From basic science to future medical options for treatment of ulcerative colitis

European Journal of Gastroenterology and Hepatology

Volumn 9, Issue 9, 1997, Pages 864-871

  Rask Madsen, Jørgen ^a,b  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b HVIDOVRE HOSPITAL   (Denmark)

Author keywords

Animal studies; Colitis; Cytokines; Drug therapy; Gene therapy; Humoral immunity; Inflammatory bowel disease

Indexed keywords

CELL ADHESION MOLECULE; GLUCOCORTICOID; MESALAZINE;

CROHN DISEASE; DISEASE COURSE; DISEASE PREDISPOSITION; GENETIC DISORDER; HUMAN; IMMUNOPATHOGENESIS; INFLAMMATION; INFLAMMATORY CELL; MEDIATOR; PRIORITY JOURNAL; REVIEW; ULCERATIVE COLITIS;

EID: 0030780003     PISSN: 0954691X     EISSN: None     Source Type: Journal    
DOI: 10.1097/00042737-199709000-00008     Document Type: Review

References (76)

1. Shanahan F: Current concepts of the pathogenesis of inflammatory bowel disease. J Med Sci 1994, 163:544-549. Authoritative review, discussing the interactions among genetic predisposing factors (multiple genes), exogenous triggers (microflora) and endogenous modifying influences (psychoneuroendocrine system) in IBD.
2. Nielsen OH, Rask-Madsen J: Mediators of inflammation in chronic inflammatory bowel disease. Scand J Gastroenterol 1996, 31 (suppl. 216):149-159. Author's comprehensive review on the role of soluble mediators of inflammation in IBD.
3. Eliakim R, Rachmilewitz D: Inflammatory bowel disease: the asthma of the intestine. Inflamm Bowel Dis 1996, 2:122-132. Review on IBD, which points out the similarities between chronic relapsing inflammatory diseases of the lung and the gut as regards pathogenesis and treatment.
4. Rutgeerts P, d'Haens G, Hiele M, et al.: Appendectomy protects against ulcerative colitis. Gastroenterology 1994, 106:1251-1253. In 174 consecutive UC patients, absence of appendectomy and of smoking were closely related to the development of UC. Before onset of disease 0.6% versus 25.4% of 161 controls had undergone appendectomy.
5. Selby WS, Janossy G, Bofill M, et al: Intestinal lymphocyte subpopulations in inflammatory bowel disease, an analysis by immunohistological and cell isolation techniques. Gut 1984, 25:32-40. Lymphocyte subpopulations in the intestinal mucosa of patients with UC or CD were studied using a double marker immunofluorescence technique. The majority of intraepithelial lymphocytes were T-cells and over 80% of these were of suppressor-cytotoxic phenotype with a small population of helper type.
6. Choy MY, Walker-Smith JA, Williams CB, et al.: Differential expression of CD25 (interleukin-2 receptor) on lamina propria T cells and macrophages in the intestinal lesions in Crohn's disease and ulcerative colitis. Gut 1990, 31:1365-1370. In UC patients, increased numbers of CD25+ cells make up 5-33% of lamina propria cells and form subepithelial aggregates.
7. Mullin GE, Lazenby AJ, Harris ML, et al.: Increased interleukin-2 mRNA in the intestinal mucosal lesions of Crohn's disease but not ulcerative colitis. Gastroenterology 1992, 102:1620-1627. Inflammatory lesions of CD, but not UC, have higher levels of IL-2 mRNA transcripts, suggesting that T-cell activation and lymphokine secretion in the intestine may be important in the pathogenesis of CD.
8. Breese EJ, Michie CA, Nicholls SW, et al.: Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology, 1994, 106:1455-1466. TNF-α-secreting cells are increased in the mucosa of inflamed intestine and higher levels are seen in CD than in UC, probably reflecting the extensive T-cell activation in CD.
