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Claudio Fiocchi

Publications and source records attributed to Claudio Fiocchi.

48 records · Page 3Linked to original sources
PubMed2003

Hydrogen peroxide contributes to motor dysfunction in ulcerative colitis.

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.

Calcium↗
PubMed2003

Platelets trigger a CD40-dependent inflammatory response in the microvasculature of inflammatory bowel disease patients.

BACKGROUND & AIMS: Platelets circulate in an activated state in patients with inflammatory bowel disease (IBD), but their role in the pathogenesis of IBD is unclear. The recent demonstration that activated platelets express CD40 ligand (L) provides a mechanism of interaction with CD40-positive endothelial cells, inducing them to produce proinflammatory mediators. We investigated whether platelets from patients with IBD express enhanced levels of CD40L and induce human intestinal microvascular endothelial cells (HIMEC) to up-regulate cell adhesion molecule (CAM) expression and secrete chemokines. METHODS: CD40L expression was assessed in resting and thrombin-activated platelets by flow cytometry and in mucosal microthrombi by confocal microscopy. Platelet-HIMEC cocultures were used to study CAM up-regulation, and interleukin (IL)-8 and RANTES production by HIMEC. RESULTS: IBD platelets expressed significantly higher CD40L levels than those of healthy subjects, and CD40L-positive platelets were detected in IBD-involved mucosa. Activated platelets up-regulated expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 as well as production of interleukin 8 by HIMEC in a CD40-dependent fashion. High levels of RANTES were present in platelet-HIMEC cocultures and platelets were identified as the source of this chemokine, which mediated T-cell adhesion to HIMEC. CONCLUSIONS: These results show that platelets can actively contribute to mucosal inflammation and represent a previously unrecognized component of IBD pathogenesis.

Blood Platelets↗
PubMed2003

A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-kappa B.

BACKGROUND & AIMS: To elucidate extracellular matrix (ECM) changes underlying intestinal fibrosis, a frequent complication of inflammatory bowel disease, we developed a murine model of chronic colitis associated with intestinal fibrosis. METHODS: Chronic inflammation was established by weekly intrarectal administration of trinitrobenzene sulfonic acid (TNBS). In 2 variations of the model an antisense oligonucleotide for nuclear factor kappa B (NF-kappa B) p65 was given prophylactically or therapeutically to block chronic inflammation-associated fibrosis. Colonic inflammation and fibrosis were determined by histology. Total collagen level was estimated by hydroxyproline quantification. Colonic expression of collagens (Col1a2, Col3a2), ECM remodeling genes (matrix metalloproteinase [MMP]-1, -3, and tissue inhibitor of matrix metalloproteinase [TIMP]-1), and inflammation-modulating cytokines (tumor necrosis factor alpha [TNF-alpha], interferon gamma [IFN-gamma], transforming growth factor beta 1 [TGF-beta 1], and insulin-like growth factor 1 [IGF-1]) were assessed by semiquantitative reverse-transcription polymerase chain reaction. Control and TNBS-treated colonic mesenchymal cells were characterized by morphology, phenotype, and functional response to TNF-alpha and IFN-gamma. RESULTS: Colons of TNBS-treated mice contained acute and chronic inflammatory infiltrates, increased collagen, fibrogenic tissue architecture, and increased expression of TNF-alpha, TGF-beta 1, IGF-1, Col1a2, MMP-1, and TIMP-1. Colonic mesenchymal cells from TNBS-treated mice were also morphologically distinct from those of the control mice, with increased TIMP-1 expression in response to IFN-gamma treatment. Fibrosis persisted for 2-4 weeks after cessation of the TNBS treatment. In mice given NF-kappa B antisense prophylactically, 67% were fibrosis-free, whereas of those treated after establishing chronic inflammation, 43% were free of fibrosis. CONCLUSIONS: Extended TNBS treatment of mice yielded chronic intestinal inflammation-associated fibrosis with extensive fibrogenic ECM changes that could be counteracted by specific blockade of NF-kappa B.

Animals↗
PubMed2003

Inflammatory bowel disease-associated gene expression in intestinal epithelial cells by differential cDNA screening and mRNA display.

