Abstract
Inhibition of type IV phosphodiesterase (PDE IV) activity reduces the production of various proinflammatory cytokine and suppresses neutrophil activation. Nonsteroidal anti-inflammatory drugs such as aspirin induce gastric mucosal lesions. In the pathogenesis of aspirin-induced gastric mucosal lesion, the contributions, of activated inflammatory cells and proinflammatory cytokine production are critical. The specific PDE IV inhibitor rolipram is known to be a potent inhibitor of inflammation by increasing intracellular cyclic AMP in leukocytes. The aim of the present study was to determine whether rolipram can ameliorate aspirin-induced gastric mucosal lesions in rats and whether the agent can inhibit the inrease in neutrophil accumulation and the production of proinflammatory cytokines. Gastric lesions were produced by administration of aspirin (200 mg/kg) and HCl (0.15 N; 8.0 ml/kg). Rolipram was injected 30 min before aspirin administration. The tissue myeloperoxidase concentration in gastric mucosa was measured as an indicat or of neutrophil infiltration. The gastric mucosal concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were determined by ELISA. The intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. Gastric mucosal lesions induced by aspirin were significantly inhibited by treatment with rolipram. The mucosal myeloperoxidase concentration was also suppressed by rolipram. Increases in the gastric content of TNF-α and IL-1β after aspirin administration were inhibited by pretreatment with rolipram. We demonstrated that the specific type IV PDE inhibitor, rolipram, could have a potent antiulcer effect, presumably mediated by its anti-inflammatory properties.
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Refrences
Eric V, Pierre M, Pierre L, Michel R: In vitro effect of nonsteroidal anti-inflammatory drugs on proteoglycanase and collagenase activity in human osteoarthritic cartilage. Arth Rheum 34:1332–1335, 1991
Jane H, Eric FM, Sami M, Morry Z, Les P, Nicolas JG, Peter JM, O’Hare JP: Effects of nonsteroidal anti-inflammatory drugs and water immersion. Arth Rheum 37:1132–1137, 1994
Rashad S, Revell P, Hemingway A, Low F, Rainaford K, Walker F: Effect of nonsteroidal anti-inflammatory drugs on the course of osteoarthritis. Lancet 2(8662):519–522, 1989
Paul LB, Ramnik X, Naifang LU, Nanthakumar NN, Mary D, Daniel KP, Brian S: Mechanism of NSAIDs-induced gastrointestinal injury defined using mutant mice. Gastroenterology 119:699–705, 2000
Yoshikawa T, Naito Y, Kishi A, Tomii T, Kaneko T, Iinuma S, Ichikawa H, Yasuda M, Takahashi S, Kondo M: Role of active oxygen, lipid peroxidation, and antioxidants in the pathogenesis of gastric mucosal injury induced by indomethacin in rats. Gut 34:732–737, 1993
Takeuchi K, Ueshima K, Hironaka Y, Fujioka Y, Matsumoto J, Okabe S: Oxygen free radicals and lipid peroxidation in the pathogensis of gastric mucosal lesions induced by indomethacin in rats. Relation to gastric hypermotility. Digestion 49:175–184, 1991
Andrews FJ, Malcontenti-Wilson C, O’Brien PE: Effect of nonsteroidal anti-inflammatory drugs on LFA-1 and ICAM-1 expression in gastric mucosa. Am J Physiol 266:G657–G664, 1994
John LW, Catherine MK, Granger DN: Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophil-dependent process. Am J Physiol 259:G462–G467, 1990
Yoshida N, Yoshikawa T, Nakamura Y, Arai M, Matsuyama K, Iinuma S, Yagi N, Naito Y, Miyasaka M, Kondo M: Role of neutrophil-mediated inflammation in aspirin-induced gastric mucosal injury. Dig Dis Sci 40:2300–2304. 1995
Yoshida N, Takemura T, Granger DN, Anderso DC, Wolf RE, Mclntire LV, Kvietys PK: Molecular determinations of aspirin-induced neutrophil adherence to endothelial cells. Gastroenterology 105:715–724, 1993
Naito Y, Yoshikawa T, Yagi N, Matshuyama K, Yoshida N, Seto K, Yoneta T: Effects of polaprezinc on lipid peroxidation, neutrophil accumulation, and TNF-α expression in ratswith aspirin-induced gastric mucosal injury. Dig Dis Sci 46:845–851, 2001
Peter K, Hayley JH, Mauro P: Effect of rolipram in a murine model of acute inflammation: comparison with the corticoid dexamethasone. Eur J Pharmacol 281:69–74, 1995
Mary SB, Joan O’ LB, Miriam B, Siegfried BC, Lenora BC, Klaus ME, Uma SP, Julia AR, Theodore JT: Association of the anti-inflammatory activity of phosphodiesterase 4(PDE4) inhibitors with either inhibition of PDE4 catalytic activity or competition for [3H] rolipram binding. Biochem Pharmacol 51:949–956, 1996
Chitta SK, Carrie LS, Michael PD, Daniel WC: Regulation of IL-15-stimulated TNF-α production by rolipram. J Immunol 163:2836–2843, 1999
Mark DO, Joel L, Liping H, Diane LR, David FS, Gail S: Enhanced protection from renal ischemia: Reperfusion injury with A2A-adenosine receptor activation and PDE4 inhibition. Kidney Int 59:2114–2125, 2001
