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Effect of Carboxamide Derivative IS-741 on Rat Spontaneous Chronic Pancreatitis

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Abstract

This study aimed to analyze the therapeutic effects of the carboxamide derivative IS-741 on spontaneous chronic pancreatitis (CP) in the WBN/Kob rat. Four-week-old male WBN/Kob rats were fed with MB-3, and IS-741 (0.012% in MB-3) was orally administered for 12 weeks. Cytokine-induced neutrophil chemoattractant (CINC), interleukin (IL) -6, pancreatitis-associated protein (PAP), and p8 mRNAs in the pancreas were detected with semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Histological examination of the pancreas showed that hemorrhage, interstitial edema, and inflammatory cell infiltration were markedly less severe at 12 weeks, while fibrosis and acinar degeneration were also milder at 16 weeks, in the IS-741-treated rats than in untreated rats. The above-mentioned genes were significantly suppressed in IS-741-treated rats at 12 weeks. Our results show that IS-741 exerts a potentially therapeutic effect on experimental CP by suppressing the expressions of the proinflammatory cytokines (IL-6 and CINC) and pancreatic acute phase proteins (PAP and p8).

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REFERENCES

  1. DiMagno EP, Layer P, Clain JE: Chronic pancreatitis. In The Pancreas: Biology, Pathobiology and Diseases, 2nd ed. VLW Go, EP DiMagno, JD Gardner, E Lebenthal, HA Reber, GA Scheele (eds). New York, Raven Press, pp 665–706, 1993

    Google Scholar 

  2. Kloppel G, Maillet B: Pathology of acute and chronic pancreatitis. Pancreas 8:659–670, 1993

    Google Scholar 

  3. Heath DI, Cruickshank A, Gudgeon M, Jehanli A, Shenkin A, Imrie CW: Role of interleukin-6 in mediating the acute phase protein response and potential as an early means of severity assessment in acute pancreatitis. Gut 34:41–45, 1993

    Google Scholar 

  4. Inagaki T, Hoshino M, Hayakawa T, Ohara H, Yamada T, Yamada H, Iida M, Nakazawa T, Ogasawara T, Uchida A, Hasegawa C, Miyaji M, Takeuchi T: Interleukin-6 is a useful marker for early prediction of the severity of acute pancreatitis. Pancreas 14:1–8, 1997

    Google Scholar 

  5. Gukovskaya AS, Gukovsky I, Zaninovic V, Song M, Sandoval D, Gukovsky S, Pandol SJ: Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-α. J Clin Invest 100:1853–1862, 1997

    Google Scholar 

  6. Saurer L, Reber P, Schaffner T, Buchler MW, Buri C, Kappeler A, Walz A, Friess H, Mueller C: Differential expression of chemokines in normal pancreas and in chronic pacreatitis. Gastroenterology 118:356–367, 2000

    Google Scholar 

  7. Exley AR, Leese T, Holliday MP, Swann RA, Cohen J. Endotoxaemia and serum tumour necrosis factor as prognostic markers in severe acute pancreatitis. Gut 33:1126–1128, 1992

    Google Scholar 

  8. Dusetti NJ, Ortiz EM, Mallo GV, Dagorn JC, Iovanna JL: Pancreatitis-associated protein I (PAP I), an acute phase protein induced by cytokines: Identification of two functional interleukin-6 response elements in the rat PAP I promoter region. J Biol Chem 270:22417–224121, 1995

    Google Scholar 

  9. Mallo GV, Fiedler F, Calvo EL, Ortiz EM, Vasseur S, Keim V, Morisset J, Iovanna JL: Cloning and expression of the rat p8 cDNA, a new gene activated in pancreas during the acute phase of panreatitis, pancreatic development, and regeneration, and which promotes cellular growth. J Biol Chem 272:32360–32369, 1997

    Google Scholar 

  10. Su S-B, Motoo Y, Xie M-J, Sakai J, Taga H, Sawabu N: Expression of pancreatitis-associated protein in rat spontaneous chronic pancreatitis: effect of herbal medicine Saikokeishito (TJ-10). Pancreas 19:239–247, 1999