9. Hirata I, Berrebi G, Austin LL, et al.: Immunohistological characterization of intraepithelial and lamina propria lymphocytes in control ileum and colon and in inflammatory bowel disease. Dig Dis Sci 1986, 31:593-603. Using monoclonal antibodies to T- and B-lymphocytes, to natural killer cells, and to HLA-DR antigen, the lymphocyte population within the epithelial and lamina propria regions was characterized in control tissues and inflamed intestine and colon.
10. Podolsky DK, Fournier DA: Alterations in mucosal content of colonie glycoconjugates in inflammatory bowel disease defined by monoclonal antibodies. Gastroenterology 1988, 95:379-387. The presence of several glycoconjugates in colonie mucosa was assessed through indirect immunofluorescent staining with three anti-HCM mucosal antibodies, which was significantly altered in mucosa from patients with UC.
11. Pladdet IE, Pena AS, Oudejans CBM: Mucin genes as markers for the genetic predisposition of ulcerative colitis. Gastroenterology 1995, 108:A895. Patterns for the SMUC40 probe, which is specific for the MUC2 gene, and the SIB139 probe, which is specific for the MUC3 gene, were studied. A difference in the VNTR pattern of MUC2 gene was identified in UC patients.
12. Satsangi J, Jewell DP, Rosenberg WMC, et al.: Genetics of inflammatory bowel disease. Gut 1994, 35:696-700. Comprehensive progress report on evidence for genetic predisposition, pathophysiology of genetic susceptibility, genetics and the immune response, and the extent of disease heterogeneity in IBD.
13. Bioque G, Bouma G, Crusius JBA, et al.: Evidence for genetic heterogeneity in IBD: 1. The interleukin-1 receptor antagonist in the predisposition to suffer from ulcerative colitis. Eur J Gastroenterol Hepatol 1996, 8:105-110. Genotype and allele frequencies of the polymorphic region in the IL-1 ra gene were determined by the polymerase chain reaction (PCR) in 111 unrelated patients with UC. The study confirmed that the IL-1ra gene is a marker for genetic susceptibility and severity in UC.
14. Satsangi J, Parkes M, Hashimoto L, et al.: Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet 1996, 14:199-202.
15. Rosenberg WMC, Prince C, Kaklamanis L, et al.: Ulcerative colitis is differentiated from other colonie inflammation by CD44 v3 and v6 expression. Gastroenterology 1995, 108:A906. CD44 v6 was significantly overexpressed on colonic cells in UC compared with those in CD and expression of CD44 v6 and v3 correlated with disease severity in UC, but not CD. The authors tentatively conclude that CD44 variants may form a target for immunotherapy.
16. Satsangi J, Welsh KI, Bunce M, et al.: Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet 1996, 347:1212-1217. For linkage analysis, 74 families in whom two or more siblings had IBD were studied. Among 83 affected sibling pairs both pairs had CD on 42 occasions and UC on 29 occasions and one sibling had CD and the other UC on 12 occasions. In the association study, including 175 UC patients, the sharing of alleles among affected sibling pairs provided evidence for linkage with the DRB1 locus and the DR3 DQ2 haplotype and was found to be predictive of extensive UC, but not of need for surgery.
17. Bouma G, Xia B, Crusius JBA, et al: Distribution of four polymorphisms in the tumour necrosis factor (TNF) genes in patients with inflammatory bowel disease (IBD). Clin Exp Immunol 1996, 103:391-396. In 153 Dutch patients with IBD (89 UC) a weak association between the polymorphism at position -308 in the promoter region of the TNF-α gene and UC was found and the allele 2 was found to be decreased in UC patients. No differences in the distribution of TNF haplotypes between P-ANCA-positive and -negative UC patients were observed. The authors conclude that TNF genes may be markers of subsets of patients with UC.
18. Orholm M, Munkholm P, Langholz E, et al.: Familial occurrence of inflammatory bowel disease. N Engl J Med 1991, 324:84-88. The first-degree relatives of 637 patients with UC or CD had a 10-fold increase in the risk of having the same disease as the patients, after standardization for age and sex, suggesting that these disorders have a genetic cause.