Sekut L, Yarnall D, Stimpson SA, Noel LS, Bateman-Fite R, Clark RL, Brackeen MF, Menius JA, Jr, Connolly KM: Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation. Clin Exp Immunol 100:126–132, 1995
Nakamura C, Otaka M, Odashima M, Jin M, Konishi N, Horikawa Y, Matsuhashi T, Watanabe S: Rolipram, a specific type IV phosphodiesterase inhibitor, ameliorates indomethacin-induced gastric mucosal injury in rats. Pathophysiology 9:195–200, 2003
Brodie DA, Hanson HW: A study of the factors involved in the production of gastric ulcers by restraint technique. Gastroenterology 38:353–361, 1960
Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254, 1976
Trevethic MA, Clayton NM, Strong P, Harman IW: Do infiltrating neutrophils contribute to the pathogenesis of indomethacin induced ulceration of the gastric antrum. Gut 34:156–160, 1993
Toroudi HP, Rahgozar M, Bakhtiarian A, Djahanguiri B: Potassium channel modulatora and indomethaxin-induce gastric ulceration in rats. Scand J Gastroenterol 34:962–966, 1999
Santucci L, Fiorucci M, Giansanti M, Brunori PM, Di Matteo FM, Morelli A: Role of tumor necrosis factor α release and leukocyte margination in indomethaxin-induced gastric injury in rats. Gastroenterology 108:393–401, 1995
Stephen JB, Morise Z, Sven T, Laureen M, Granger DN, Matthew BG: Role of the proteasome in rat indomethacin-induced gastropathy. Gastroenterology 116:865–873, 1999
Jeffrey LL, Michael VP, Lee EG, Christopher RS: The toxicity of repeated exposures to rolipram, a Type IV phosphodiesterase inhibitor, in rats. Pharmacol Toxicol 78:44–49, 1996
Theudore JT: Phosphodiesterase isozymes. Am J Respir Crit Care Med 157:351–370, 1998
Joseph AB: Cyclic nucleotide phosphodiesterases: Functional implications of multiple isoforms. Physiol Rev 75:725–748, 1995
Torphy TJ: Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 157:351–370, 1998
Moore AR, Willoughby DA: The role of cAMP regulation in controlling inflammation. Clin Exp Immunol 101:387–389, 1995
Bourne HR, Lichtenstein LM, Melmon KL, Henney CS, Weinstein Y, Shearer GM: Modulation of inflammation and immunity by cyclic AMP. Science 184:19–28, 1974
Sekut L, Yarnall D, Stimpson SA, Noel LS, Bateman-Fite R, Clark RL, Brackeen MF, Menius JR JA, Connolly KM: Anti-inflammatory activity of phosphodiesterase(PDE)-IV inhibitors in acute and chronic models of inflammation. Clin Exp Immunol 100:126–132, 1995
Reuter BK, Wallence JL: Phosphodiesterase inhibitors prevent NSAID enteropathy independent of effects on TNF-α release. Am J Physiol 277:G847–G854, 1999
Semmler J, Wachtel H, Endres S: The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-alpha production by human mononuclear cells. Int J Immunopharmacol 15:409–413, 1993
Santucci L, Fiorucci M, Giansanti M, Brunori PM, Di Matteo FM, Morelli A: Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumor necrosis factor alpha. Gut 35:909–915, 1994
Yoshikawa T, Takano H, Naito Y, Oyamada H, Ueda S, Kondo M: Augmentative effects of tumor necrosis factor-alpha (human, natural type) on polymorphonuclear leukocyte-derived superoxide generation induced by various stimulants. Int J Immunopharmacol 14:1391–1398, 1992
Kokura S, Wolf RE, Yoshikawa T, Granger DN, Aw TY: T-Lymphocyte-derived tumor necrosis factor exacerbates anoxia-reoxygenation-induced neutrophil-endothelial cell adhesion. Circ Res 86:205–213, 2000
Kahky MP, Daniel CO, Cruz AB, Gaskill HV 3rd: Portal infusion of tumor necrosis factor increases mortality in rats. J Surg Res 49:138–145, 1990
Spatafora M, Chiappara G, D’Amico D, Volpes D, Melis M, Pace E, Merendino A: Effect of indomethacin on the kinetics of tumour necrosis factor alpha release and tumour necrosis factor alpha gene expression by human blood monocytes. Pharmacol Res 23:247–257, 1991
Martich GD, Parker MM, Cunnion RE, Suffredini AF: Effects of ibuprofen and pentoxifylline on the cardiovascular response of normal humans to endotoxin. J Appl Physiol 73:925–931, 1992
Yasumoto K, Okamoto S, Mukaida N, Murakami S, Mai M, Matsushima K: Tumor necrosis factor alpha and interferon gamma synergistically induce interleukin 8 production in a human gastric cancer cell line through acting concurrently on AP-1 and NF-kB-like binding sites of the interleukin 8 gene. J Biol Chem 267:22506–22511, 1992
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Odashima, M., Otaka, M., Jin, M. et al. Rolipram, a Specific Type IV Phosphodiesterase Inhibitor, Ameliorates Aspirin-Induced Gastric Mucosal Injury in Rats. Dig Dis Sci 50, 1097–1102 (2005). https://doi.org/10.1007/s10620-005-2711-9
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DOI: https://doi.org/10.1007/s10620-005-2711-9