    Google Scholar 

  11. Motoo Y, Sawabu N, Xie M-J, Su S-B, Mallo GV, Iovanna JL: p8 expression is induced in acinar cells during chronic pancreatitis. Dig Dis Sci 46:1640–1646, 2001

    Google Scholar 

  12. Yotsuya S, Shikama H, Nakano I, Sakai K, Kato M, Sugi H, Takada H, Koga Y: A novel synthetic anti-acute pancreatitis agent, IS-741. Digestion 60(suppl 1):34–39, 1999

    Google Scholar 

  13. Adachi K, Yotsuya S, Umaniwa J, Ohara K, Shikama H: Effect of IS-741, a new synthetic anti-acute pancreatitis agent, on nertrophil infiltration in the pancreatic tissue in acute pancreatitis in rats. J Jpn Panc Soc 13:239, 1998 (Abstract in Japanese)

    Google Scholar 

  14. Isaji S, Hayashi J, Higashiguchi T, Yokoi H, Ogura Y, Noguchi T, Kawarada Y: Effect of IS-741 (a new synthetic antiinflammatory agent) on acute necrotizing pancreatitis in dogs. Digestion 60:47–51, 1999

    Google Scholar 

  15. Liang J, Yamaguchi Y, Matsumura F, Okabe K, Akizuki E, Matsuda T, Ohshiro H, Nakano S, Ishihara K, Ogawa M: Novel carboxamide derivative (IS-741) attenuates lung injury in rats with cerulein-induced pancreatitis complicated by endotoxemia. Dig Dis Sci 44:341–349, 1999

    Google Scholar 

  16. Tsuchitani M, Saegusa T, Narama I, Nishikawa T, Gonda T: A new diabetic strain of rat (WBN/Kob). Lab Anim 19:200–207, 1985

    Google Scholar 

  17. Nakama K, Shichinohe K, Kobayashi K, Naito K, Uchida O, Yasuhara K, Tobe M: Spontaneous diabetes-like syndrome in WBN/Kob rats. Acta Diabetol Lat 22:335–342, 1985

    Google Scholar 

  18. Kobori O, Gedigk P, Totovic V: Adenomatous changes and adenocarcinoma of glandular stomach in Wistar rats induced by N-methyl-N-nitro-N-nitrosoguanidine: An electron microscopic and histochemical study. Virchows Arch A Pathol Anat 373:37–54, 1977

    Google Scholar 

  19. Ohashi K, Kim JH, Hara H, Aso R, Akimoto T, Nakama K: WBN/Kob rats: A new spontaneously occurring model of chronic pancreatitis. Int J Pancreatol 6:231–247, 1990

    Google Scholar 

  20. Xie M-J, Motoo Y, Su S-B, Sawabu N: Expression of clusterin in pancreatic acinar cell injuries in vivo and in vitro. Pancreas 22:126–134, 2001

    Google Scholar 

  21. Sugiyama M. Kobori O, Atomi Y, Wada N, Kuroda A, Muto T: Effect of oral administration of protease inhibitor on pancreatic exocrine function in WBN/Kob rats with chronic pancreatitis. Pancreas 13:71–79, 1996

    Google Scholar 

  22. Klöppel G, Maillet B: Chronic pancreatitis: Evolution of disease. Hepatogastroenterology 38:408–412, 1991

    Google Scholar 

  23. Watanabe K, Konishi K, Fujioka M, Kinoshita S, Nakagawa H: The neutrophil chemoattractant produced by the rat kidney epithelial cell line NRK-52E is a protein related to the KC/gro protein. J Biol Chem 264:19559–19561, 1989

    Google Scholar 

  24. Watanabe K, Suematsu M, Iida M, Takaishi K, Iizuka Y, Suzuki H, Suzuki M, Tsuchiya M, Tsurufuji S: Effect of rat CINC/gro, a member of the interleukin-8 family, on leukocytes in microcirculation of the rat mesentery. Exp Mol Pathol 56:60–69, 1992

