esophageal stents in benign disease: A cause for concern. SurgLaparosc Endosc 1998;8:403.
17. Dumonceau JM, Cremer M, Lalmand B, et al. Esophagealfistula sealing: Choice of stent, practical management, andcost. Gastrointest Endosc 1999;49:708.
18. Adam A, Watkinson AF, Dussek J. Boerhaave syndrome: totreat or not to treat by means of insertion of a metallic stent.J Vasc Intervent Radiol 1995;6:7416.
19. Yuasa N, Hattori T, Kobayashi Y, et al. Treatment of spon-taneous esophageal rupture with a covered self-expandingmetal stent. Gastrointest Endosc 1999;49:77780.
20. Eubanks PJ, Hu E, Nguyen D, et al. Case of Boerhaavessyndrome successfully treated with a self-expanding metallicstent. Gastrointest Endosc 1999;49:7803.
21. Goldin E, Fiorini A, Ratan Y, et al. A new biodegradable andself-expanding stent for benign esophageal strictures. Gastroi-ntest Endosc 1996;43:294 (abstract).
22. Fry SW, Fleischer DE. Management of a refractory benignesophageal stricture with a new biodegradable stent. Gastrin-test Endosc 1997;45:17982.
23. Lee JG, Hsu R, Leung JW. Are self-expanding metal meshstents useful in the treatment of benign esophageal stenosesand fistulas? An experience of four cases. Am J Gastroenterol2000;95:19205.
24. Vaezi MF, Richter JE. Current therapies for achalasia: Com-parison and efficacy. J Clin Gastroenterol 1998;27:2135.
25. Spiess AE, Kahrilas PJ. Treating achalasia: From whaleboneto laparoscope. JAMA 1998;280:63842.
26. Orringer MB, Marshall B, Iannettoni MD. Transhiatalesophagectomy: Clinical experience and refinements. AnnSurg 1999;230:392400.
27. Axelrad AM, Fleischer DE, Gomes M. Nitinol coil esophagealprosthesis: Advantages of removable self-expanding metallicstents. Gastrointest Endosc 1996;43:15560.
28. Segalin A, Bonavina L, Siardi C, et al. Can the expandableesophageal metal Endocoil stent be safely removed? Endos-copy 1997;29:3379.
Reprint requests and correspondence: Kevin M. McGrath,M.D., 216 Bell Building, Box 3902, Duke University MedicalCenter, Durham, NC 27710.
Received Mar. 9, 2000; accepted Apr. 28, 2000.
Nonsteroidal Anti-inflammatoryDrugs in Patients WithInflammatory Bowel DiseaseIt has been .100 yr since the first nonsteroidal anti-inflam-matory drug (NSAID), acetylsalicylic acid, was synthesizedby German chemists of the Bayer Corporation (1899) (1).However, salicylic acid, which is found in willow andpoplar tree bark, has been used since antiquity in the treat-ment of pain, arthritis, and fever. However, it was not untila report by Douthwaite and Lintott in 1938 (2) that providedthe first evidence of gastric injury secondary to aspirin. Bythe 1970s, large studies documented a clear associationbetween the use of NSAIDs and gastroduodenal mucosalulcerations. Also, over the past 25 yr, evidence has accu-mulated of the clear relationships between NSAIDs andmultiple types of mucosal injury to the distal small intestine
and colon, including both de novo lesions and exacerbationsof pre-existing disease (3).
There are a considerable number of published reports thatNSAIDs can exacerbate or lead to reactivation of preexis-tent inflammatory bowel disease (IBD), including the studyof Felder et al. (4) in this issue of The American Journal ofGastroenterology. In 1997, Evans reported on a prospectivecase-control study using a database to evaluate the relation-ship of NSAIDs and the risk of incident colitis secondary toIBD (5). Two hundred patients met the criteria of colitis dueto inflammatory bowel disease (IBD) (Crohns colitis, n 5113; UG, n 5 85; undetermined, n 5 2). A total of 1178age- and sex-matched controls were compared to the IBDpatients. An odds ratio (OR) was calculated for current,recent, and past exposures to NSAIDs. An increased risk ofincident colitis due to IBD was associated with current andrecent exposure to NSAIDs (OR 2.96 [Cl: 95%, 1.326.64]and 2.51 [Cl: 95%, 1.135.55], respectively). These findingssupport the hypothesis that NSAIDs are implicated in colitisassociated with IBD.
The mechanism by which NSAIDs can cause the exac-erbation of IBD is not known. However, a probable con-tributing factor in leading to an exacerbation of colitis byNSAIDs is inhibition of colonic prostaglandin (PG) synthe-sis (6). The key enzyme in the synthesis of PG is cycloox-ygenase (COX). COX exists in two isoforms. COX-1 is aconstitutive enzyme and is involved in maintaining mucosalintegrity in the gastrointestinal (GI) tract. COX-1 is ex-pressed in many tissues including stomach, small intestine,colon, and others. On the other hand, COX-2 is an inducibleenzyme that is expressed primarily only at sites of inflam-mation. Proinflammatory cytokines such as tumor necrosisfactor induce COX-2 expression.
