaptation and demonstrated induction of the epithelial sodium channel (ENaC), prostasin, and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and activation of sodium transport mediated by those molecules in the remnant ileum (AJP276:G975, Surgery137:75). Aldosterone infusion also induced the expression of these molecules (J GI Surg9:236), suggesting locally enhanced mineralocorticoid action in the absence of systemic effects may be therapeutically beneficial in patients with persistent diarrhea after TPC. Objective: The aims of the present study were to develop a new drug delivery system that targets ileal epithelial cells, to induce the molecules for sodium absorption and to investigate whether this system has therapeutic roles for postoperative diarrhea following TPC. Methods: We established D-aldosterone-containing D,L-lactide/glycolide copolymer (PLGA) microspheres (Ald-PLGA). Ald-PLGA are absorbed in the terminal ileum and gradually release aldosterone in rats. Blood and terminal ileal tissues were collected two weeks after the administration of Ald-PLGA, D-aldosterone or PLGA alone. We measured the aldosterone concentrations in plasma and ileal tissues. We evaluated mRNA expressions of three subunits of ENaC, prostasin, 11β-HSD2, sodium/glucose co-transporter 1 (SGLT-1), and α1-, and β1-subunit of Na/K ATPase in epithelial cells of the ileum. Protein expression of ENaC α-subunit and ENaC-mediated sodium transport were evaluated by immunohistochemical and electrophysiological techniques, respectively. Results: Significantly high levels (200 pg/g) of tissue aldosterone in the absence of elevated plasma levels were detected only in the Ald-PLGA-treated rats. Epithelial expression of ENaC subunits, prostasin and 11β-HSD2 but not of SGLT-1 and Na/K ATPase subunits mRNAs increased significantly only in the Ald-PLGA-treated animals. ENaC protein expression was enhanced in the brush border of the ileal epithelia only in the Ald-PLGA-treated rats. That was the case in amiloride-sensitive electrogenic sodium transport. Conclusion: Ald-PLGA successfully induced the expression of several molecules participating in aldosterone-mediated sodium absorption and activated sodium transport in the ileal mucosa, both of which are essential for intestinal adaptation. Pre- and/or post-operative treatment with this drug may compensate for the excessive loss of sodium and water following TPC.
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