    Google Scholar 

  25. Watanabe K, Kinoshita S, Nakagawa H: Purification and characterization of cytokine-induced neutrophil chemoattractant produced by epithelial cell line of normal rat kidney (NRK-52E cell). Biochem Biophys Res Commun 161:1093–1099, 1989

    Google Scholar 

  26. Gross V, Andreese R, Leser H-G, Ceska M, Liehl E, Lausen M, Farthmann EH, Scholmerich J: Interleukin-8 and neutrophil activation in acute pancreatitis. Eur J Clin Invest 22:200–203, 1992

    Google Scholar 

  27. Pezzilli R, Billi P, Miniero R, Fiocchi M, Cappelletti O, Morselli-Labate AM, Barakat B, Sprovieri G, Miglioli M: Serum interleukin-6, interleukin-8, and β2-microglobulin in early assessment of severity of acute pancreatitis. Dig Dis Sci 40:2341–2348, 1995

    Google Scholar 

  28. Rau B, Steinbach G, Gansauge F, Mayer JM, Grunert A, Beger HG: The potential role of procalcitonin and interleukin-8 in the prediction of infected necrosis in acute pancreatitis. Gut 41:832–840, 1997

    Google Scholar 

  29. Osman MO, Kristensen JU, Jacobsen NO, Lausten SB, Deleuran B, Deleuran M, Gesser B, Matsushima K, Larsen CG, Jensen SL: A monoclonal anti-inteleukin 8 antibody (WS-4) inhibits cytokine response and acute lung injury in experimental severe acute necrotising pancreatitis in rabbits. Gut 43:232–239, 1998

    Google Scholar 

  30. Frevert CW, Huang S, Danaee H, Paulauskis JD, Kobzik L: Functional characterization of the rat chemokine KC and its importance in neutrophil recruitment in a rat model of pulmonary inflammation. J Immunol 154:335–344, 1995

    Google Scholar 

  31. Tosato G, Seamon KB, Goldman ND, Sehgal PB, May LT, Washington GC, Jones KD, Pike SE: Monocyte derived human B-cell growth factor identified as interferon-β2 (BSF-2, IL-6). Science 239:502–504, 1988

    Google Scholar 

  32. Astaldi GC, Janssen MC, Lansdorp PM, Zeijlemarker WP, Willems C: Human endothelial culture supernatant (HECS): Evidence for a growth-promoting factor binding to hybridoma and myeloma cells. J Immunol 126:1170–1173, 1981

    Google Scholar 

  33. Keim V, Rohr G, Stöckert HG, Haberich FJ: An additional secretory protein in the rat pancreas. Digestion 29:242–249, 1984

    Google Scholar 

  34. Iovanna JL, Orelle B, Keim V, Dagorn J-C: Messenger RNA sequence and expression of rat pancreatitis-associated protein, a lectin-related protein overexpressed during acute experimental pancreatitis. J Biol Chem 266:24664–24669, 1991

    Google Scholar 

  35. Motoo Y, Taga K, Su S-B, Xie M-J, Sawabu N: Arginine induces apoptosis and gene expression of pancreatitisassociated protein (PAP) in rat pancreatic acinar AR4—2J cells. Pancreas 20:61–66, 2000

    Google Scholar 

  36. Keim V, Iovanna JL, Rohr G, Usadel K, Dagorn J-C: Characterization of a rat pancreatic secretory portein associated with pancreatitis. Gastroenterology 100:775–782, 1991

    Google Scholar 

  37. Keim V, Willemer S, Iovanna JL, Adler G, Dagorn J-C: Rat pancreatitis-associated protein is expressed in relation to severity of experimental pancreatitis. Pancreas 9:606–612, 1994

    Google Scholar 

  38. Vasseur S, Mallo GV, Fiedler F, Bodeker H, Canepa E, Moreno S, Iovanna JL: Cloning and expression of the human p8, a nuclear protein with mitogenic activity. Eur J Biochem 259:670–675, 1999

    Google Scholar 

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Xie, MJ., Motoo, Y., Su, SB. et al. Effect of Carboxamide Derivative IS-741 on Rat Spontaneous Chronic Pancreatitis. Dig Dis Sci 47, 139–147 (2002). https://doi.org/10.1023/A:1013232024148

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