Ulcerative Colitis: Fiocchi C

Sturm A, de Souza HS, Fiocchi C. · Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany. · Curr Drug Targets. · Pubmed #18473766 No free full text.

Abstract: Both forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), represent prototypical conditions whose most salient features are the presence of chronic inflammation involving various parts of the intestinal tract and an increased risk of cancer, which is a complication directly related to the duration and activity of gut inflammation. Several factors have been implicated in the unrelenting mucosal inflammation of IBD, prominent among them being the presence of a persistently elevated number of activated T cells in the mucosa of CD and UC patients. These T cells display various defects of proliferation and apoptosis, and these abnormalities are credited with directly contributing to the pathogenesis of IBD and possibly the progression to colon cancer. This notion is supported by the observation that T cells are also prominently found infiltrating most tumors and are functionally impaired compared to T cells in the circulation. This establishes a parallel that may constitute a link between chronic intestinal inflammation and the development of malignancies in the inflamed intestine. This article will review some of the basic features of human intestinal mucosal T cells, examine the mechanisms underlying the processes of cell cycling and cell death, describe the defective proliferative and apoptotic function detected in CD and UC, and discuss the implications of modulating T cell apoptosis in IBD for therapeutic purposes and eventually decreasing the risk of cancer development.

Scaldaferri F, Fiocchi C. · Department of Gastroenterology and Hepatology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · J Dig Dis. · Pubmed #17970872 No free full text.

Abstract: Over the past few years, none of the numerous conditions that are grouped under the broad designation of 'chronic inflammatory or autoimmune disorders' has undergone as much scientific and clinical progress as the two main forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC). Progress has occurred in all major areas relevant to IBD pathogenesis, which include the external environment, genetics, microbial factors, and the immune system. This review presents an update on the specific major advances that have occurred in each of these four areas, briefly discusses the therapeutic implications of the observed progress, and points out the additional work that needs to be accomplished in the next few years to reach a full understanding of IBD etiopathogenesis.

Kugathasan S, Fiocchi C. · Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. · Semin Pediatr Surg. · Pubmed #17602969 No free full text.

Abstract: A modern approach to inflammatory bowel disease (IBD) research has been under way for little over one-half century, but only during the last two decades has progress accelerated and finally generated tangible results that have been translated into practical and better therapeutic strategies. The areas where progress has been more evident are those currently believed to be the key components of IBD pathogenesis, and include the environment, genetics, enteric microbiology, and immune reactivity. Progress in these different areas has been somewhat uneven, yielding a better understanding of the mechanisms behind gut inflammation and tissue injury rather than of specific etiological agents or predisposing factors. However, with the rapidly increasing utilization of novel methodological approaches like genetics, genomics, proteomics, and pharmacogenomics, it is reasonable to anticipate that the etiopathogenesis of IBD will be unveiled in the next couple of decades and more definitive, perhaps disease-modifying, approaches will be uncovered and implemented.

Ouyang Q, Tandon R, Goh KL, Pan GZ, Fock KM, Fiocchi C, Lam SK, Xiao SD. · Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China. · J Gastroenterol Hepatol. · Pubmed #17074013 No free full text.

Abstract: At the present there are no large-scale epidemiologic data on inflammatory bowel disease (IBD) in the Asia-Pacific region, but several studies have shown an increased incidence and prevalence of IBD in this region. Compared to the West, there appears to exist a time lag phenomenon. With regard to the two main forms of IBD, ulcerative colitis (UC) is more prevalent than Crohn's disease (CD). In addition to geographic differences, ethnic differences have been observed in the multiracial Asian countries. Moreover, the genetic backgrounds are different in the Asian compared to Western patients. For instance, NOD2/CARD15 variants have not been found in Asian CD patients. In general, the clinical course of IBD seems to be less severe in the Asia-Pacific region than in Western countries. Diagnosis of IBD in this region poses special problems. The lack of a gold standard for the diagnosis of IBD, and the existence of a variety of infectious enterocolitis with similar manifestations to those of IBD make the differential diagnosis particularly difficult. So far, Western diagnostic criteria have been introduced for the diagnosis of IBD. A stepwise approach to exclude non-IBD enterocolitis also must be introduced, and a definite diagnosis must include typical histological features. In some patients, follow up and therapeutic trials might be necessary to obtain a definitive diagnosis. A better understanding of the pathogenesis of IBD will allow the development of better diagnostic markers. The management of IBD also poses some special problems in the Asia-Pacific Region. There is often a delay in using proper medications for IBD, and alternative local remedies are still widely used. With a combination of Western guidelines and regional experiences, similar principles can be used for induction and maintenance of remission. A stepwise selection of medications is advocated depending on the extent, activity and severity of the disease. Comprehensive and individualized approaches are suggested for different IBD patients. Deeper understanding of disease pathogenesis and the unique characteristics of IBD in the Asia-Pacific region, combined with reasonable and practical guidelines for drug management and the future use of biological agents would improve the therapeutic outlook of IBD in this region.

