Abstract
Many of the complications of septic shock are believed to be a consequence of elevated circulating levels of tumor necrosis factor (TNF), which is an important mediator of tissue injury. Prostaglandins (PGs) of the E series have recently been reported to inhibit TNF productionin vitro. We investigated thein vivo effect of misoprostol, a PGE1 analog, on endotoxin-induced gastric mucosal injury and TNF production. For the gastric mucosal injury studies, groups of animals were pretreated with intragastric misoprostol (100 and 200 μg/kg) or with antacid (2 ml/animal of Maalox Plus) 30 min prior to a challenge with intravenousE. coli lipopolysaccharide (LPS) at 5.0 mg/kg. Stomachs were examined 3 hr after LPS. Systemic endotoxin alone induced microscopic edema, vascular congestion, and polymorphonuclear (PMN) infiltration of the gastric mucosa. Pretreatment with misoprostol, but not with antacid, significantly and dose-dependently reduced the gastric mucosal injury. For the TNF studies, groups of rats were given either misoprostol (100 or 200 μg/kg, intragastric), or saline 1 hr prior to LPS challenge. Serum samples were obtained 1.5 hr after LPS challenge. Misoprostol dose-dependently and significantly (P<0.01) inhibited TNF activity. We conclude that misoprostol is a potent inhibitor of TNF systemic production and inhibits the gastric mucosal injury induced by endotoxemia. These studies suggest a potentially important therapeutic role for misoprostol in inflammatory diseases in which TNF exerts a contributory role.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Schuster DP, Rawley H, Feinstein S: Prospective evaluation of the risk factor of upper gastrointestinal bleeding after admission to a medical intensive care unit. Am J Med 76:623–630, 1984
Skillman JJ, Brushnell LS, Goldman H, Silen W: Respiratory failure, hypotension, sepsis and jaundice. A clinical syndrome associated with lethal hemorrhage from acute stress ulceration of the stomach. Am J Surg 117:523–530, 1969
Robert A, Nezamise JE, Lancaster C, Hanchar AJ: Cytoprotection by prostaglandin in rats. Prevention of gastric necrosis produced by alcohol, HCl, NaOH, hypertonic NaCl, and thermal injury. Gastroenterology 77:433–443, 1979
Colton DG, Driskill DR, Phillips EL, Poy P, Dajani EZ: Effect of SC-29333, an inhibitor of gastric secretion on canine gastric mucosal blood flow and serum gastrin levels. Arch Int Pharmacodyn Ther 236:86–95, 1978
Larsen KR, Jensen NF, David EK, Jensen JC, Moody FG: The cytoprotective effect of 15-deoxy-16-alpha, betahydroxy-16-methyl PGE1 methyl ester (SC-29333) versus aspirin-shock gastric ulcerogensis in the dog. Prostaglanidns 21(suppl):119–124, 1981
Akdamar K, Agrawal NM, Ertan A: Inhibition of nocturnal gastric secretion in normal human volunteers by misoprostol: A synthetic prostaglandin E1 methyl ester analog. Am J Gastroenterol 77:902–904, 1982
Wilson DE, Quadros E, Rajapaksa T, Adams A, Noar M: Effect of misoprostol on gastric acid and mucus secretion in man. Dig Dis Sci 31(suppl):126S-129S, 1986
Dajani EZ: Overview of the mucosal protective effects of misoprostol in man. Prostaglandins 33(suppl):117–129, 1987
Godiwala T, Agrawal NM, Groot K, Arimura A, Dajani EZ: Is cytoprotection by misoprostol against ethanol-induced gastric mucosal injury in man mediated by somatostatin. Prostaglandins 33(suppl):130–131, 1987
Dajani EZ, Wehrschütz E: Prostaglandins and the integrity of the gastrointestinal mucosa.In Erosionen in Magen und Duodenum. Y Van Maercke, W Bergemann (eds). New York, VCH Publishers, 1987, pp 211–216
Ito S, Lacy ER: Morphology of rat gastric mucosal damage, defence and restitution in the presence of luminal ethanol. Gastroenterology 88:250–260, 1985
Tarnawski A, Hollander D, Stachura J, Krause WJ, Gargely A: Prostaglandin protection of the gastric mucosa against alcohol injury: A dynamic time related process. Gastroenterology 88:334–352, 1985
Beutler B, Cerami A: Cachectin: More than a tumor necrosis factor. N Engl J Med 316:379–385, 1987
Tracey KJ, Beutler SF, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey III TJ, Zentella A, Albert JD, Shires GT, Cerami A: Shock and tissue injury induced by recombinant human cachectin. Science 234:470–474, 1988
Strieter RM, Remick DG, Lynch JP II, Genord M, Raiford C, Spengler SL: Differential regulation of tumor necrosis factor-alpha in human alveolar macrophages and peripheral blood monocytes: A cellular and molecular analysis. Am J Respir Cell Mol Biol 1:57–63, 1989
Pohlman TH, Stannes KA, Beatty PG, Oxchs HD, Harlan JM: An endothelial cell surface interleukin i, and tumor necrosis factor alpha increases neutrophil adherence by CDW-18 depended mechanism. J Immunol 136:4548–4553, 1986
Shalaby MR, Aggrawal BB, Ainkdernecht E, Svendersky LP, Finkle BS, Palladino A Jr: Activation of human polymorphonuclear neutrophil function by interferon-gamma and tumor necrosis factors. J Immunol 135:2069–2073, 1985
