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Biomedical subjects

Claudio Fiocchi

Publications and source records attributed to Claudio Fiocchi.

At least 37 records · Page 2Linked to original sources
PubMed2005

Significance of glucocorticoid receptor expression in colonic mucosal cells of patients with ulcerative colitis.

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.

Adolescent↗
PubMed2005

An oral supplement enriched with fish oil, soluble fiber, and antioxidants for corticosteroid sparing in ulcerative colitis: a randomized, controlled trial.

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.

Administration, Oral↗
PubMed2005

Hydrogen peroxide reduces lower esophageal sphincter tone in human esophagitis.

BACKGROUND & AIMS: We have previously used the normal lower esophageal sphincter (N-LES) of human organ donors to examine the physiologic signal transduction of lower esophageal sphincter (LES) circular muscle. Now, for the first time, we have obtained a human LES specimen with esophagitis (E-LES) and characterized its pathophysiologic mechanical and inflammatory profiles. METHODS: E-LES was examined histologically, and its in vitro circular muscle contraction and production of inflammatory mediators were compared with those of N-LES. RESULTS: E-LES exhibited scattered erosions and displayed inflammatory cells in the epithelial layer, basal zone hyperplasia, and elongation of lamina propria papillae, characteristic of chronic reflux esophagitis. E-LES muscle strips developed lower in vitro tone (0.78 g) than N-LES (3.3 +/- 0.2 g). E-LES tone was essentially restored to normal by the H2O2 scavenger catalase, suggesting that H2O2 was responsible for reduction of tone. NOX5 cDNA was higher and H2O2 levels were 4 times higher in E-LES circular muscle (0.85 nmol/mg protein) than in N-LES (0.19 +/- 0.05 nmol/mg protein). When N-LES smooth muscle was incubated in H2O2 (70 micromol/L, 2 hours), platelet activating factor (PAF), prostaglandin E2 (PGE2), and F2-isoprostane increased 2.5, 5.2, and 36 times, respectively. In E-LES, levels of PAF, PGE2, and F2-isoprostane were 4, 6, and 40 times, respectively, higher than in N-LES. PAF, PGE2, and F2 isoprostane produced dose-dependent reductions in tone of N-LES muscle strips. CONCLUSIONS: We conclude that an excessive production of H2O2 triggers an increased production of PAF, PGE2, and F2-isoprostane, which are responsible for reducing LES tone in human esophagitis.

Dinoprost↗
PubMed2005

Signal transducers and activators of transcription 3 signaling pathway: an essential mediator of inflammatory bowel disease and other forms of intestinal inflammation.

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.

Adult↗
PubMed2005

Inflammatory bowel disease pathogenesis: therapeutic implications.

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.

Colitis, Ulcerative↗
PubMed2005

Platelet activation and the CD40/CD40 ligand pathway: mechanisms and implications for human disease.

The discovery that platelets express CD40 and the CD40 ligand has transformed these cells, once seen as exclusively involved in coagulation and thrombosis, into active players of immunity and inflammatory injury. Many of the broad and potent biological activities mediated through the CD40/CD40 pathway by immune and nonimmune cells are also exerted by activated platelets. This occurs either through the constitutive expression of CD40 on the platelet surface or the activation-induced expression of the CD40 ligand, which is membrane bound and released from the surface in a soluble form. The most prominent activities mediated by the platelet CD40/CD40 ligand pathway include inflammatory, immunoregulatory, and hemostatic functions, all of which contribute to the newly expanded view of platelets as key biological mediators involved in disease processes such as atherosclerosis, inflammatory bowel disease, and diabetes. Therefore, considering platelet CD40 and CD40 ligand as novel biological targets is justified and supported by animal studies. The clinical profit to be gained from blocking this molecular pair will be determined by results in humans with conditions in which the platelet CD40/CD40 ligand pathway is crucially involved in disease pathogenesis.

Animals↗
PubMed2005

The emergence of inflammatory bowel disease in the Asian Pacific region.

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.

Asia↗
PubMed2004

Dual function of the extracellular matrix: stimulatory for cell cycle progression of naive T cells and antiapoptotic for tissue-derived memory T cells.

Tissue T cells encounter Ag in a distinct microenvironment, where they are embedded in the interstitial extracellular matrix (ECM). In contrast, while naive T cells are exposed to Ag in the lymph node, immediately after naive T cells are activated they must extravasate into the ECM to function effectively. Because integrin-mediated adhesion to the ECM modulates cell cycle progression and survival in adherent nonimmune cells, we hypothesize that blood and tissue-derived T cells have similarly adapted their behavior to their first or continued encounter with ECM. T cells from peripheral blood (PBT) and tissue (the intestinal lamina propria T cell (LPT)) were stimulated with anti-CD3-coated beads in the presence or absence of native ECM derived from intestinal fibroblasts, plate-immobilized fibronectin, or collagen type I. Native ECM and collagen, but not fibronectin, induced in anti-CD3 activated PBT a 4- to 5-fold increase in the entry, progression, and completion of the cell cycle over that triggered by anti-CD3 alone. Neutralizing beta1 integrin Abs abrogated this increase. None of these ECM proteins stimulated cell cycle progression in LPT. In contrast, anti-CD3 activation of LPT in the presence of native ECM and fibronectin reduced activation-induced cell death by 40%. These results demonstrate that naive and effector/memory T cells respond differently upon exposure to specific ECM components. When naive PBT encounter Ag in the context of ECM, their progression through the cell cycle is enhanced, favoring clonal expansion; while tissue T cell longevity may be mediated by interactions with the ECM.