Danese S, Fiocchi C. · Division of Gastroenterology, Istituto Clinico Humanitas-IRCCS in Gastroenterology, Milan, Italy. · World J Gastroenterol. · Pubmed #16937461 links to  free full text

Abstract: Theories explaining the etiopathogenesis of inflammatory bowel disease (IBD) have been proposed ever since Crohn's disease (CD) and ulcerative colitis (UC) were recognized as the two major forms of the disease. Although the exact cause(s) and mechanisms of tissue damage in CD and UC have yet to be completely understood, enough progress has occurred to accept the following hypothesis as valid: IBD is an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. Among an almost endless list of environmental factors, smoking has been identified as a risk factor for CD and a protective factor for UC. Among microbial factors, no convincing evidence indicates that classical infectious agents cause IBD, while mounting evidence points to an abnormal immune response against the normal enteric flora as being of central importance. Gut inflammation is mediated by cells of the innate as well as adaptive immune systems, with the additional contribution of non-immune cells, such as epithelial, mesenchymal and endothelial cells, and platelets.

Ouyang Q, Tandon R, Goh KL, Ooi CJ, Ogata H, Fiocchi C. · Department of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China. · Curr Opin Gastroenterol. · Pubmed #15930979 No free full text.

Abstract: PURPOSE OF REVIEW: Inflammatory bowel disease has been traditionally considered rare in the Asian Pacific region, but recent evidence indicates that both Crohn disease and ulcerative colitis are becoming increasingly common among local populations. This review will validate this significant epidemiological and clinical observation using data published in the current Asian literature and information presented at the 2004 Asian Pacific Digestive Week in Beijing, China. RECENT FINDINGS: A progressive rise in the incidence and prevalence of inflammatory bowel disease is discernible is most Asian Pacific countries, more so for ulcerative colitis than Crohn disease. Some ethnic differences are notably evident, as Indians suffer more inflammatory bowel disease than Chinese or Malays. Age of onset and gender are similar to those of Western patients, as are the distribution and extent of disease which, however, tends to be clinically less severe than in European and North American patients. A family history is occasionally elicited, whereas smoking and appendectomy appear to have the same impact on inflammatory bowel disease as seen in the West. A remarkable difference is the absence of any association of Asian Crohn disease with NOD2/CARD15 mutations, as repeatedly observed in white and Jewish populations. Intestinal tuberculosis is still common in the Asian Pacific region, and poses major diagnostic and therapeutic hurdles, often delaying the diagnosis of true Crohn disease. SUMMARY: Investigation of inflammatory bowel disease in the Asian Pacific region offers the unprecedented opportunity to study the 'early stages' of the disease, and may provide new clues to its pathophysiology by identifying key environmental factors and distinct genetic make-ups.

Fiocchi C. · Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. · Chin J Dig Dis. · Pubmed #15667551 No free full text.

Abstract: The pathogenesis of inflammatory bowel disease (IBD) is complex, involving environmental, genetic, microbial, and immune factors. Therefore, treatment should target components that either predispose to or mediate the chronic inflammatory response of IBD. At the moment it is assumed that all components are necessary to have the typical manifestations of IBD but, in reality, it is unclear to what extent each factor contributes to the disease process, and whether some are more important than others. In addition, some factors are not practical targets; for example, environmental factors are poorly defined, too numerous, and require changes that cannot be implemented by the physician or the patient alone. The same is true for genetic factors that are still not amenable to therapeutic manipulations for technical and ethical reasons. This leaves microbial and immune factors as the two categories that can be selected for therapeutic intervention and where all current treatments are focused. The commensal gut flora can be qualitatively or quantitatively modified with antibiotics, probiotics, or diet, and a better characterization of enteric bacteria strains should help greatly in developing more effective therapies. Most current drugs are focused on inhibiting pro-inflammatory molecules produced by immune cells, including biological agents that block specific cytokines such as tumor necrosis factor-alpha. It is anticipated that combination therapies targeting multiple pathogenic components will prove more effective than those blocking single components of IBD pathogenesis.

Wen Z, Fiocchi C. · Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4952, USA. · Clin Dev Immunol. · Pubmed #15559364 links to  free full text

Abstract: The pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), is still unclear, but both autoimmune and immune-mediated phenomena are involved. Autoimmune phenomena include the presence of serum and mucosal autoantibodies against intestinal epithelial cells in either form of IBD, and against human tropomyosin fraction five selectively in UC. In addition, perinuclear antineutrophil cytoplasmic antibodies (pANCA) are common in UC, whereas antibodies against Saccharomyces cerevisiae (ASCA) are frequently found in CD. Immune-mediate phenomena include a variety of abnormalities of humoral and cell-mediated immunity, and a generalized enhanced reactivity against intestinal bacterial antigens in both CD and UC. It is currently believed that loss of tolerance against the indigenous enteric flora is the central event in IBD pathogenesis. Various complementary factors probably contribute to the loss of tolerance to commensal bacteria in IBD. They include defects in regulatory T-cell function, excessive stimulation of mucosal dendritic cells, infections or variants of proteins critically involved in bacterial antigen recognition, such as the products of CD-associated NOD2/CARD15 mutations.

