Intestinal inflammation and colorectal cancer:A doubleedged sword?

Chronic inflammation is thought to be the leading cause of many human cancers including colorectal cancer(CRC).Accordingly,epidemiologic and clinical studies indicate that patients affected by ulcerative colitis and Crohn's disease,the two major forms of inflammatory bowel disease,have an increased risk of developing CRC.In recent years,the role of immune cells and their products have been shown to be pivotal in initiation and progression of colitis-associated CRC.On the other hand,activation of the immune system has been shown to cause dysplastic cell elimination and cancer suppression in other settings.Clinical and experimental data herein reviewed,while confirming chronic inflammation as a risk factor for colon carcinogenesis,do not completely rule out the possibility that under certain conditions the chronic activation of the mucosal immune system might protect from colonic dysplasia.

Emerging role of IL-23/IL-17 axis in H pylori-associated pathology

Colonization of stomach by H pylori is followed by a marked infiltration of the mucosa with polymorphonuclear leukocytes, macrophages, and lymphocytes that very often remains asymptomatic, but in some circumstances can lead to the development of gastroduodenal ulceration, gastric carcinoma, and mucosa-associated lymphoid tissue lymphoma. The molecular mechanisms by which H pylori triggers and maintains the local immune response are complex, but there is evidence that cytokines produced by both immune and non-immune cells contribute to amplify the ongoing inflammation. H pylori infection is associated with a marked mucosal induction of T helper (Th) type 1 and Th17-type cytokines that is governed by specific antigen-presenting cell-derived molecules, such as interleukin (IL)-12 and IL-23. In this paper, we will review the available data on the expression and role of IL-23 and IL-17 in H pylori- related gastritis.

Interleukin-12 and Th1 immune response in Crohn’s disease: Pathogenetic relevance and therapeutic inplication

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share clinical and pathological characteristics. The most accredited hypothesis is that both CD and UC result from a deregulated mucosal immune response to normal constituents of the gut microflora. Evidence, however, indicates that the main pathological processes in these two diseases are distinct. In CD, the tissue- damaging inflammatory reaction is driven by activated type 1 helper T-cell (Th1), whereas a humoral response predominates in UC. Consistently, a marked accumulation of macrophages making interleukin (IL)-12, the major Th1-inducing factor, is seen in CD but not in UC mucosa. Preliminary studies also indicate that administration of a monoclonal antibody blocking the IL-12/p40 subunit can be useful to induce and maintain clinical remission in CD patients. Notably, the recently described IL-23 shares the p40 subunit with IL-12, raising the possibility that the clinical benefit of the anti-IL-12/p40 antibody in CD may also be due to the neutralization of IL-23 activity. This review summarizes the current information on the expression and functional role of IL-12 and IL- 12-associated signaling pathways both in patients with CD and experimental models of colitis, thus emphasizing major differences between IL-12 and IL-23 activity on the development of intestinal inflammation.

Post-endoscopic retrograde cholangio-pancreatography pancreatitis:Is time for a new preventive approach?

Acute pancreatitis is the most common serious complication of endoscopic retrograde cholangio-pancre-atography (ERCP) and its incidence may exceed 25% in some high-risk patient subsets. In some patients, pancreatitis may follow a severe course with pancreatic necrosis, multiorgan failure, permanent disability and even death. Hence, approaches which minimize both the incidence and severity of post-ERCP pancreatitis are worth pursuing. Pancreatic stents have been used with some success in the prevention of post-ERCP, while so far pharmacological trials have yielded disappointing results. A recent multicenter, randomized, placebo-controlled, double-blind trial has shown that rectally administered indomethacin is effective in reducing the incidence of post-ERCP pancreatitis, the occurrence of episodes of moderate-to-severe pancreatitis and the length of hospital stay in high-risk patients. These results together with the demonstration that rectal administration of indomethacin is not associated with en-hanced risk of bleeding strongly support the use of this drug in the prophylaxis of post-ERCP pancreatitis.

Impairment of ghrelin synthesis in Helicobacter pyloricolonized stomach:New clues for the pathogenesis of H.pylori-related gastric inflammation

Ghrelin,the ligand of growth hormone secretagogue receptor 1a,takes part in several functions of the digestive system,including regulation of appetite,energy homeostasis,gastric acid secretion and motility.Ghrelin has also immunoregulatory properties and is supposed to inhibit some inflammatory pathways that can mediate gastric damage.Interestingly,ghrelin synthesis is reduced in the gastric mucosa of patients with Helicobacter pylori(H.pylori)infection,a worldwide condition inducing a T helper(Th)1/Th17 cell responsedriven gastritis,which may evolve towards gastric atrophy and cancer.In this article,we review the available data on the expression of ghrelin in H.pylori infection and discuss how the defective ghrelin synthesis may contribute to sustain the ongoing inflammatory response in this disease.