19. Satsangi J, Grootscholten C, Holt H, et al.: Clinical patterns of familial inflammatory bowel disease. Gut 1996, 38:738-741. In 54 families in whom one parent and at least one child were affected and in 155 families in whom at least two siblings were affected, the differences in age of onset between parents and children were not explained by a simple cohort effect and may reflect influence of genetic factors.
20. Sartor RB: Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn's disease. Gastroenterol Clin North Am 1995, 24:475-507. Comprehensive review on the potential role of proinflammatory products of commensal bacteria in the pathogenesis of IBD.
21. Koutroubakis I, Manousos ON, Meuwissen SGM, et al.: Review. Environmental risk factors in inflammatory bowel disease. Hepatogastroenterology 1996, 43:381-393. Comprehensive review on environmental risk factors in IBD (including smoking) suggesting that UC and CD are heterogeneous disorders of multifactorial aetiology in which hereditary and environmental factors interact to produce the disease.
22. Calkins BM: A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci 1989, 34:1841-1854. Meta-analysis of selected studies suggesting that 'not smoking' and UC and 'smoking' and CD are consistent with a causal relationship. Tobacco may, therefore, contain some substance beneficial to UC patients.
23. Carlsson HE, Lagercranz R, Perlman P: Immunological studies in patients with ulcerative colitis, Crohn's disease and other diseases. Scand J Gastroenterol 1977, 12:707-714.
24. Takahashi F, Shah HS, Wise ES, et al.: Circulating antibodies against human colonic extract enriched with a 40 kDa protein in patients with ulcerative colitis. Gut 1990, 31:1016-1020. The authors report on the presence of circulating antibodies in serum from 79 UC patients. They used an enzyme-linked immunosorbent assay with a highly enriched preparation of a 40 kDa protein from normal colon extracts. Seventy-nine per cent of patients with symptomatic UC had optical density values above the means for all other groups and 55% had values beyond two standard deviations of the values for all other groups.
25. r 40 kD putative autoantigen in ulcerative colitis. Gastroenterology 1993, 34:650-657. The above (reference 24) 40 kDa antigen was re-examined by in-situ colour immunofluorescence staining including the murine antibody 7E12H12. Activated complement and IgC1 often co-localized with the named antigen apically on the epithelium in active UC, but not in CD, supporting the notion that an autoimmune response to this antigen may be a pathogenetic mechanism for epithelial damage in UC.
26. Das KM, Dasgupta A, Mandal A, Geng X: Autoimmunity to cytoskeletal protein tropomysin: a clue to the pathogenetic mechanism for ulcerative colitis. J Immunol 1993, 150:2487-2493. In the present study (see references 24 and 25) the authors purified P40 from human colon to apparent homogeneity, sequenced two peptides after proteolytic digestion, and demonstrated that the P40 belongs to the tropomyosin family. They also demonstrated that serum from 95% of patients with UC contains antibodies that are reactive to tropomyosin.
27. Madara JL, Podolsky DK, King NW, et al.: Characterization of spontaneous colitis in cotton top tamarins (Sanguinis oedipus) and its response to sulfasalazine. Gastroenterology 1985, 88:13-19. Spontaneous colitis in the cotton-top tamarin (CTT) was characterized by means of colonie biopsies, haematocrits, serum albumins and stools for bacteriological and parasitic examination. Histological evidence of active colitis was found in 50% of adult animals. Oral sulphasalazine ameliorated the effects of the disease.
28. Podolsky DK, Lobb R, King N, et al: Attenuation of colitis in the cotton-top tamarin by anti-α4 integrin monoclonal antibody. J Clin Invest 1993, 92:372-380. Parenteral administration of an anti-α4 integrin monoclonal antibody designated HP1/2 that binds VLA4 (α4β1) and presumably α4β7 integrins resulted in significant attenuation of acute colitis in cotton-top colitis, suggesting that adhesion molecules are important in sustaining acute colitis and that their disruption may result in therapeutic benefit.
29. 4 production were dose dependency suppressed.
30. Elson CO, Sartor RB, Tennyson, GS, et al.: Experimental models of inflammatory bowel disease. Gastroenterology 1995, 109:1344-1367. Comprehensive review on recent experimental animal models of IBD.