Danese S, Sans M, Fiocchi C. · Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, (BRB 425), 10900 Euclid Avenue, Cleveland, OH 44106-4952, USA. · Autoimmun Rev. · Pubmed #15288007 No free full text.

Abstract: Environmental factors are essential components of the pathogenesis of inflammatory bowel disease (IBD) and primarily responsible for its growing incidence around the globe. Epidemiological, clinical and experimental evidence support an association between IBD and a large number of seemingly unrelated environmental factors, which include smoking, diet, drugs, geographical and social status, stress, microbial agents, intestinal permeability and appendectomy. Data supporting the involvement of each of these factors in predisposing to, triggering, or modulating the course or outcome of IBD vary from strong to tenuous. Smoking and the enteric bacterial flora are the ones for which the most solid evidence is currently available. Smoking increases the risk of Crohn's disease (CD) and worsens its clinical course, but has a protective effect in ulcerative colitis (UC). Presence of enteric bacteria is indispensable to develop gut inflammation in most animal models of IBD, and modulation of the quantity or quality of the flora can be beneficial in patients with IBD. Surprisingly, evidence for a major role of the diet in inducing or modifying IBD is limited, while that for nonsteroidal anti-inflammatory drugs is more convincing than for oral contraceptives. Northern geographic location, and a high social, economical, educational or occupational status increase the risk of IBD, an observation fitting the hygiene hypothesis for allergic and autoimmune diseases. Stress is also associated with IBD, but more as a modifier than an inducing factor, and its contribution is more obvious in IBD animal models than human IBD. Finally, an increased intestinal permeability may increase the risk for developing CD, whereas an appendectomy lowers the risk of developing UC.

Danese S, Motte Cd Cde L, Fiocchi C. · Catholic University of Rome, Rome, Italy. · Am J Gastroenterol. · Pubmed #15128364 No free full text.

Abstract: Both Crohn's disease (CD) and ulcerative colitis (UC) are associated with abnormalities of platelet number and function. In the peripheral circulation the state of platelet activation is typically increased, and inflammatory bowel disease (IBD)-involved mucosa frequently contains platelet aggregates within mucosal microthrombi. The relevance of platelet dysfunction to IBD pathogenesis is still unclear, but there is solid evidence demonstrating that platelets, in addition to their traditional role in hemostasis, can also function as potent proinflammatory cells. Upon activation, platelets secrete a large number of biologically active molecules able to induce or amplify an inflammatory process through many of the same cellular and molecular pathways conventionally utilized by immune cells mediating IBD. The aim of this article is to review data on the existence of platelet dysfunction in IBD, substantiate platelets' inflammatory potential, discuss the implications of abnormal platelet activity for chronic intestinal inflammation, and consider the potential benefits of platelet modulation for treatment of IBD.

Fiocchi C. · Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Ohio 44106-4952, USA. · Dig Liver Dis. · Pubmed #12038817 No free full text.

Abstract: Perception of a disease state by the practising physician is based on how easily the diagnosis can be made and how predictable the outcome of the chosen therapy is. The academic investigator perceives the same disease based on how well its cause and mechanism are understood, and how rational pathophysiology-based treatments are. Because of incomplete knowledge, neither the practising physician nor the academic investigator are comfortable in dealing with inflammatory bowel disease, and both seek help in the dogmas and heresies inevitably associated with chronic disease of unknown aetiology.

Gurudu S, Fiocchi C, Katz JA. · Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, OH 44106-5066, USA. · Best Pract Res Clin Gastroenterol. · Pubmed #11977930 No free full text.

Abstract: Although inflammatory bowel disease (IBD) usually presents in adolescents and young adults, both ulcerative colitis and Crohn's disease can also present in older adults. The diagnosis of IBD in the elderly is often difficult and can easily be confused with diverticulitis or ischaemic colitis. The symptoms and complications of IBD in the elderly are similar to those found in younger patients. However, when IBD presents later in life the disease is often less extensive and milder. Older IBD patients are treated with the same medications as younger patients, although the risk for drug toxicity is greater, especially with corticosteroid therapy. Comorbid illness in older patients often has a significant impact on the outcome of medical and surgical therapy for IBD but, in the absence of significant co-morbid disease, most elderly IBD patients can expect a good response to therapy.

Seidner DL, Lashner BA, Brzezinski A, Banks PL, Goldblum J, Fiocchi C, Katz J, Lichtenstein GR, Anton PA, Kam LY, Garleb KA, Demichele SJ. · Department of Gastroenterology\A30, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. · Clin Gastroenterol Hepatol. · Pubmed #15822041 No free full text.

