Inflammatory Bowel Diseases

Inflammatory Bowel Disease (IBD) comprises several diseases, including ulcerative colitis and Crohn s disease. Ulcerative cohtis is a disease of the colon, originating in the rectum and extending proximally to a variable extent. It frequently affects the entire colon but never 

1 Direct evidence of increased production of free radicals 

2 ROM production by peripheral blood monocytes Production of ROM by peripheral blood monocytes in response to a variety of stimuli is increased in patients with active IBD (Table 10.2), su esting that such cells may respond to local stimulants within the gut more readily than in normal subjects or those with quiescent disease, and so may play a role in perpetuating the inflammatory response, cent studies have su ested that peripheral blood monocytes in Crohn s disease may be primed by the baaerial cell wall products LPS and peptidoglycanpolysaccharide (Muraki et al., 1992). 

Author (year) Assay used Separation procedure Stimulus Active Inactive Active Inactive 

2 Production of Mucosal Damage 2.3.1.2.1 Cell culture Stimulated neutrophils are known to be cytotoxic to cells in vitro (Dull et al., 1987 Dallegri et al., 1990 Grisham et al., 1990b). Several in vitro systems have been used to demonstrate oxidative damage to intestinal cells. Xanthine/XO increased Cr release and decreased [ H]thymidine uptake by IEC-18 small intestinal epithelial cell monolayers in a dose-dependent manner (Ma et al., 1991). Rat enterocytes show decreased trypan blue exclusion and increased protein release when incubated with neutrophils stimulated 

CCR3 CCL5, CCL7, CCLll, CCL13 Eosino, T cell (Th2), MC 

Finally, there is growing evidence that besides Th2 cells, T regulatory (Treg) cells are involved in the development asthma [91, 92]. 

Last but not least, the eosinophil is another important participant in the pathogenesis of asthmatic inflammation and about 80% of the asthma patients show an increased number of eosinophils. Airway epithelial cells are an important source of chemokines and contribute to recruitment of eosinophils to and within the lung. Predominantly, the CCR3 ligand CCLll (eotaxin) attracts and activates eosinophils by acting via the most prominent chemokine receptor on eosinophils CCR3. 

The term inflammatory bowel disease is used to describe chronic inflammatory conditions of the gastro-intestinal (GI) tract Inflammatory bowel disease is an 

Chemokines play a major role in regulating the complex interactions between the gut flora, the intestinal epithelium, immune mediators, and elfeetor cells. The interplay between nonimmune cells (particularly epithelial eells) and classical immune eompetent cell subsets is probably best documented and understood in the intestine. However, the task of unraveling the complexity of the emerging chemokine-mediated cell interaetions and functions in the 

This work was supported by grants DK54427 and DK33506 to HCR. JHN is supported by a Research Fellowship Award from the Crohn s and Colitis Foundation of America (CCFA). 

Roberts, A. I., Pablos, J. L., Thelen, S., Uguccioni, M., Li, X. Y., Marsal, J., Arenzana-Seisdedos, F., Delaunay, T., Ebert, E. C., Moser, B., and Parker, C. M. (2000). Constitutive expression of stromal derived factor-1 by mucosal epithelia and its role in HIV transmission and propagation. Curr. Biol. 10, 325-328. 

Andres, P. G., Beck, P. L., Mizoguchi, E., Mizoguchi, A., Bhan, A. K., Dawson, T., Kuziel, W. A., Maeda, N., MacDermott, R. P., Podolsky, D. K., and Reinecker, H. C. (2000). Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis Lack of CC chemokine receptor 5 expression results in a NKl.l-i- lymphocyte-associated Th2-type immune response in the intestine. J. Immunol. 164, 6303-6312. 

Luther, S. A., Forster, R., Sedgwick, J. D., Browning, J. L., Lipp, M., and Cyster, J. G. (2000). A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309-314. 

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Diarrhea is a common problem that is usually self-limiting and of short duration. Increased accumulations of small intestinal and colonic contents are known to be responsible for producing diarrhea. The former may be caused by increased intestinal secretion which may be enterotoxin-induced, eg, cholera and E. col] or hormone and dmg-induced, eg, caffeine, prostaglandins, and laxatives decreased intestinal absorption because of decreased mucosal surface area, mucosal disease, eg, tropical spme, or osmotic deficiency, eg, disaccharidase or lactase deficiency and rapid transit of contents. An increased accumulation of colonic content may be linked to increased colonic secretion owing to hydroxy fatty acid or bile acids, and exudation, eg, inflammatory bowel disease or amebiasis decreased colonic absorption caused by decreased surface area, mucosal disease, and osmotic factors and rapid transit, eg, irritable bowel syndrome. 