31. Taurog JD, Maika SD, Simmons WA, et al.: Susceptibility to inflammatory disease in HLA-B27 transgenic rat lines correlate with the level of B27 expression. J Immunol 1993, 150:4168-4178. Rats transgenic for HLA-B27 and human β2-microglobulin were studied. Two lines developed spontaneous inflammatory disease and one line developed disease when homozygous for the transgene locus. Immuno-cytochemistry showed that the B27 antigen is expressed at high levels in cells of the lamina propria, but not at all in colonic epithelial cells. The data suggest that the B27 transgene is expressed in a copy number-dependent, position-independent manner in lymphoid tissue and that disease results from the expression of B27 above a critical threshold level.
32. Mombaerts P, Mizoguchi E, Grusby MJ, et al.: Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell 1993, 75:274-282. Spontaneous development of IBD was observed in several immunodeficient mouse strains created via gene targeting in embryonic stem cells. The authors suggest that the disease requires the presence of B-lymphocytes and the absence of class II major histocompatibility complex (MHC)-restricted CD4+ αβ T-cells and that dysfunction of the mucosal immune system may underlie the pathogenesis of some types of IBD in humans.
33. Sadlack B, Mertz H, Schorle H, et al.: Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 1993, 75:253-261. Mice deficient for IL-2 develop an IBD with clinical and histological similarity to UC and a high number of activated T- and B-cells, elevated immunoglobulin secretion, anti-colon antibodies and aberrant expression of class II MHC molecules. The data suggest a primary role of the immune system in the aetiology of UC and disease may result from an abnormal immune response to a normal antigenic stimulus.
34. Kühn R, Löhler J, Rennick D, et al.: Interleukin-10 deficient mice develop chronic enterocolitis. Cell 1993, 75:263-274. In IL-10-deficient mice, lymphocyte development and antibody responses are normal, but most animals suffer from chronic enterocolitis with mucosal hyperplasia, inflammatory reactions and aberrant expression of MHC class Il molecules on epithelia. Mutants kept under specific pathogen-free conditions develop only a local inflammation, indicating that the inflammation originates from uncontrolled immune responses stimulated by enteric antigens.
35. Sands BE, Podolsky DK, Tremaine WJ, et al.: Chimeric monoclonal anti-tumour necrosis factor antibody (cA2) in the treatment of severe, steroid-refractory ulcerative colitis (UC). Gastroenterology 1996, 110:A1008. Preliminary results of multicentre, double-blind placebo-controlled trial (terminated due to poor enrolment) with 55% treatment failure (only 11 patients enrolled) compared to 100% in the placebo group. One patient entered remission.
36. Kett K, Rognum TO, Brandtzaeg P: Mucosal subclass distribution of immunoglobulin-G producing cells is different in ulcerative colitis and Crohn's disease of the colon. Gastroenterology 1987, 93:919-924. Subclass distribution of colonie IgG-producing immunocytes in UC and CD was examined using paired immunofluorescence staining. A significantly higher median proportion of IgG1 immunocytes was found in UC (81.3%) than in CD (66.5%) and the median proportion of IgG2 immunocytes was significantly higher in CD (24.9%) than in UC (9.4%).
37. Wakefield AJ, Sawyerr AM, Dhillon AP, et al.: Pathogenesis of Crohn's disease: multifocal gastrointestinal infarction. Lancet 1989, 334:1057-1062. Specimens of resected small and large intestine from 15 CD patients were examined by macrophotography, histopathology and scanning or transmission electron microscopy. Vascular injury, focal arteritis, fibrin deposition, arterial occlusion (muscularis propria), followed by tissue infarction or neovascularization was observed. The authors suggest that CD is mediated by multifocal gastrointestinal infarction.
38. Andoh A, Fujiyama Y, Bamba T, et al.: Differential cytokine regulation of complement C3, C4, and factor B synthesis in human intestinal epithelial cell line, Caco-2. J Immunol 1993, 151:4259-1247. Studies on the human colonie adenocarcinoma cell line, Caco-2, suggest that intestinal epithelial cells are local production sites of C3, C4 and factor B and that local C synthesis in the intestine is independently regulated by cytokines, derived from monocytes/macrophages and T-cells resident in the mucosal microenvironment.