Interleukin-21 triggers effector cell responses in the gut

In the gut of patients with Crohn's disease and patients with ulcerative colitis,the major forms of inflammatory bowel diseases(IBD) in humans,the tissue-damaging immune response is mediated by an active cross-talk between immune and non-immune cells.Accumulating evidence indicates also that cytokines produced by these cells play a major role in initiating and shaping this pathologic process.One such cytokine seems to be interleukin(IL)-21,a member of the common γ-chainreceptor family.IL-21 is produced in excess in the in-flamed intestine of patients with IBD mostly by activated CD4+ T helper cells co-expressing interferon-γ and follicular T helper cells.Moreover,both in vitro and in vivo studies indicate that excessive IL-21 production leads to the activation of multiple signaling pathways that expand and sustain the ongoing mucosal inflammation.In this article,we review the available data supporting the pathogenic role of IL-21 in IBD.

Small intestine contrast ultrasonography vs computed tomography enteroclysis for assessing ileal Crohn's disease

AIM:To compare computed tomography enteroclysis(CTE) vs small intestine contrast ultrasonography(SICUS) for assessing small bowel lesions in Crohn's disease(CD),when using surgical pathology as gold standard.METHODS:From January 2007 to July 2008,15 eligible patients undergoing elective resection of the distal ileum and coecum(or right colon) were prospectively enrolled.All patients were under follow-up.The study population included 6 males and 9 females,with a median age of 44 years(range:18-80 years).Inclusion criteria:(1) certain diagnosis of small bowel requiring elective ileo-colonic resection;(2) age between 18-80 years;(3) elective surgery in our Surgical Unit;and(4) written informed consent.SICUS and CTE were performed ≤ 3 mo before surgery,followed by surgical pathology.The following small bowel lesions were blindly reported by one sonologist,radiologist,surgeon and histolopathologist:disease site,extent,strictures,abscesses,fistulae,small bowel dilation.Comparison between findings at SICUS,CTE,surgical specimens and histological examination was made by assessing the specificity,sensitivity and accuracy of each technique,when using surgical findings as gold standard.RESULTS:Among the 15 patients enrolled,CTE was not feasible in 2 patients,due to urgent surgery in one patients and to low compliance in the second patient,refusing to perform CTE due to the discomfort related to the naso-jejunal tube.The analysis for comparing CTE vs SICUS findings was therefore performed in 13 out of the 15 CD patients enrolled.Differently from CTE,SICUS was feasible in all the 15 patients enrolled.No complications were observed when using SICUS or CTE.Surgical pathology findings in the tested population included:small bowel stricture in 13 patients,small bowel dilation above ileal stricture in 10 patients,abdominal abscesses in 2 patients,enteric fistulae in 5 patients,lymphnodes enlargement(> 1 cm) in 7 patients and mesenteric enlargement in 9 patients.In order to compare findings by using SICUS,CTE,histology and surgery,characteristics of the small bowel lesions observed in CD each patient were blindly reported in the same form by one gastroenterologistsonologist,radiologist,surgeon and anatomopathologist.At surgery,lesions related to CD were detected in the distal ileum in all 13 patients,also visualized by both SICUS and CTE in all 13 patients.Ileal lesions > 10 cm length were detected at surgery in all the 13 CD patients,confirmed by SICUS and CTE in the same 12 out of the 13 patients.When using surgical findings as a gold standard,SICUS and CTE showed the exactly same sensitivity,specificity and accuracy for detecting the presence of small bowel fistulae(accuracy 77% for both) and abscesses(accuracy 85% for both).In the tested CD population,SICUS and CTE were also quite comparable in terms of accuracy for detecting the presence of small bowel strictures(92% vs 100%),small bowel fistulae(77% for both) and small bowel dilation(85% vs 82%).CONCLUSION:In our study population,CTE and the non-invasive and radiation-free SICUS showed a comparable high accuracy for assessing small bowel lesions in CD.

Common immunologic mechanisms in inflammatory bowel disease and spondylarthropathies

Spondyloarthropathies(SpA) are commonly observed extra-intestinal manifestations of both Crohn's disease(CD) and ulcerative colitis(UC), the two major forms of inflammatory bowel diseases(IBD).However, the immunological link between these two clinical entities is still poorly understood.Several lines of evidence indicate that SpA may originate from the relocation to the joints of the immune process primarily induced in the gut.The transfer of the intestinal inflammatory process into the joints implicates that immune cells activated in the gut-draining lymph nodes can localize, at a certain point of the intestinal disease, either into the gut or into the joints.This is indicated by the over-lapping expression of adhesion molecules observed on the surface of intestinal and synovial endothelial cells during inflammation.Moreover bacterial antigens and HLA-B27 expression may be implicated in the reactivation of T cells at the articular level.Finally, accumulating evidence indicates that a T helper 17 cell-mediated immune response may contribute to IBD and IBD-related SpA with a crucial role played by tumor necrosis factor-α in CD and to a lesser extent in UC.