Colon inflammation 1. AEA levels are elevated in the colon of DNBS-treated mice and in the colon submucosa of TNBS-treated rats, two animal models of inflammatory bowel diseases, and in the biopsies of patients with ulcerative colitis, to control inflammation 1. Inhibitors of degradation (both FAAH and cellular re-uptake)... 

Infliximab Anti-TNFa Inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis... 

Anticytokine antibodies Infliximab Chimeric (mouse/human) monoclonal antibody against TNEa. Effective in the treatment of severe forms of rheumatoid arthritis where it can halt disease progression, or inflammatory bowel disease (EBD). 

KC706 stabilizes the inactive conformation of the mitogen-activated protein kinase p38a, a protein kinase involved in inflammatory reactions and cardiovascular functions. KC706 therefore holds the potential to treat conditions such as rheumatoid arthritis, psoriasis, inflammatory bowel disease and cardiovascular disease. This compound is currently being tested in phase II clinical trials with patients suffering from rheumatoid arthritis. 

In addition to those described above, some of the newest compounds emerging in SERM development are ER 3-selective ligands and pathway-selective modulators that target the interaction of the ERs with the transcription factor NFkB. While such compounds are in the early stages of clinical evaluation, thus far they demonstrate great potential for use in the treatment of inflammatory disorders such as arthritis, inflammatory bowel disease, and like other SERMs, cancer [4]. 

The first mouse monoclonal antibody specific for human CD3 was produced in 1979 and named orthoclone OKT3. Aside from its use in the laboratory, OKT3 became the first anti-CD3 antibody to be utilized in transplantation medicine, but its wider application was hampered by its immunogenic and mitogenic properties (reviewed in [6]). Consequently, humanized and engineered anti-CD3 antibodies were developed to circumvent these limitations (Table 1). Since T cells and the TCR are involved in many immunological diseases, it is not surprising that the application of CD3 antibodies is not restricted to the field of transplantation. For example, CD3 antibodies are tested in clinical studies of diseases such as autoimmune diabetes (type 1 diabetes), immune-mediated inflammatory arthritis and inflammatory bowel disease [7]. 

Baumgart DC, Sandborn WJ (2007) Inflammatory bowel disease clinical aspects and established and evolving therapies. Lancet 369 1641-1657... 

Human tumor necrosis factor (TNF) (Fig. 1) is a hormone-like proinflammatory peptide belonging to the group of cytokines. It is mainly produced by cells of the immune system in response to infection, inflammation, or cell damage. Disregulated TNF is an important factor in many pathological situations, like sqDsis, rheumatoid arthritis, inflammatory bowel disease (Crohn s disease), and Cachexia. The cytotoxic activity of TNF is of interest in development of new antitumoral strategies. 

The antidiarrheal drugs are used cautiously in patients with severe hepatic impairment or inflammatory bowel disease Antidiarrheals are classified as Pregnancy Category B drugs and should be used cautiously during pregnancy and lactation. 

The a-glucosidase inhibitors are contraindicated in patients with a hypersensitivity to the drug, diabetic ketoacidosis, cirrhosis, inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or predisposition to intestinal obstruction, or chronic intestinal diseases. Acarbose and miglitol are used cautiously in patients with renal impairment or pre-existing gastrointestinal (GI) problems such as irritable... 

The glucocorticoids are administered with caution to patients with renal or hepatic disease hypothyroidism, ulcerative colitis, diverticulitis, peptic ulcer disease, inflammatory bowel disease hypertension, osteoporosis, convulsive disorders, or diabetes. The glucocorticoids... 

Edwards-Levy, F., Andry, M. C. Levy, M. C. (1994). Determination of free amino group content of serum-albumin microcapsules. II. Effect of variations in reaction-time and terephthaloyl chloride concentration. International Journal of Pharmaceutics, Vol. 103, 3, (March 1994), pp. (253-257), ISSN 0378-5173 Friend, D. R. (2005). New oral delivery systems for treatment of inflammatory bowel disease. Advanced Drug Delivery Reviews, Vol. 57, 2, (January 2005), pp. (247-265), ISSN 0169-409X... 