Abstract: BACKGROUND & AIMS: N-3 fatty acids from fish oil, antioxidants, and short-chain fatty acids (SCFAs) produced during the fermentation of soluble fiber may attenuate inflammation associated with ulcerative colitis (UC). We assessed the efficacy of a nutritionally balanced oral supplement enriched with fish oil, fructooligosaccharides, gum arabic, vitamin E, vitamin C, and selenium on disease activity and medication use in adults with mild to moderate UC. METHODS: A total of 121 patients with UC and a disease activity index (DAI) from 3-9 on a 12-point scale were block randomized for extent of disease and smoking status. In addition to their usual diet, patients consumed 18 oz of the oral supplement or a carbohydrate-based placebo formula each day for 6 months. Clinical and histologic responses were assessed at 3 and 6 months or at the final visit. A change in average prednisone use between groups was tested by using a linear mixed-effects model. RESULTS: Eighty-six patients completed the study. Baseline characteristics were not different between groups except for a higher total DAI score in the oral supplement group (7.3 +/- 1.3; n = 36) compared with the placebo group (6.2 +/- 2.0; n = 50) ( P < .05). Both groups showed significant and similar degree of improvement at 6 months in DAI (-2.5 for oral supplement and -2.8 for placebo) and histologic index (-1.9 for oral supplement vs. -2.0 for placebo). Both intent-to-treat and completed patients given oral supplement had a significantly greater rate of decrease in the dose of prednisone required to control clinical symptoms over 6 months as compared with the placebo group ( P < .001). CONCLUSIONS: The improvement in clinical response combined with a decreased requirement for corticosteroids suggest that this enriched oral supplement can be a useful adjuvant therapy in patients with UC.

Levine AD, Fiocchi C. · Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. · Curr Opin Gastroenterol. · Pubmed #17031093 No free full text.

Abstract: The immunology of inflammatory bowel disease continues to be an intense area of investigation for clues to the pathogenesis of Crohn disease and ulcerative colitis. As typical with complex diseases, inflammatory bowel disease research is continuously evolving. Without abandoning traditional areas of study, such as humoral and cellular immunity and cytokines, investigation is broadening to explore new molecules and biologic phenomena. Novel cytokines and cell adhesion molecules appear to be involved in inflammation, while the role of nitric oxide is being clarified. Leukocyte resistance to apoptosis appears to be a major contributing factor to Crohn disease. Epithelial cell-derived defensins and receptors are arising as key molecules mediating the interaction of innate and acquired mucosal immunity with the enteric flora, and explaining how the latter participates in gut inflammation. The results of these combined studies are opening novel therapeutic horizons whose implementation offers better forms of treatment.

Katz JA, Itoh J, Fiocchi C. · Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. · Curr Opin Gastroenterol. · Pubmed #17023960 No free full text.

Abstract: In spite of expanding knowledge of cellular and molecular mechanisms of intestinal inflammation, the etiology and pathogenesis of inflammatory bowel disease (IBD) remain obscure. The link between the environment and IBD is still circumstantial, but definite progress is occurring in defining genetic susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC). The notion that normal enteric flora play a role in initiating or maintaining IBD is gaining momentum. Some components of the flora may act as noxious agents, whereas others (probiotics) seem to have a protective effect. The importance of the mucosal immune system to IBD is established, and evidence is accumulating that nonimmune components, such as epithelial, mesenchymal, and endothelial cells, also contribute to gut inflammation. The effect of cytokines in intestinal immunity is being elucidated by studies on their molecular mechanism, particularly the activation of nuclear factor (NF)-kappaB. Finally, the beneficial effects of cytoprotective prostaglandins and cell adhesion molecule (CAM) blockade promise novel therapeutic opportunities derived from an improved understanding of IBD pathogenesis.

Bousvaros A, Sylvester F, Kugathasan S, Szigethy E, Fiocchi C, Colletti R, Otley A, Amre D, Ferry G, Czinn SJ, Splawski JB, Oliva-Hemker M, Hyams JS, Faubion WA, Kirschner BS, Dubinsky MC, Anonymous00395. · Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA. · Inflamm Bowel Dis. · Pubmed #16954808 links to  free full text

