Abstract
Neutrophils have been implicated in the acute formation of gastric mucosal erosions induced by nonsteroidal antiinflammatory drugs. The aims of the present study were to determine, in rats, the role of neutrophils in the pathogenesis of etodolac- and indomethacin-induced gastrointestinal ulceration and blood loss. Both drugs caused gastrointestinal ulceration, which was associated with increased blood loss, a rise in plasma haptoglobin concentration, and a rise in the number of circulating neutrophils. A marked infiltration of neutrophils occurred only in ileal tissue. Pretreatment with a selective antineutrophil serum induced a significant neutropenia, which failed to inhibit either etodolac- or indomethacin-induced gastrointestinal ulceration and blood loss. A further study demonstrated that the antineutrophil serum did not prevent gastric erosions induced by indomethacin, but it inhibited carrageenan paw edema, which is dependent, in part, on neutrophil infiltration and activation. It is concluded that neutrophils do not contribute to gastrointestinal ulceration and blood loss induced by nonsteroidal antiinflammatory drugs. Furthermore, in contrast with previous studies, our results provide no evidence that neutrophils contribute to indomethacin-induced acute gastric erosion formation.
Similar content being viewed by others
References
Davenport HW: Salicylate damage to the gastric mucosal barrier. N Engl J Med 276:1307–1312, 1967
Robert A: Cytoprotection by prostaglandins. Gastroenterology 77:761–767, 1979
Miller TA, Jacobson ED: Gastrointestinal cytoprotection by prostaglandins. Gut 20:75–87, 1979
Whittle BJR: The mechanisms of gastric damage by nonsteroid anti-inflammatory drugs.In Biological Protection with Prostaglandins, Vol 2. MM Cohen (ed). Boca Raton, Florida, CRC Press, 1986, pp. 1–27
Wallace JL, Keenan CM, Granger DN: Gastric ulceration induced by nonsteroidal antiinflammatory drugs in a neutrophil-dependent process. Am J Physiol 259(Gastrointest Liver Physiol 22):G462-G467, 1990
Lee M, Aldred K, Lee E, Feldman M: Aspirin-induced acute gastric mucosal injury is a neutrophil-dependent process in rats. Am J Physiol 263(Gastrointest Liver Physiol 26):G920-G926, 1992
Wallace JL, Afors K-E, McKnight GW: A monoclonal antibody against the CD18 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in the rabbit. Gastroenterology 100:878–883, 1991
Roth SH, Bennett RE: Nonsteroidal anti-inflammatory drug gastropathy: Recognition and response: Arch Intern Med 147:2093–2100, 1987
Armstrong CP, Blower AL: Nonsteroidal antiinflammatory drugs and life threatening complications of peptic ulceration. Gut 28:527–532, 1987
Fries JF, Williams CA, Bloch DA, Michel BA: Nonsteroidal anti-inflammatory drug-associated gastropathy: Incidence and risk factor models. Am J Med 91:213–222, 1991
Madhok R, MacKenzie JA, Lee FD, Bruckner FE, Terry TR, Sturrock RD: Small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs for rheumatoid arthritis. Q J Med 225:53–58, 1986
Aabakken L, Osnes M: Non-steroidal anti-inflammatory drug-induced disease in the distal ileum and large bowel. Scand J Gastroenterol 24(suppl 163):48–55, 1989
Morris AJ, Madhok R, Sturrock RD, Cappell HA, MacKenzie JF: Enteroscopic diagnosis of small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs. Lancet 337:520, 1991
Allison MC, Howatson AG, Torrance CJ, Lee FD, Russell RI: Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 327:749–754, 1992
Bjarnason I, Zanelli G, Smith T, Prouse P, Williams P, Smethurst P, Delacey G, Gumpel MJ, Levi AJ: Nonsteroidal antiinflammatory drug-induced intestinal inflammation in humans. Gastroenterology 93:480–489, 1987
Melarange R, Gentry C, Durie M, O'Connell C, Blower PR: Gastrointestinal irritancy, antiinflammatory activity, and prostanoid inhibition in the rat. Differentiation of effects between nabumet one and etodolac. Dig Dis Sci 39:601–608, 1994