JACOBASCH G, SCHMIEDL D, KRUscHEWSKi M, SCHMEHL K (1999) Dietary resistant starch and chronic inflammatory bowel diseases. Int J Colorectal Dis. 14 201-11. 

Rice bran fiber has fructo-oligosaccharides - a pre-biotic that helps friendly bacteria to proliferate in the gastrointestinal environment and improves intestinal and colon health (Tomlin and Read, 1988). Recent studies in humans (Kahlon and Chow, 1997) have revealed that rice bran fiber not only normalizes bowel function, but also helps in conditions such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and Crohn s disease, and lowers the lipid levels. Rice bran fiber has been shown to significantly reduce renal stones (Jahnen et al., 1992). It is a good source of fiber in weight loss programs and therapeutic fiber diets for diabetics and heart patients. Fiber diets prevent cancer of the colon and large bowel, control obesity and improve bowel function. 

The fiber of rice bran products, especially the RiceMucil is helpful in maintaining normal gastrointestinal and colon health (Tomlin and Read, 1988). It helps in bowel regularity. Patients with irritable bowel syndrome, inflammatory bowel disease and colitis get excellent relief with RiceMucil . As has been mentioned in the earlier part of this chapter, the fiber of rice bran is non-bloating and lactose free, and the acidic environment the fiber creates during the fermentation of undigested food improves colon health and induces all the healthy enzymes and fnendly bacteria to proliferate (Folino et al, 1995 Life Sciences News Letter, 1999). It has been scientifically demonstrated to have an excellent nutritional support for gut and colon health. 

Table 10.2 Oxidative metabolism of monocytes in inflammatory bowel disease...

Adeyemi, E.O., Neumann, S., Chadwick, V.S., Hodgson, H.J.F. and Pepys, M.B. (1985). Circulating human leucocyte elastase in patients with inflammatory bowel disease. Gut 26, 1306-1311. 

AUgayer, H., Gugler, R., Bohme, P., Schmidt, M., Hofer, P. and Kruis, W. (1991). Is free radical scavenging necessary in the treatment of inflammatory bowel disease Gastroenterology 100, 581-582. 

Burdelski, M., Oellericch, M., Pippenger, C.E., Meng, X., Rodeck, B., Latta, A. and Kucher, K. (1990). Free radical scavenging enzyme activities in erythrocytes of paediatric patients with Crohn s disease. In Trends in Inflammatory Bowel Disease Therapy (ed. C. J. Williams), pp. 453-454. Kluwer Academic Publishers, Lancaster. 

Faden, H. and Rossi, T.M. (1985). Chemiluminescent response of neutrophils fixjm patients with inflammatory bowel disease. Dig. Dis. Sci. 30, 139-142. 

Fernandez-Banares, F., Abad-Lacruz, A., Xiol, X., Gine, J.J., Dolz, C., Cabre, E., Esteve, M., Gonzales-Huix and Gassull, M.A. (1989). Vitamin status in patients with inflammatory bowel disease. Am. J. Gastroenterol. 85, 744-748. 

Fretland, D.J., Widomski, D.L., Anglin, C.P., Levin, S. and Gagjnella, T.S. (1990). Colonic inflammation in the rodent induced by phorbol-12-myristate-13-acetate a potential model of inflammatory bowel disease, effect of SC-41930. Gastroenterology 98, A449. 

Grisham, M.B. and Yamada, T. (1992). Neutrophils, nitrogen oxides, and inflammatory bowel disease. Ann. N. York Acad. Sci. 664, 103-115. 

Halliwell, B. (1991). Free radical scavengers and inflammatory bowel disease. Gastroenterology 101, 872. 

Harris, M.L., Schiller, H.J., Reilly, P.M., Donowitz, M., Grisham, M.B. and Bulkley, G.B. (1992). Free radicals and other reactive oxygen metabolites in inflammatory bowel disease cause, consequence or epiphenomenon Pharmac. Ther. 53, 375-408. 

Inauen, W., Bilzer, M., Rowedder, E., Halter, F. and Lauterbutg, B.H. (1988). Decreased gjutathione (GSH) in colonic mucosa of patients with inflammatory bowel disease mediated by oxygen free radicals Gastroenterology 94, A199. 

KeUeher, D., Feighery, C. and Weir, D.G. (1990). Chemiluminescence by polymorphonuclear leucocyte subpopulations in chronic inflammatory bowel disease. Influence of the cell separation procedure. Digestion 45, 158-165. 

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