Abstract: It is estimated that of the >1 million individuals in the United States with inflammatory bowel disease (IBD), approximately 100,000 are children. IBD that begins in childhood affects the individual at a critical period of growth and development. Children with Crohn's disease and ulcerative colitis may experience complications such as growth failure, school absence, and depression. In addition, because children with IBD have fewer environmental confounders such as smoking, children may be an excellent population to study microbial and immune interactions. Despite these opportunities, the discipline of pediatric IBD investigation is still in its infancy. In September of 2005, a group of investigators with expertise in pediatric IBD met in Boston (Massachusetts) to review the current status of childhood IBD research and to develop research priorities that warranted funding from the Crohn's and Colitis Foundation of America. The group included pediatricians, internists, basic scientists, clinical investigators, and members of the administrative staff and board of the Crohn's and Colitis Foundation of America. The research needs in respective areas were outlined by the heads of 10 focus groups, each with expertise in their respective fields (genetics, psychosocial issues, epidemiology, microbiology, immunology, quality improvement, pharmacogenomics, nutrition, growth and skeletal health, and clinical trials). Before the conference, heads of the research focus groups developed their proposals with experts in the field. At the end of the conference, members of the focus groups and members of the steering committee rated the proposed areas of study in terms of feasibility and importance. It was recommended that the Crohn's and Colitis Foundation of America focus its initial efforts in pediatric IBD in 5 areas: the effects of inflammation on growth and skeletal development, the genetics of early-onset IBD, the development of quality improvement interventions to standardize and improve clinical care of children with IBD, the immunology of childhood IBD, and the diagnosis and treatment of psychosocial sequelae of childhood IBD. At the conclusion of the meeting, investigators discussed the formation of a multicenter collaborative network to advance clinical and basic research in the field.

Danese S, Sans M, de la Motte C, Graziani C, West G, Phillips MH, Pola R, Rutella S, Willis J, Gasbarrini A, Fiocchi C. · Division of Gastroenterology, Istituto Clinico Humanitas, IRCCS in Gastroenterology, Rozzano, Milan, Italy. · Gastroenterology. · Pubmed #16762629 No free full text.

Abstract: BACKGROUND & AIMS: Angiogenesis is a critical component of neoplastic and chronic inflammatory disorders, but whether angiogenesis also occurs in inflammatory bowel disease (IBD) has yet to be established. We assessed mucosal vascularization, expression of endothelial alphaVbeta3 integrin, angiogenic factors, and their bioactivity in Crohn's disease (CD) and ulcerative colitis (UC) mucosa. METHODS: Mucosal endothelium was immunostained for CD31 and factor VIII and quantified by digital morphometry. alphaVbeta3 expression was studied in vivo by confocal microscopy and in vitro by flow cytometric analysis of human intestinal microvascular endothelial cells (HIMECs). Vascular endothelial growth factor (VEGF), interleukin (IL)-8, and bFGF levels were measured in mucosal extracts and cells and angiogenic bioactivity shown by induction of HIMEC migration and the corneal and chorioallantoic membrane angiogenesis assays. RESULTS: Microvessel density was increased in IBD mucosa. Endothelial alphaVbeta3 was strongly expressed in IBD but only sporadically in normal mucosa and was up-regulated in HIMECs by VEGF, tumor necrosis factor alpha, and bFGF. IBD mucosal extracts induced a significantly higher degree of HIMEC migration than control mucosa, and this response was mostly dependent on IL-8 and less on basic fibroblast growth factor or vascular endothelial growth factor. Compared with normal mucosa, IBD mucosal extracts induced a potent angiogenic response in both the corneal and chorioallantoic membrane assays. CONCLUSIONS: These results provide morphological, phenotypic and functional evidence of potent angiogenic activity in both CD and UC mucosa, indicating that the local microvasculature undergoes an intense process of inflammation-dependent angiogenesis. Thus, angiogenesis appears to be an integral component of IBD pathogenesis, providing the practical and conceptual framework for anti-angiogenic therapies in IBD.

Fiocchi C. · Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. · Minerva Gastroenterol Dietol. · Pubmed #16491045 No free full text.

Abstract: Inflammatory bowel disease (IBD) still presents major challenges to the understanding of its cause, mechanisms of inflammation, and therapeutic choices to control the damaged tissue. Both types of IBD, ulcerative colitis and Crohn's disease, have been known and investigated for over half century but neither one is fully understood nor can be satisfactorily managed. While many gaps in our knowledge still exist, the last two decades have witnessed an unprecedented progress not only in the etiology but mainly in the mechanisms underlying the chronic inflammatory response. The pattern of IBD epidemiology has drastically changed since World War II, with an increased frequency in countries that have adopted a ''westernized'' life style. A parallel and important phenomenon is the continuous drop in age of onset in children. Unfortunately, only few epidemiological clues are available, with the exception of smoking and diet. What in smoking alters the course of IBD is still a mystery and which, among thousands of additives, could represent a risk factor will remain unknown for the foreseeable future. The current emphasis on the study of the enteric flora as the source of potential antigens against which the mucosal immune system reacts appear well justified. The data from animal models appears particularly convincing. Thus, after decades of relying almost exclusively on patient-derived information, numerous animal models are generating precious new information on IBD pathogenesis. In experimental IBD the genetic background of the animal markedly influences the course of the disease, and the same is probably true in humans. The identification of NOD2 as the first mutated gene associated with a subgroup of Crohn's disease patients is the first evidence that genetics are pointing to the right direction for understanding how the environment interacts with genes to cause IBD. For many years immunology has been the main source of scientific information on mechanisms of IBD. Cytokines, chemokines and other soluble factors dominate immunological studies aimed at understanding how different anti-inflammatory and pro-inflammatory mediators are improperly regulated and how immune imbalance can be restored. The extent to which T-cells live or die is also a key determinant of chronicity. In addition to classical immune cells, epithelial, endothelial, mesenchymal and nerve cells are slowly gaining more importance in IBD pathogenesis, as they contribute to the ultimate fate of tissue damage. Medical and surgical therapies are vastly better now that they were only a couple of decades ago, but they are still far from satisfactory. Steroid and aminosalicylates are still the most common drugs after 60 years of use, and it is time to renovate our therapeutic approach to a more effective one. The value of biologicals has been highlighted by the recent success of anti-TNF therapy. Timing of therapy must also change. The concept of the step-by-step approach is slowly fading away, and the idea of an ''all-out'' approach with multiple concomitant drugs early in the disease is gaining credibility. New reports on early aggressive therapies, and the demonstration that early and late experimental IBD are caused by different mechanisms are changing the way we think about managing IBD. Both ulcerative colitis and Crohn's disease will continue to challenge the medical establishment for year to come, but the possibility that IBD can be conquered is more realistic now that never before.