39. 2), modulation of bioactivity, synergy with other soluble mediators, and regulation of immunosuppression.
40. Barrett KE: Cytokine interactions with epithelium. Can J Gastroenterol 1996, 10:323-328. Review on cytokine interactions in basic research.
41. MacDonald TT, Murch SH: Aetiology and pathogenesis of chronic inflammatory bowel disease. Baillière's Clin Gastroenterol 1994, 8:1-34. Outstanding, comprehensive review of the aetiology and pathogenesis of IBD.
42. Evans RC, Clark L, Heath P, et al.: Treatment of ulcerative colitis with an engineered human anti-TNFα antibody CDP571. Gastroenterology 1996, 110:A905. Preliminary open trial in 15 patients with UC treated with a single intravenous infusion of 5 mg/kg of CDP571. Consistent improvement in Powell-Tuck score, C-reactive protein, number of liquid stools, sigmoidoscopy and histology scores was seen in the initial 2 weeks after infusion.
43. Munck A, Mendel DB, Smith LI, et al.: Glucocorticoid receptors and actions. Am Rev Respir Dis 1990, 141:S2-S10. Review on glucocorticoid receptors and actions.
44. Cole AT, Hawkey CJ: Treatment of inflammatory bowel disease from now to the millennium. Baillière's Clin Gastroenterol 1994, 8:351-379. Outstanding, comprehensive review on current and future treatment of IBD.
45. 4 was observed, suggesting more severe tissue damage in this disease.
46. 2 concentrations did not change significantly.
47. Laursen LS, Lauritsen K, Bukhave K, et al.: Selective 5-lipoxygenase inhibition by zileuton in the treatment of relapsing ulcerative colitis: a randomized double-blind placebo-controlled multicentre trial. Eur J Gastroenterol Hepatol 1994, 6:209-215. Randomized, double-blind, placebo-controlled trial on the efficacy of zileuton 800 mg twice daily in 76 UC patients, showing a clinical response more often in the zileuton group and significantly so in patients without concurrent sulphasalazine treatment.
48. 4 by more than 85%.
49. 2 in rectal dialysates are sensitive markers of disease activity in active UC. In patients responding to therapy there was a significant decrease in concentrations of these eicosanoids. A significant correlation between eicosanoid levels and disease activity, as judged by clinical, endoscopic and histological activity indices, was demonstrated.
50. 4, concentrations decreased after administration of indomethacin 150 mg/day. These differential reductions accord with the theory that glucocorticoids act through activation of lipocortin.
51. Hawkey C, Gassull M, Lauritsen K, et al.: Efficacy of zileuton, a 5-lipoxygenase inhibitor, in the maintenance of remission in patients with ulcerative colitis. Gastroenterology 1994, 106:A697. Six-month, randomized, double-blind, placebo-controlled, study to evaluate the efficacy of zileuton 600 mg four times daily, 5-ASA 400 mg four times daily and placebo in the maintenance of remission in 323 (308 evaluable) UC patients. Relapse rates were 42%, 35% and 51%, respectively, suggesting that zileuton was not more effective than 5-ASA, but superior to placebo.
52. Belluzzi A, Brignola C, Campieri M, et al.: Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease. N Engl J Med 1996, 334:1557-1560. One-year, randomized, double-blind, placebo-controlled study to investigate the effects of an enteric-coated fish oil preparation for maintenance of remission in 78 CD patients. The risk reduction of relapse was 41% and accompanied by an increase in serum levels of markers of inflammation.
53. Collins CE, Cahill MR, Newland AC, et al.: Platelets circulate in an activated state in inflammatory bowel disease. Gastroenterology 1994, 106:840-845. Platelet surface expression of P-selectin and GP53 (markers of activa-tion) were increased in UC (9 of 21 for P-selectin; 10 of 21 for GP53). Increased circulating platelet aggregates, platelet aggregability in vitro and serum beta-thromboglobulin were detected in active disease.