Gamble JR, Harlan JM, Klebanoff SL, Vadas MA: Stimulation of adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci USA 82:8667–8671, 1985
Le J, Vilcek J: Tumor necrosis factor and interleukin 1: Cytokines with multiple overlapping biological activities. Lab Invest 56:234–248, 1987
Kinkel SL, Spengler M, May MM, Spengler R, Larrick J, Remick D: Prostaglandin E2 regulates macrophage-derived tumor necrosis factor gene expression. J Biol Chem 263:5380–5384, 1988
Scales WE, Chensue SW, Otterness J, Kinkel SL: Regulation of monokine gene expression: Prostaglandin E2 suppresses tumor necrosis factor but not interleukin-1 alpha or beta mRNA and cell associated bioactivity. J Leukocyte Biol 45(5):416–421, 1989
Nelson S, Bagby GJ, Bainton BG, Wilson LA, Thompson JJ, Summer WR: Compartmentalization of intraalveolar and systemic lipopolysaccharide induced tumor necrosis factor and pulmonary inflammatory response. J Infect Dis 159(2):189–194, 1989
Wilson F: Surgical intensive care units.In Major Issues in Critical Care Medicine. JE Parrillo, SM Ayres (eds). Baltimore, Williams and Wilkins, 1984, pp 17–33
Parrillo JE: Septic shock in humans: Clinical evaluation, pathophysiology, and therapeutic approach.In Textbook of Critical Care. 2nd ed. WC Shoemaker, Thompson WL, Holbrook P (eds). Philadelphia, Saunders, 1989, pp 1006–1023
Tracey KJ, Lowry SF, Cerami A: Cachetin: A hormone that triggers acute shock and chronic cachexia. J Infect Dis 157:413–420, 1988
Arvidsson S, Haglund U: On the pathogenesis of acute gastric mucosal lesions in septic shock. Scand J Gastroenterol (Suppl) 105:67–74, 1984
Arvidsson S, Fält K, Haglund U: Gastric mucosal damage in spesis-effects of pretreatment with a synthetic prostaglandin E1 analogue. Gut 26:1025–1031, 1985
Zinner MJ, Rypins EB, Martin LR, Jonansson O, Hoover EL, Swab EA, Fakouhi TD: Misoprostol versus antacid titration for preventing stress ulcers in post-operative surgical ICU patients. Ann Surg 210:500–595, 1989
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
Ferguson Chanowitz KM, Katocs AS Jr, Pickett WC, Kaplan JB, Sasse PM, Kerwar SS: Platelet-activating factor or a platelet-activating factor antagonist decreases tumor necrosis factor-alpha in the plasma of mice treated with endotoxin. J Infect Dis 162:1081–1086, 1990
Dajani EZ, Bianchi RG, Calhoun DW: Synergistic actions of propantheline bromide with cimetidine and thiopropazate hydrochloride in the prevention of stress ulcer formation in rats. J Pharmacol Exp Ther 210:373–377, 1979
Dajani EZ, Bianchi RG, Casler JJ, Weet JF: Gastric antiulcer and antisecretory effect of carbenoxolone, aldosterone and desoycoricosterone in rats. Arch Int Pharmacodyn Ther 242:128–138, 1979
Bianchi RG, Casler JJ, Dajani EZ: Gastric antisecretory and antiulcer activity of SC-29333: A synthetic E-prostaglandin analog. Pharmacologist 23:121, 1981 (abstract)
Dajani EZ: Perspectives on the pharmacology of misoprostol.In Ulcer Disease: New Aspects of Pathogenesis and Pharmacology. S Szabo, C Pfeifer (eds). Boca Raton, Florida, CRC Press, 1989, pp 321–334
Oliff A: The role of tumor necrosis factor (cachetin) in cachexia. Cell 54:141–142, 1988
Levine B, Kalman J, Mayer L, Fillit HM, Packer M: Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 323:236–241, 1990
Kwiatkowski D, Hill AVS, Sambou I, Twumasi P, Castracane J, Manogue KR, Cerami A, Brewster DR, Greenwood BM: TNF concentration in fatal, non-fatal cerebral and uncomplicated plasmodium falciparum malaria. Lancet 336:1201–1204, 1990
Silva CL, Foss NT: Tumor necrosis factor in leprosy patients. J Infect Dis 159:787–790, 1989
Scuderi P, Sterling KE, Lam KS, Finley PR, Ryan KJ, Ray CG, Peterson E, Slymen DJ, Salmon SE: Raised serum levels of tumor necrosis factor in parasitic infections. Lancet 2:1364–1365, 1986
Maury CP, Teppo AM: Tumor necrosis factor in the serum of patients with systemic lupus erythematosus. Arthritis Rheum 32:146–150, 1989
Saxe T, Palladino MA Jr, Heinegard D, Talal N, Wolheim FA: Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum 31:1041–1045, 1988
Balkwill F, Osborne R, Burke F et al: Evidence for tumor necrosis factor/cachectin production in cancer. Lancet 2:1229–1232, 1987
Lädevirta J, Maury CPJ, Teppo AM, Repo H: Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med 85:289–291, 1988
Author information
Authors and Affiliations
Additional information
The study was funded by the Section of Gastroenterology, Department of Medicine, Tulane University.
Preliminary communication of this work was recently presented in abstract form: Mahatma M, Yagel, RV, Sitton J, Sbeiti M, Hoda, Nelson S, Agrawal N: Prevention of endotoxin-induced gastric injury by misoprostol. J Am Coll Gastroenteral85:1237, 1990.
Rights and permissions
About this article
Cite this article
Mahatma, M., Agrawal, N., Dajani, E.Z. et al. Misoprostol but not antacid prevents endotoxin-induced gastric mucosal injury. Digest Dis Sci 36, 1562–1568 (1991). https://doi.org/10.1007/BF01296398
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01296398