Cao W, Fiocchi C, Pricolo VE. · Dept. of Medicine, Brown Medical School and Rhode Island Hospital, 55 Claverick St., Rm. 337, Providence, RI 02903, USA. · Am J Physiol Cell Physiol. · Pubmed #16033908 links to  free full text

Abstract: We have previously shown that sigmoid circular muscle cells from patients with ulcerative colitis (UC) exhibit reduced contraction and Ca2+ signaling in response to the neurotransmitter neurokinin A (NKA) and that IL-1beta and H2O2 may contribute to these reduced responses in UC. In addition, we have found that nitric oxide (NO) levels were significantly increased in UC circular muscle. To establish the site of origin for IL-1beta, H2O2, and NO, we assembled an in vitro system in which normal or UC mucosa were sealed between two chambers filled with oxygenated Krebs solution. Because the mucosa consists of full-thickness mucosa and submucosa, it is expected that whatever is released into the undernatant from the submucosal side may diffuse to the circular muscle layer in the intact colon. Treatment of normal sigmoid circular muscle cells for 2 h with undernatants collected from the UC submucosal side (UCS) significantly decreased contraction induced by NKA and thapsigargin and the NKA- and caffeine-induced Ca2+ signal in Ca2+-free medium. In addition, UC mucosa released into the undernatant on its submucosal side significantly more H2O2, IL-1beta, and NO than normal mucosa. The reduction in contraction and Ca2+ signal induced by UCS was partially reversed by pretreatment with an IL-1beta antibody or with catalase. The NO scavenger hemoglobin partially prevented UCS-induced reduction in contraction and Ca2+ signaling in response to NKA but not the reduced response to thapsigargin or caffeine. Sodium nitroprusside inhibited NKA but not the caffeine-induced Ca2+ signal. We conclude that in UC the mucosa releases IL-1beta, H2O2, and NO, which may contribute to the impaired Ca2+ release and altered sigmoid muscle contractility.

Zhang H, Ouyang Q, Wen ZH, Fiocchi C, Liu WP, Chen DY, Li FY. · Department of Gastroenterology, Sichuan University West China Hospital, Chengdu 610041, Sichuan Province, China. · World J Gastroenterol. · Pubmed #15793862 links to  free full text

Abstract: AIM: Glucocorticoid (GC) resistant ulcerative colitis (UC) remains a serious disease and is difficult to manage. Although the molecular basis of GC insensitivity is still unknown, GC receptors (GRalpha and GRbeta) may play an important role in it. This study was aimed to investigate the relationship between the expression of GRalpha and GRbeta in colonic mucosal cells of patients with UC, the efficacy of GC therapy and the intensity of inflammation. METHODS: Twenty-five cases of UC were classified into: GC sensitive (n = 16) and GC resistant (n = 9) cases. Patients consisted of mild (n = 6), moderate (n = 8) and severe (n = 11) cases. GRalpha and GRbeta expression in colonic mucosal specimens were investigated by immunohistochemistry, and compared between GC resistant and sensitive groups, and also among various degrees of inflammation. RESULTS: All cases were positive for GRalpha and GRbeta expression. Both positive association between GRalpha expression and the response of UC to GC and strong negative association between GRbeta expression and the response of UC to GC were identified. There was no significant association between GRalpha/GRbeta expression and the degree of inflammation of UC. CONCLUSION: These findings suggest that both GRalpha and GRbeta may play an important role in the action of GC, and that GRbeta functions as a dominant negative inhibitor of GRalpha. Expression of GRalpha and GRbeta in colonic mucosal cells of patients with UC may serve as predictors of glucocorticoid response, but can not function as markers of inflammatory intensity.