Intestinal epithelial cells are actively involved in the pathogenesis of inflammatory bowel disease resulting in an altered functional phenotype. The modulation of epithelial gene expression may occur as a consequence of proliferative, metabolic, immune, inflammatory, or genetic abnormalities. Differential screening of epithelial-cell-derived cDNA libraries (from control, ulcerative colitis, and Crohn's disease epithelial cells) and differential display of mRNA were used for investigation of disease-associated gene expression and modulation. Intestinal epithelial gene expression was successfully analyzed by both approaches. Using differential screening with clones encoding mitochondrial genes, quantitative overexpression was observed in both ulcerative colitis and Crohn's disease, while a unique expression of small RNA was noticed in Crohn's disease cells using Alu-homologous clones. Differential display demonstrated that several genes were differentially displayed among control, ulcerative colitis, and Crohn's disease epithelial cells. This was confirmed by immunohistochemical staining of pleckstrin, desmoglein 2 and voltage-dependent anion channel in control and inflammatory bowel disease mucosal samples. In summary, several inflammatory bowel disease-related associations were found. Since both differential screening and display have advantages and limitations, the combination of both techniques can generate complementary information, facilitate search for novel genes, and potentially identify genes uniquely associated with inflammatory bowel disease.

Adolescent↗
PubMed2002

Inflammatory bowel disease.

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.

Aged↗
PubMed2002

Critical role of caspases in the regulation of apoptosis and proliferation of mucosal T cells.

BACKGROUND & AIMS: Caspases are critical mediators of apoptosis and proliferation of peripheral blood T cells (PBT), but their role in lamina propria T cells (LPT), a cell population highly susceptible to apoptosis, has not been explored. METHODS: RA(+), RO(+) PBT, and LPT were activated with CD3, CD2, and CD28 antibodies, and caspase activity, apoptosis, and proliferation were measured by a fluorometric assay, DNA content, and thymidine incorporation, respectively. Levels of FLIP, an endogenous inhibitor of caspase 8, were measured by immunoblotting. RESULTS: In RA(+) and RO(+) PBT, activation leads to significant increase of caspase activity but not cell death, whereas in LPT a lower elevation of caspase activity was followed by a marked degree of apoptosis. Based on the results of its inhibition, caspase 8 seemed to be essential for LPT apoptosis but, in contrast to RA(+) PBT, had no effect on proliferation. In addition, compatible with their differential susceptibility to apoptosis, levels of FLIP were lower in LPT than PBT. CONCLUSIONS: The high susceptibility of LPT to apoptosis is associated with a distinct regulation of caspase 8 activity, which seems to reflect their mucosal origin rather than simply their memory status. This unique behavior may allow proper control of mucosal T-cell proliferation while still permitting elimination by apoptosis in the face of excessive antigenic pressure.

Apoptosis↗
PubMed2002

Etiopathogenesis of inflammatory bowel disease: the importance of the pediatric perspective.

Inflammatory bowel disease (IBD) is now recognized as a common chronic disease affecting children and adolescents. This article will review recent advances made in the fields of genetics, epidemiology, gut ecology, and immunology regarding the etiopathogenesis of IBD, with particular emphasis on the contributions made by pediatric studies. Areas where further study of the pediatric age group would be beneficial will be highlighted.

Child↗
PubMed2002

p53 negatively regulates intestinal immunity by delaying mucosal T cell cycling.

To mount an effective immune response, T cells must divide in response to antigen contact. To maintain tolerance, mucosal lamina propria T cells (LPTs) may adapt their cycling to an antigen-rich gut stimulatory environment. Here, we compared the cell cycle kinetics of LPTs and peripheral blood T cells (PBTs) before and after CD3- and CD2-mediated activation. While CD3-activated naive (CD45RA(+)) and memory (CD45RO(+)) PBTs peaked in the S and G2/M phase at 2-3 days, CD3-activated LPTs peaked at 4-6 days. In contrast, CD2 activation induced modest PBT but vigorous LPT cycling. The doubling time of CD3-activated PBTs was 1 day, while that of CD3- or CD2-activated LPTs was 2 days. LPTs failed to upregulate cyclin-dependent kinase 4 and cyclin D3, but Rb phosphorylation and cyclin A and B1 upregulation were induced by CD2 engagement. The extents of clonal expansion in LPT and PBT were comparable, indicating that LPTs' slow replication delays but does not hinder cell division. CD2-activated LPTs displayed a striking upregulation of p53, whose blockade by antisense oligonucleotides accelerated their S phase transit time to that of CD3-activated PBTs. By slowing LPT cycling, p53 may act as a negative regulator of mucosal immunity, promoting immunological tolerance by preventing excessive T cell replication.

Blotting, Western↗
PubMedDate not supplied

Inflammatory bowel disease: autoimmune or immune-mediated pathogenesis?

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.

Antibodies, Fungal↗