Mclarange R, Gentry C, Blower PR, Toseland CDN, Spangler R. Nabumetone, in contrast with etodolac, lacks gastrointestinal irritancy in the rat; assessment by the inflammatory marker, haptoglobin, and blood loss. Inflammopharmacol 3:259–270, 1995
Clarke BS: A method for occult blood in faeces using noncarcinogenic reagents. Med Lab Tech 28:187–190, 1971
Boyle E, Freeman PC, Goudie AC, Mangan FR, Thomson M: The role of copper in preventing gastrointestinal damage by acidic anti-inflammatory drugs. J Pharm Pharmacol 28:865–868, 1976
Grisham MB, Hernandez LA, Granger DN: Xanthine oxidase and neutrophil infiltration in intestinal ischaemia. Am J Physiol 251(Gastrointest Liver Physiol 14):G567-G574, 1986
Smith SM, Holm-Rutili L, Perry MA, Grisham MB, Afors K-E, Granger DN: Role of neutrophils in haemorrhagic shock-induced gastric mucosal injury in the rat. Gastroenterology 93:466–471, 1987
Etienne A, Thornier F, Hecquet F, Braquet P: Role of neutrophils in gastric damage induced by platelet-activating factor. Naunyn-Schmiedeberg's Arch Pharmacol 338:422–425, 1988
Kvietys PR, Twohig B, Danzell J, Specian RD: Ethanol-induced injury to the rat gastric mucosa. Gastroenterology 98:909–920, 1990
Melarange R, Gentry C, Blower PR, Toseland CDN, Spangler R: Nabumetone, an effective antiinflammatory agent, lacks gastrointestinal irritancy in the rat when dosed orally for one month: comparison with tiaprofenic acid and etodolac. Eur J Rheumatol Inflamm 14:15–22, 1994
Whittle BJR: Temporal relationship between cyclooxygenase inhibition, as measured by prostaglandin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology 80:94–98, 1981
Trevethick MA, Clayton NM, Bahl AK, Sanjar S, Strong P: Neutrophil depletion does not prevent indomethacin-induced ulceration of the rat gastric antrum. Agents Actions 41 (Special Conference Issue):C226-C227, 1994
Vinegar R, Truax JF, Selph JL, Johnston PR, Venable AL, McKenzie KK: Pathway to carrageenan-induced inflammation in the hind limb of the rat. Fed Proc 46:118–130, 1987
Trevethick MA, Clayton NM, Strong P, Harmon IW: Do infiltrating neutrophils contribute to the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum? Gut 34:156–160, 1993
Anthony A, Dhillon AP Nygard G, Hudson M, Piasecki C, Strong P, Trevethick MA, Clayton NM, Jordan CC, Pounder RE, Wakefield AJ: Early histological features of small intestinal injury induced by indomethacin. Aliment Pharmacol Ther 7:29–40, 1993
Thomsen MK, Skak-Nielson T, Ahnfelt-Rønne I: Effects of etodolac, indomethacin and sodium salicylate on canine neutrophil function. Agents Actions 29:54–55, 1990
Kaplan HB, Edelson HS, Korchak HM, Given WP, Abramson S, Weissmann G: Effects of non-steroidal anti-inflammatory agents on human neutrophil functionsin vitro andin vivo. Biochem Pharmacol 33:371–378, 1984
Abramson S, Korchak H, Ludwig R, Edelson H, Haines K, Levin RI, Herman R, Rider L, Kimmel S, Weissmann G: Modes of action of aspirin-like drugs. Proc Natl Acad Sci USA 82:7227–7231, 1985
Shelly J, Hoff SF: Effects of non-steroidal anti-inflammatory drugs on isolated human polymorphonuclear leukocytes (PMN): Chemotaxis, superoxide production, degranulation andN-formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP) receptor binding. Gen Pharmacol 29:329–334, 1989
Dinarello CA: Clinical relevance of interleukin 1 and its multiple biological activities. Bull Inst Pasteur 85:267–285, 1987
Gauldie J: Interleukin-1 in the acute phase response.In Acute Phase Proteins in the Acute Phase Response. MB Pepys (ed). London, Springer-Verlag, 1989, pp 1–20
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Melarange, R., Gentry, C., Nigel Toseland, C.D. et al. Neutropenia does not prevent etodolac- or indomethacin-induced gastrointestinal damage in the rat. Digest Dis Sci 40, 2694–2703 (1995). https://doi.org/10.1007/BF02220462
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02220462