Musso A, Dentelli P, Carlino A, Chiusa L, Repici A, Sturm A, Fiocchi C, Rizzetto M, Pegoraro L, Sategna-Guidetti C, Brizzi MF. · Division of Gastroenterology, Ospedale San Giovanni Battista, University of Torino, Torino, Italy. · Inflamm Bowel Dis. · Pubmed #15677901 No free full text.

Abstract: Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of chronic inflammatory bowel disease (IBD), are characterized by mucosal immune cell activation that is driven by a cytokine imbalance. Several cytokines involved in IBD act through the activation of the signal transducers and activators of transcription (STAT) family. We investigated the activation of STAT3 in the mucosa of CD and UC patients, and evaluated whether this event is specific for IBD patients. Using immunofluorescence and immunoblotting, total and phosphorylated STAT3 levels were assessed in biopsy specimens, isolated lamina propria mononuclear cells, and peripheral blood mononuclear cells from patients with CD, UC, other forms of intestinal inflammation, and control subjects. Immunoblotting revealed phosphorylated STAT3 in mucosal biopsy specimens from patients with CD, UC, celiac disease, and acute self-limited colitis, but not in the normal mucosa of control subjects. In IBD patients, STAT3 activation was confined to actively inflamed areas. Accordingly, activated STAT3 was detected in isolated lamina propria mononuclear cells from inflamed IBD tissues, but not in peripheral blood mononuclear cells from control subjects or IBD patients. Immunofluorescence demonstrated that the sources of activated STAT3 were macrophages and T lymphocytes, but not neutrophils. STAT3 activation also was detected in T cells infiltrating the duodenal mucosa of celiac disease patients. We conclude that STAT3 signaling occurs in both CD and UC, where it is strictly confined to areas of active inflammation and is limited to infiltrating macrophages and T cells. The occurrence of STAT3 signaling in other acute and chronic intestinal inflammatory conditions suggests that, rather than a specific feature of IBD, it represents a fundamental signaling pathway that is shared by multiple forms of gut inflammation.

Sturm A, Leite AZ, Danese S, Krivacic KA, West GA, Mohr S, Jacobberger JW, Fiocchi C. · Department of Medicine, University Hospitals of Cleveland, Case Western Reserve University School of Medicine (BRB 425), 10900 Euclid Ave, Cleveland, Ohio, 44106-4952, USA. · Gut. · Pubmed #15479683 links to  free full text

Abstract: BACKGROUND: Different abnormalities of T cell effector function distinguish Crohn's disease (CD) from ulcerative colitis (UC). Because cell cycling determines effector function, pathogenic events in CD and UC may depend on cell cycle changes unique to each condition. METHODS: Cell cycle kinetics, cycle regulatory molecule expression, apoptosis, caspase and telomerase activity, and cellular expansion were evaluated in CD2 and CD3 activated control, CD, and UC lamina propria T cells. RESULTS: Compared with normal cells, CD T cells cycle faster, express increased phosphorylated Rb and decreased phosphorylated p53 levels, display less caspase activity but more telomerase activity, die less, and undergo vigorous cellular expansion. In contrast, UC T cells cycle slower, express normal levels of phosphorylated Rb and p53, display more caspase activity but have no telomerase activity, die more, and have a limited capacity to expand. CONCLUSIONS: T cell cycle abnormalities in CD indicate a state of hyperreactivity compatible with loss of tolerance, but a hyporeactive state compatible with anergy in UC. Thus distinct and divergent T cell cycle characteristics underlie the pathogenesis of the two main forms of inflammatory bowel disease.

Cao W, Vrees MD, Potenti FM, Harnett KM, Fiocchi C, Pricolo VE. · Department of Surgery, Brown Medical School and Rhode Island Hospital, 2 Dudley St., Suite 470, Providence, RI 02905, USA. · J Pharmacol Exp Ther. · Pubmed #15205451 links to  free full text

Abstract: We have shown that neurokinin A-induced contraction of human sigmoid circular muscle (HSCM) is reduced in patients with ulcerative colitis and that interleukin (IL)-1beta may play a role in this change. We now examine changes in the signal transduction pathway mediating neurokinin A-induced contraction of HSCM and explore the role of IL-1beta and of H(2)O(2) in these changes. In Fura 2-AM-loaded ulcerative colitis HSCM cells, neurokinin A- and caffeine-induced peak Ca(2+) increase and cell shortening were significantly reduced. In normal cells, neurokinin A-induced contraction was decreased by protein kinase C inhibitor chelerythrine and by calmodulin inhibitor CGS9343B [1,3-dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepin-4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-one (1:1) maleate]. In ulcerative colitis muscle cells, contraction was inhibited only by chelerythrine but not by CGS9343B. IL-1beta treatment of normal HSCM strips and cells reproduced the changes observed in ulcerative colitis. IL-1beta-induced reduction in caffeine-induced peak Ca(2+) increase and contraction was reversed by catalase, suggesting a role of H(2)O(2). IL-1beta-induced H(2)O(2) production was inhibited by mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059 (2'-amino-3'-methoxyflavone) and by cytosolic phospholipase A2 (cPLA(2)) inhibitor AACOCF3 (arachidonyltrifluoromethyl ketone), but neither by p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole] nor by nuclear factor-kappaB (NF-kappaB) inhibitory peptide NF-kappaB SN50 (H-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu-Ala-Pro-Val-Gln-Arg-Lys-Arg-Gln-Lys-Leu-Met-Pro-OH). IL-1beta significantly increased the phosphorylation of extracellular signal-regulated kinase 1 (ERK1)/ERK2 MAPKs and cPLA(2) and IL-1beta-induced cPLA(2) phosphorylation was blocked by PD98059. We conclude that Ca(2+) stores of HSCM cells may be reduced in ulcerative colitis and that the signal transduction pathway of neurokinin A-induced contraction switches from calmodulin- and protein kinase C-dependent in normal cells to protein kinase C-dependent in ulcerative colitis cells. IL-1beta reproduces these changes, possibly by production of H(2)O(2) via sequential activation of MAPKs (ERK1/ERK2) and cPLA(2).