Adjuvants, Immunologic↗
PubMed2004

Proinflammatory cytokines alter/reduce esophageal circular muscle contraction in experimental cat esophagitis.

Cholinergic mechanisms are largely responsible for esophageal contraction in response to swallowing or to in vitro electrical field stimulation (EFS). After induction of experimental esophagitis by repeated acid perfusion, the responses to swallowing and to EFS were significantly reduced but contraction in response to ACh was not affected, suggesting that cholinergic mechanisms are damaged by acid perfusion but that myogenic mechanisms are not. Measurements of ACh release in response to EFS confirmed that release of ACh was reduced in esophagitis compared with normal controls. To examine factors contributing to this neuropathy, normal esophageal strips were incubated for 1-2 h with the proinflammatory cytokines IL-1beta (100 U/ml), IL-6 (1 ng/ml), or TNF-alpha (1 ng/ml). IL-1beta and IL-6 levels, measured by Western blot analysis, increased in esophagitis compared with normal circular muscle. IL-1beta and IL-6 reduced contraction in response to EFS (2-10 Hz, 0.2 ms) but did not affect ACh-induced contraction, suggesting that these cytokines inhibit ACh release without affecting myogenic contractile mechanisms. EFS-induced ACh release was significantly reduced in normal esophageal strips by incubation in IL-1beta or IL-6, suggesting that they may contribute to the contractility changes. TNF-alpha at 1 ng/ml, however, did not affect the response to ACh or to electrical stimulation but inhibited both at higher concentrations. TNF-alpha levels were low in normal muscle and did not increase with esophagitis. The data suggest that the proinflammatory cytokines IL-1beta and IL-6 contribute to reduced esophageal contraction by inhibiting release of ACh from myenteric neurons.

Acetylcholine↗
PubMed2004

Interleukin 1beta-induced production of H2O2 contributes to reduced sigmoid colonic circular smooth muscle contractility in ulcerative colitis.

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).

Calcium↗
PubMed2004

Cutting edge: T cells trigger CD40-dependent platelet activation and granular RANTES release: a novel pathway for immune response amplification.

Platelets, in addition to exerting hemostatic activity, contribute to immunity and inflammation. The recent report that platelets express CD40 led us to hypothesize that CD40 ligand (CD40L)-positive T cells could bind to platelets, cause their activation, and trigger granular RANTES release, creating a T cell recruitment feedback loop. Platelets were cocultured with resting or activated autologous T cells and their activation was assessed by P-selectin expression. RANTES binding to endothelial cells was assessed by confocal microscopy, and its biological activity was demonstrated by a T cell adhesion assay. CD40L-positive T cells induced platelet activation through a contact-mediated, CD40-dependent pathway resulting in RANTES release, which bound to endothelial cells and mediated T cell recruitment. Soluble CD40L induced the same events via p38, but not extracellular signal-regulated kinase, phosphorylation. These results show the existence of a novel platelet-dependent pathway of immune response amplification which brings these nonimmune cells close to the level of pathogenic relevance traditionally attributed to classical immune cells.

Adjuvants, Immunologic↗
PubMed2004

Inflammatory bowel disease: the role of environmental factors.

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.

Animals↗
PubMed2004

CD40-mediated immune-nonimmune cell interactions induce mucosal fibroblast chemokines leading to T-cell transmigration.

BACKGROUND AND AIMS: The CD40 pathway is a key mediator of inflammation and autoimmunity. We investigated cell adhesion molecule (CAM) up-regulation and chemokine production by CD40-positive human intestinal fibroblasts (HIF) and microvascular endothelial cells (HIMEC) induced by CD40 ligand (CD40L)-positive T cells and soluble CD40L and their effect on T-cell adhesion and transmigration. METHODS: Expression of CD40, CD40L, and CAM was assessed by immunohistochemistry, confocal microscopy and flow cytometric analysis, and chemokine production using enzyme-linked immunosorbent assay. Calcein-labeled T cells were used to assay HIF adhesion and Transwell HIMEC transmigration. RESULTS: Ligation of CD40-positive HIF and HIMEC by CD40L-positive T cells or soluble CD40L induced up-regulation of CAM expression as well as interleukin-8 and RANTES production. The specificity of these responses was shown by inhibition with a CD40L blocking antibody and by CD40 signaling-dependent p38 mitogen-activated protein kinase phosphorylation. On CD40 ligation, HIF increased their T-cell binding capacity and generated chemoattractants able to induce T-cell migration through HIMEC monolayers. CONCLUSIONS: Activation of the CD40/CD40L system in the gut mucosa may trigger a self-sustaining loop of immune-nonimmune cell interactions leading to an antigen-independent influx of T cells that contributes to chronic inflammation.

CD40 Antigens↗
PubMed2004

Platelets in inflammatory bowel disease: clinical, pathogenic, and therapeutic implications.

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.

Blood Platelet Disorders↗
PubMed2004

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients.

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.

Adult↗