The ability of NSAIDs (including selective cyclooxygen-ase-2 inhibitors) to exacerbate pre-existing colonic ulcer-ation and inflammation in laboratory animals is well docu-mented. In a trinitrobenzene sulfuric acid model of colitis inthe rat, COX-2 expression was markedly increased afterinitiation of colitis (7). Exacerbations of colitis with colonicperforation resulted after therapy with selective COX-2 in-hibitors.
COX-1 messenger RNA (mRNA) has been identified inthe normal human colon by reverse-transcription polymer-ase chain reaction (8) and immunoblotting analysis (9).Singer et al. investigated the expression and distribution ofCOX-1 and COX-2 in the normal ileum, normal colon,ulcerative colitis, Crohns colitis, and Crohns ileitis (10). Inboth the small intestine and colon, COX-1 is expressed inthe lower crypt, but its expression is lost as the epithelialcells differentiate and migrate higher in the crypt. COX-1protein was expressed at equal levels in normal, Crohnsdisease (CD), and ulcerative colitis (UC) colonic cells.COX-2 protein was not detected in normal epithelium butwas detected in CD and UC. COX-2 is not expressed inepithelial cells in areas removed from active inflammation(11).
1859AJG August, 2000 Editorials
Therefore, the authors concluded that COX-1 expressionis unchanged in IBD (10). COX-2 was undetected in thenormal ileum and colon. However COX-2 was induced byinflammatory mediators in the more differentiated cells (i.e.,apical epithelial cells) of inflamed foci in IBD.
In 1997, Hendel et al. evaluated COX-2 expression in acontrolled, clinical study (UC, n 5 22; CD, n 5 11; inde-terminate IBD, n 5 2) (12). Proctoscopy with biopsies forthe determination of mRNA of COX-1 and COX-2 wereobtained on all patients. Biopsies were obtained from themost endoscopically involved mucosal sites and comparedto patients with inactive IBD and healthy controls. Differ-ences in COX-1 mRNA were not detected. However thefraction of patients demonstrating COX-2 in mRNA assignificantly increased correlated with disease activity (p ,0.001). Hendel et al. concluded that COX-2 is involved inthe inflammatory response of chronic IBD.
The PGs produced through the epithelial cell COX-2 inIBD have a multifunctional role. PGs act over a shortdistance; therefore, the cellular distribution of COX-2 isimportant. Uribe et al. (1992) reported that PG E2 maymodulate cell proliferation in the small intestinal epitheliumof the rat (13). In addition to promoting epithelial prolifer-ation in the face of injury, PGs participate in the regulationof cytokine synthesis (10). Also the delay in wound healingwith COX-2 inhibition may relate to the loss of vasodilationand enhanced vascular permeability induced by PGs (14).
Expression of COX-2 in epithelial cells in IBD may act asa protective response, based on the following concepts.First, there is the expression of COX-2 in other types of GIinjury (15). Second, inhibition of GI wound healing canoccur by selective COX-2 inhibitors (10). Finally, therapeu-tic efficacy of exogenous PGs does occur in GI injury.Therefore, the inhibition of epithelial COX-2 in IBD pa-tients by NSAIDs could result in impairment of woundhealing.
The study by Bonner et al. (16) in this issue of theAmerican Journal of Gastroenterology certainly reflects thatthere maybe subsets of IBD patients who can tolerateNSAID with less likelihood of an exacerbation of IBD.Because of the demographics of the clinic population inSouthern Florida, the study is based on older age IBD.Unfortunately, there can be confounding factors in studyingIBD in the elderly. Many diseases of the colon, includingIBD, may have atypical symptoms and findings in the el-derly. Second, other bowel diseases such as ischemia, di-verticulitis, and infectious colitis can mimic IBD in those ofretirement age. Therefore, recognition of specific intestinaldiseases can be obscure. In addition, altered immune re-sponses may occur in the elderly (17). However, the effectsof aging on changes in COX-2 expression are not known.Finally, wound healing can be a part of the natural progres-sion or continuum of the inflammatory state (15). Also, thesuccess of wound healing is based on factors in the elderlythat could alter this progression. Factors such as a patientsage and the presence of concurrent illnesses that occur
frequently in the elderly (atherosclerosis, diabetes, etc.)could alter wound healing.
In summary, PG production through COX-2 may promoteepithelial proliferation and wound healing. Therefore,NSAIDs, including selective COX-2 inhibitors, which in-hibit PG synthesis, may impair the natural progression orcontinuum of the inflammatory state toward wound healing.
John OBrien, M.D.Department of Gastroenterology
University of Indiana Medical CenterIndianapolis, Indiana
1. Vance JR, Flower RJ, Rotting RM. History of aspirin and itsmechanism of action. Stroke 1990;21(suppl IV):1223.
2. Douthwaite AH, Lintott JAM. Gastroscopic observation of theeffect of aspirin and certain other substances on the stomach.Lancet 1938;2:1222