Fukushima K, Fiocchi C. · Div. of Gastroenterology, Univ. Hospitals of Cleveland, Case Western Reserve Univ. School of Medicine (BRB 425 10900 Euclid Ave., Cleveland, OH 44106-4952, USA. · Am J Physiol Gastrointest Liver Physiol. · Pubmed #15068964 links to  free full text

Abstract: Ulcerative colitis (UC) is a condition characterized by chronic inflammation targeted at the epithelial layer. In addition to being involved in immune phenomena, UC epithelial cells exhibit decreased oxidation of butyrate, downregulation of oxidative pathway regulatory genes, and overexpression of mitochondrial (mt) genes. We investigated whether these events, which translate an altered energy metabolism, are associated with an abnormal pattern of mtDNA deletions. Highly purified colonocytes were isolated from surgically resected control, involved and uninvolved inflammatory bowel disease mucosa. The frequency, type, and number of mtDNA deletions were assessed by PCR amplification, Southern blot analysis, and cloning and sequencing of amplified DNA fragments. The 4977 mtDNA deletion was less frequent in UC than control and Crohn's disease (CD) epithelium, regardless of patient age. Several other deletions were detected, but all were less common in UC than control and CD cells. The frequency, variety, and number of mtDNA deletions were invariably lower in colonocytes isolated from inflamed mucosa than in autologous cells from noninflamed mucosa. In conclusion, in the absence of inflammation, UC colonocytes exhibit an mtDNA deletion pattern similar to that of control cells, indicating a normal response to physiological levels of oxidative stress. In active inflammation, when oxidative stress increases, the frequency, variety, and number of mtDNA deletions decrease. Because comparable abnormalities are absent in active CD, the mtDNA deletion pattern of active UC suggests that colonocytes respond uniquely to inflammation-associated stress in this condition.

Cao W, Vrees MD, Kirber MT, Fiocchi C, Pricolo VE. · Dept. of Medicine, Brown Medical School and Rhode Island Hospital, 593 Eddy St., SWP-510, Providence, RI 02903, USA. · Am J Physiol Gastrointest Liver Physiol. · Pubmed #14670823 links to  free full text

Abstract: Ulcerative colitis (UC) affects colonic motor function, but the mechanism responsible for this motor dysfunction is not well understood. We have shown that neurokinin A (NKA) may be an endogenous neurotransmitter mediating contraction of human sigmoid colonic circular muscle (HSCCM). To elucidate factors responsible for UC motor dysfunction, we examined the role of hydrogen peroxide (H(2)O(2)) in the decrease of NKA-induced response of HSCCM. As previously demonstrated, NKA-induced contraction or Ca(2+) increase of normal muscle cells is mediated by release of Ca(2+) from intracellular stores, because it was not affected by incubation in Ca(2+)-free medium (CFM) containing 200 microM BAPTA. In UC, however, CFM reduced both cell contraction and NKA-induced Ca(2+) increase, suggesting reduced Ca(2+) release from intracellular stores. In normal Ca(2+) medium, NKA and KCl caused normal Ca(2+) signal in UC cells but reduced cell shortening. The decreased Ca(2+) signal and contraction in response to NKA or thapsigargin were partly recovered in the presence of H(2)O(2) scavenger catalase, suggesting involvement of H(2)O(2) in UC-induced dysmotility. H(2)O(2) levels were higher in UC than in normal HSCCM, and enzymatically isolated UC muscle cells contained much higher levels of H(2)O(2) than normal cells, which were significantly reduced by catalase. H(2)O(2) treatment of normal cells in CFM reproduced the reduction of NKA-induced Ca(2+) release observed in UC cells. In addition, H(2)O(2) caused a measurable, direct release of Ca(2+) from intracellular stores. We conclude that H(2)O(2) may contribute to reduction of NKA-induced Ca(2+) release from intracellular Ca(2+) stores in UC and contribute to the observed colonic motor dysfunction.