Wireless capsule endoscopy and proximal small bowel lesions in Crohn’s disease

AIM: To investigate the prevalence of proximal small bowel (SB) lesions detected by wireless capsule endoscopy (WCE) in Crohn's disease (CD). METHODS: WCE was performed in 64 patients: 32 with CD of the distal ileum, and 32 controls with iron-deficiency anemia (IDA) or diarrhea. WCE was performed using the Given SB-WCE, followed by small intestine contrast ultrasonography (SICUS). Findings compatible with CD by using WCE included erosions, aphthoid or deep ulcers, and strictures/stenosis. RESULTS: WCE detected proximal SB lesions in 16/32 (50%) patients (14 aphthoid ulcers, 2 deep ulcers, one stricture), which appeared not to be related to clinical parameters [epigastric pain, age, smoking, non-steroidalanti-inflammatory drugs (NSAIDs), IDA]. Among patients with proximal SB lesions, 6 (37%) were smokers, 3 (19%) NSAID users, 3 (19%) had epigastric pain and 4 (25%) had IDA. SICUS detected proximal SB lesions in 3/32 patients (19%) also showing lesions with WCE. No correlations were observed between proximal SB lesions assessed by WCE or by SICUS (χ2 = 1.5, P = 0.2). CONCLUSION: The use of WCE allows the detection of previously unknown upper SB lesions in a high proportion of patients with a previous diagnosis of CD involving the distal ileum.

Low efficacy of levofloxacin-doxycycline-based third-line triple therapy for Helicobacter pylori eradication in Italy

AIM:To evaluate a levofloxacin-doxycycline-based triple therapy with or without a susceptibility culture test in non-responders to Helicobacter pylori(H.pylori) eradication.METHODS:A total of 142(99 women,43 men; mean 53.0 ± 12.7 years) non-responders to more than two H.pylori eradication therapies underwent susceptibility culture tests or were treated with a seven-day triple therapy consisting of esomeprazole,20 mg b.i.d.,levofloxacin,500 mg b.i.d.,and doxycycline,100 mg b.i.d.,randomly associated with(n = 71) or without(n = 71) Lactobacillus casei DG.H.pylori status was checked in all patients at enrollment and at least 8 wk after the end of therapy.Compliance and tolerability of regimens were also assessed.RESULTS:H.pylori eradication was achieved in < 50% of patients [per prototol(PP) = 49%; intention to treat(ITT) = 46%].Eradication rate was higher in patients administered probiotics than in those without(PP = 55% vs 43%; ITT = 54% vs 40%).Estimated primary resistance to levofloxacin was 18% and multiple resistance was 31%.Therapy was well tolerated,and side effects were generally mild,with only one patient experiencing severe effects.CONCLUSION:Third-line levofloxacin-doxycycline triple therapy had a low H.pylori eradication efficacy,though the success and tolerability of this treatment may be enhanced with probiotics.

Familial colorectal cancer screening: When and what to do?

Colorectal cancer(CRC) is the third leading cause of death worldwide and represents a clinical challenge.Family members of patients affected by CRC have an increased risk of CRC development.In these individuals,screening is strongly recommended and should be started earlier than in the population with average risk,in order to detect neoplastic precursors,such as adenoma,advanced adenoma,and nonpolypoid adenomatous lesions of the colon.Fecal occult blood test(FOBT) is a non invasive,widespread screening method that can reduce CRC-related mortality.Sigmoidoscopy,alone or in addition to FOBT,represents another screening strategy that reduces CRC mortality.Colonoscopy is the best choice for screening highrisk populations,as it allows simultaneous detection and removal of preneoplastic lesions.The choice of test depends on local health policy and varies among countries.

Involvement of interleukin-15 and interleukin-21, two γ-chain-related cytokines, in celiac disease

Celiac disease (CD), an enteropathy caused by dietary gluten in genetically susceptible individuals, is histologically characterized by villous atrophy, crypt cell hyperplasia, and increased number of intra-epithelial lymphocytes. The nature of CD pathogenesis remains unclear, but recent evidence indicates that both innate and adaptive immune responses are necessary for the phenotypic expression and pathologic changes characteristic of CD. Extensive studies of molecules produced by immune cells in the gut of CD patients have led to identification of two cytokines, namely interleukin (IL)-15 and IL-21, which are thought to play a major role in orchestrating the mucosal inflammatory response in CD. Here we review the current knowledge of the expression and function of IL-15 and IL-21 in CD.