54. Skandalis N, Rotenberg A, Meuwissen S, et al: Ridogrel for the treatment of mild to moderate ulcerative colitis. Gastroenterology 1996, 110:A1016. Eight-week, randomized, double-blind study to compare the efficacy of ridogrel (5mg once daily, 25 mg twice daily or 150 mg twice daily) and mesalazine (800 mg three times daily). 55% (n = 22), 46% (n = 24), 42% (n = 24), and 61% (n = 23), respectively, had improved by at least one grade on endoscopie assessment. Significant differences in efficacy between the groups were not detected.
55. 50 890 μM).
56. Eliakim R, Karmeli F, Razin E, et al.: Role of platelet-activating factor in ulcerative colitis. Gastroenterology 1988, 95:1167-1172. PAF was not detected in normal colonic biopsy specimens. In specimens from patients with active UC (8.9 ± 3.5 pg/10 mg wet weight), A23187 and antihuman IgE stimulated PAF activity. Enhanced stimulation was dose dependency inhibited by sulphasalazine (SASP), 5-ASA and prednisolone, but not by sulphapyridine.
57. 2, levels in rectal dialysates.
58. Mantyh CR, Vigna SR, Bollinger RR, et al.: Differential expression of substance P receptors in patients with Crohn's disease and ulcerative colitis. Gastroenterology 1995, 109:850-860. Tissue samples from UC patients showed high concentrations of substance P (SP) receptors on colonie lymphoid aggregates and small blood vessels, but not on enteric neurons as demonstrated in CD. No increased SP binding was evident in quiescent UC.
59. Bernstein CN, Robert ME, Eysselein VE: Rectal substance P concentrations are increased in ulcerative colitis but not in Crohn's disease. Am J Gastroenterol 1993, 88:908-913. Immunoreactive substance P in extracts of rectal mucosal biopsies from UC patients was significantly increased compared with controls and CD. There was a positive correlation between rectal mucosal substance P concentrations and total histological inflammation scores as well as mucosal mononuclear cell scores.
60. Murch SH, Braegger CP, Sessa WC, et al.: High endothelin-1 immunoreactivity in Crohn's disease and ulcerative colitis. Lancet 1992, 339:381-385. Endothelin concentrations, measured by radioimmunoassay in supernatants of homogenized tissue samples, were significantly higher in CD and UC than in controls and may contribute to vasculitis in IBD by inducing ischaemia through vasoconstriction.
61. Clozel M, Breu V, Burri K, et al.: Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature 1993, 365:759-761. Report on the evidence for a pathophysiological role of endothelin-1, as brought by the first synthetic, orally active, non-peptide antagonist of endothelin receptors, Ro 46-2005.
62. Björck S, Dahlström A, Johansson L, et al.: Treatment of the mucosa with local anaesthetics in ulcerative colitis. Agent Action 1992, Spec no:C60-72. Open study in 100 consecutive UC patients treated with lignocaine (2%) enemas. More than two-thirds of proctitis/proctosigmoiditis patients and all of 17 patients with left-sided colitis went into remission, while 6 patients with pancolitis had symptomatic relief.
63. Arlander E, Öst Å, Ståhlberg D, et al.: Ropivacaine gel in active distal ulcerative colitis and proctitis - a pharmacokinetic and exploratory clinical study. Aliment Pharm Ther 1996, 10:73-81. Ropivacaine (a new local anaesthetic) given rectally as gel, 200 mg twice daily, does not accumulate over a 2-week period and carries a low risk for systemic adverse effects.
64. Kitano A, Matsumoto T, Nakamura S, et al.: New treatment of ulcerative colitis with K-76. Dis Colon Rectum 1992, 35:560-567. In an open study the complement inhibitor K-76 was as effective as monotherapy in 4 of 5 patients with UC and in 7 of 21 patients refractory to glucocortocoids and SASP.
65. G-monomethyl-L-arginine inhibited citrulline production.
66. Boughton-Smith NK, Evans SM, Hawkey CJ, et al.: Nitric oxide synthase activity in ulcerative colitis and Crohn's disease. Lancet 1993, 342:338-340. NO synthase activity in colonie mucosa of UC patients was about eight-fold higher than in control mucosa.
