An Oral Drug Delivery System Targeting Immune-Regulating Cells Ameliorates Mucosal Injury in Trinitrobenzene Sulfonic Acid-Induced Colitis
- Hiroshi Nakase1,
- Kazuichi Okazaki1,
- Yasuhiko Tabata2,
- Suguru Uose1,
- Masaya Ohana1,
- Kazushige Uchida1,
- Toshiki Nishi1,
- Andra's Debreceni1,
- Toshiyuki Itoh1,
- Chiharu Kawanami1,
- Masao Iwano1,
- Yoshito Ikada2 and
- Tsutomu Chiba1
- 1Division of Gastroenterology and Endoscopic Medicine (H.N., K.O., S.U., M.O., K.U., T.N., A.D., T.I., C.K., M.I., T.C.), 2Graduate School of Medicine, and Institute for Frontier Medical Science (Y.T., Y.I.), Kyoto University, Kyoto, Japan
Abstract
Control of immune-regulating cells in the colonic mucosa is important in the treatment of patients with inflammatory bowel disease (IBD). The aim of study was to examine the therapeutic effect of dexamethasone (DX) microspheres on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats, a model for human Crohn's disease. DX microspheres and DX alone were administered orally to rats with TNBS-induced colitis. The macroscopic score, histological score, myeloperoxidase (MPO) activity, nitric oxide (NO) production, and gene expressions of proinflammatory cytokines, cyclooxygenase (COX)-1, and COX-2 in the colonic tissue were determined. Proliferating cell nuclear antigen (PCNA) staining and expression of nuclear transcription factor (NF)-κB in colonic tissues were also investigated. Macroscopic score, histological score, MPO activity, and NO production in rats treated with DX microspheres were significantly lower than in those treated with DX alone. The gene expression of proinflammatory cytokines and COX-2 in rats treated with DX microspheres was down-regulated, compared with that in rats treated with DX alone. The number of PCNA-positive cells in the DX microsphere group was larger than in the group treated with DX alone. DX microspheres suppressed NF-κB activation in TNBS-induced colitis more strongly than DX alone. Oral administration of DX microspheres appears to ameliorate mucosal injury in TNBS-induced colitis. This drug delivery system could be an ideal therapy for human IBD.
Footnotes
-
Send reprint requests to: Dr. Kazuichi Okazaki, Division of Gastroenterology and Endoscopic Medicine, Graduate School of Kyoto University, 54 Shogoinkawara-cho, Sakyoku, Kyoto, 606-8507, Japan. E-mail:okak{at}kuhp.kyoto-u.ac.jp
-
This work was supported by Grant-in-aid for Scientific Research 09670543 from the Ministry of Culture and Science of Japan, by Grant-in-aid for Research for the Future Program JSPS-RFTF 97100201 from the Japan Society for the Promotion of Science, by Research Fellowship 03340 from the Japan Society for the Promotion of Science for Young Scientists, and by supporting research funds JFE-1997 from the Japanese Foundation for Research and Promotion of Endoscopy.
- Abbreviations:
- UC
- ulcerative colitis
- CD
- Crohn's disease
- IBD
- inflammatory bowel disease
- PDLLA
- poly-d,l-lactic acid
- DX
- dexamethasone
- DSS
- dextran sulfate sodium
- TNBS
- 2,4,6-trinitrobenzene sulfonic acid
- IFN
- interferon
- IL
- interleukin
- NF-κB
- nuclear factor-κB
- MPO
- myeloperoxidase
- NO
- nitric oxide
- COX
- cyclooxygenase
- PBS
- phosphate-buffered saline
- PCNA
- proliferating cell nuclear antigen
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- TNF
- tumor necrosis factor
- EMSA
- electrophoretic mobility shift assays
-
- Received September 9, 2000.
- Accepted February 21, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