Proteinase activated-receptors-associated signaling in the control of gastric cancer

Gastric cancer(GC)is the fourth most common cancer in the world and the second cause of cancer-related death.Gastric carcinogenesis is a multifactorial process,in which environmental and genetic factors interact to activate multiple intracellular signals thus leading to uncontrolled growth and survival of GC cells.One such a pathway is regulated by proteinase activated-receptors(PARs),seven transmembrane-spanning domain G protein-coupled receptors,which comprise four receptors(i.e.,PAR-1,PAR-2,PAR-3,and PAR-4)activated by various proteases.Both PAR-1 and PAR-2 are over-expressed on GC cells and their activation triggers and/or amplifies intracellular pathways,which sustain gastric carcinogenesis.There is also evidence that expression of either PAR-1 or PAR-2 correlates with depth of wall invasion and metastatic dissemination and inversely with the overall survival of patients.Consistently,data emerging from experimental models of GC suggest that both these receptors can be important targets for therapeutic interventions in GC patients.In contrast,PAR-4levels are down-regulated in GC and correlate inversely with the aggressiveness of GC,thus suggesting a negative role of this receptor in the control of GC.In this article we review the available data on the expression and role of PARs in GC and discuss whether manipulation of PAR-driven signals may be useful for interfering with GC cell behavior.

Role of Smad7 in inflammatory bowel diseases

Crohn's disease and ulcerative colitis,the major forms of inflammatory bowel diseases(IBD) in man,are complex diseases in which genetic and environmental factors interact to promote an excessive mucosal immune response directed against normal components of the bacterial microflora.There is also evidence that the pathologic process is due to defects in counterregulatory mechanisms,such as those involving the immunosuppressive cytokine transforming growth factor(TGF)-1.Indeed,studies in human IBD tissues and murine models of colitis have documented a disruption of TGF-1 signalling marked by a block in the phosphorylation of Smad3,a signalling molecule associated with the activated TGF-receptor,due to up-regulation of Smad7,an intracellular inhibitor of Smad3 phosphorylation.Knock-down of Smad7 with a specific antisense oligonucleotide restores TGF-1/Smad3 signalling,thus resulting in a marked suppression of inflammatory cytokine production and attenuation of murine colitis.These findings together with the demonstration that Smad7 antisense oligonucleotide is not toxic when administered in mice have paved the way for the development of a Smad7 antisense oligonucleotidebased pharmaceutical compound that is now ready to enter the clinics.In this article we review the available data supporting the pathogenic role of Smad7 in IBD and discuss whether and how Smad7 antisense therapy could help dampen the ongoing inflammation in IBD.

Molecular basis of the potential of mesalazine to prevent colorectal cancer

Patients with ulcerative colitis (UC) and Crohn's disease (CD) are at increased risk for developing colorectal cancer (CRC), and this is believed to be a result of chronic inflammation. Although conclusive evidence is still missing, both epidemiological and experimental observations suggest that certain drugs used to treat inflammation, such as mesalazine, can reduce the incidence of colitis-associated CRC. Therefore, in recent years, several studies have been conducted to dissect the mechanisms by which mesalazine interferes with CRC cell growth and survival. This review summarizes the current information on the molecular mechanisms that underlie the antineoplastic action of mesalazine.

Ileal lesions in patients with ulcerative colitis after ileo-rectal anastomosis:Relationship with colonic metaplasia

AIM:To assess whether in ulcerative colitis (UC) patients with ileo-rectal anastomosis (IRA), ileal lesions may develop in the neo-terminal-ileum and their possible relation with phenotypic changes towards colonic epithelium. METHODS: A total of 19 patients with IRA under regular follow up were enrolled, including 11 UC and 8 controls (6 Crohn’s disease, CD; 1 familial adenomatous polyposis, FAP; 1 colon cancer, colon K). Ileal lesions were identifi ed by ileoscopy with biopsies taken from the ileum (involved and uninvolved) and from the rectal stump. Staining included HE and immunohistochemistry using monoclonal antibodies against colonic epithelial protein CEP (Das-1) and human tropomyosin isoform 5, hTM5 (CG3). Possible relation between development of colonic metaplasia and ileal lesions was investigated.RESULTS: Stenosing adenocarcinoma of the rectal stump was detected in 1 UC patient. The neo-terminal ileum was therefore investigated in 10/11 UC patients. Ileal ulcers were detected in 7/10 UC, associated with colonic metaplasia in 4/7 (57.1%) and Das-1 and CG3 reactivity in 3/4 UC. In controls, recurrence occurred in 4/6 CD, associated with colonic metaplasia in 3/4 and reactivity with Das-1 and CG3 in 2/3. CONCLUSION: Present fi ndings suggest that in UC, ileal lesions associated with changes towards colonic epithelium may develop also after IRA. Changes of the ileal content after colectomy may contribute to the development of colonic metaplasia, leading to ileal lesions both in the pouch and in the neo-terminal ileum after IRA.