67. Lundberg JO, Hellström PM, Lundberg JM, et al.: Greatly increased luminal nitric oxide in ulcerative colitis. Lancet 1994:344:1673-1674. NO concentrations (analysed by a chemiluminescence technique) in luminal gas aspirated during colonoscopy were more than 100 times higher in patients with active UC than in controls.
68. Conner EM, Brand SJ, Davis JM, et al.: Basic science review. Role of reactive metabolites of oxygen and nitrogen in inflammatory bowel disease: toxins, mediators, and modulators of gene expression. Inflamm Bowel Dis 1996, 2:133-147. Comprehensive review on the role of reactive metabolites of oxygen and nitrogen in IBD, suggesting that sustained overproduction of these species may contribute to the pathophysiology by enhancing production of toxins, mediators and modulators of gene expression.
69. Ahnfelt-Rönne I, Nielsen OH: The antiinflammatory moiety of sulfasalazine, 5-aminosalicylic acid, is a radical scavenger. Agent Action 1987, 21:191-194. SASP and its main metabolites were compared with biological anti-oxidants and anti-inflammatory salicylates by using a novel spectrophotometric assay to detect free radical scavengers. 5-ASA, but not SASP, its other metabolites, or anti-inflammatory salicylates, had properties of a potent scavenger of free radicals.
70. Roediger WEW, Babidge W, Millard S: Methionine derivatives diminish sulphide damage to colonocytes - implications for ulcerative colitis. Gut 1996, 39:77-81. In isolated rat and human colonocytes, sulphide dose dependently reduced oxidative metabolite formation from n-butyrate, an action reversed by methionine derivatives (methyl donors), suggesting that sulphide detoxification may be of therapeutic value in UC.
71. Keelan E, Haskard DO: CAMs and anti-CAMs. The clinical potential of cell adhesion molecules. J R Coll Physicians Lond 1992, 26:17-24. Comprehensive review of the clinical potential of specific adhesion molecules.
72. Pedersen G, Brynskov J, Nielsen OH, et al.: Adhesion molecules in inflammatory and neoplastic intestinal diseases. Dig Dis 1995, 13:322-336. Comprehensive review of the role of adhesion molecules in IBD and colorectal cancer, suggesting that targeting adhesion molecules may be a future therapeutic approach in these disorders.
73. Watson SR, Fennie C, Lasky LA: Neutrophil influx into an inflammatory site inhibited by a soluble homing receptor-IgG chimaera. Nature 1991, 349:164-167. Administration to mice of a soluble immunoglobulin chimera (containing the murine homing receptor, gp90MEL) significantly decreased the number of neutrophils that migrate to the peritoneum in response to thioglycollate, suggesting that soluble forms of a single type of adhesion molecule (the homing receptor) could be clinically effective compounds for the inhibition of neutrophil-mediated inflammation.
74. Sandborn WJ, Tremaine W, Offord KP, et al.: A randomized, double-blind, placebo-controlled trial of transdermal nicotine for mildly to moderately active ulcerative colitis. Gastroenterology 1996, 110:A1008. Four-week, randomized, double-blind, placebo-controlled study in 64 non-smokers with active UC showing that transdermal nicotine is efficacious in mildly to moderately active UC.
75. Thomas GA, Rhodes J, Mani V, et al.: Transdermal nicotine as maintenance therapy for ulcerative colitis. N Engl J Med 1995, 332:988-992. Six-month, randomized, double-blind, placebo-controlled study in 80 patients with quiescent UC, showing that transdermal nicotine was no better than placebo in maintaining remission.
76. Mansfield JC, Holden H, Tarlow JK, et al.: Novel genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist. Gastroenterology 1994, 106:637-642. In this study, the allele 2 of IL-1ra was significantly over-represented in UC patients (35% vs. 24%) compared with controls. Carriage of at least one copy of this allele gave an odds ratio of 2.0 for UC; the association was greatest in patients with pancolitis and was not seen in CD.