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Torsten Kucharzik

Publications and source records attributed to Torsten Kucharzik.

At least 19 recordsLinked to original sources
PubMed2006

Biliary tract candidiasis: diagnostic and therapeutic approaches in a case series.

BACKGROUND: Biliary obstruction with its wide range of potential causes is a common disorder in gastroenterology. Infections of the biliary tract with Candida and other fungal species leading to obstructive jaundice have increasingly been recognized in the last few years. Besides a few case reports, there are few data in the literature giving us an idea how to diagnose and treat these patients. METHODS: We report on a series of seven patients suffering from biliary tract candidiasis who were diagnosed and treated at our institution. Predisposition factors, reliability of various diagnostic modalities, and treatment options based on our own experience are presented and discussed. RESULTS: Besides the general diagnostic modalities such as laboratory findings or ultrasonography, we often observed mycelia in the bile duct system endoscopically. Typical morphological changes in peripheral bile ducts could be detected during endoscopic retrograde cholangiopancreatography (ERCP). Aspiration of bile and subsequent microbiological analysis in combination with ERCP findings revealed diagnosis of bile duct candidiasis in all cases. Treatment included both antiinfectious drugs and endoscopic therapy such as bile duct drainage, lavage, or débridement. With respect to fungal eradication, therapy was successful in 71% of cases as proven by microbiological analysis of bile aspirates. Since many of these patients suffer not only from biliary mycosis but also from disease necessitating immunosuppression, the prognosis was poor in some cases. CONCLUSION: Biliary tract candidiasis because of immunosuppression is an increasingly recognized disease and remains a major clinical challenge. Besides laboratory analysis and ultrasonography, diagnostic modalities should include aspiration of bile during ERCP and microbiological analysis. Antiinfectious drug treatment as the main therapeutic column for biliary candidiasis should be complemented by endoscopic intervention.

Aged↗
PubMed2006

Recent understanding of IBD pathogenesis: implications for future therapies.

The inflammatory bowel diseases (IBD) are comprised of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC). Research over the last couple of years has led to great advances in understanding the inflammatory bowel diseases and their underlying pathophysiologic mechanisms. From the current understanding, it is likely that chronic inflammation in IBD is due to aggressive cellular immune responses to a subset of luminal bacteria. Susceptibility to disease is thereby determined by genes encoding immune responses which are triggered by environmental stimuli. Based on extensive research over the last decade, there are several new and novel pathways and specific targets on which to focus new therapeutics. The following review summarizes the current view on the four basic tenets of the pathophysiological basis of IBD and its implications for therapies of IBD: genetics, immune dysregulation, barrier dysfunction and the role of the microbial flora.

Bacterial Infections↗
PubMed2006

Gastric epithelial expression of macrophage migration inhibitory factor is not altered by Helicobacter pylori infection in humans.

BACKGROUND: Recent reports have shown an upregulation of macrophage migration inhibitory factor (MIF) during gastric ulcer development in a rat model and elevated counts of MIF-positive cells in biopsies from Helicobacter pylori-infected patients. H. pylori infection is a proven cofactor in humans causing gastritis and gastric ulcers. The aim of this study was to characterize MIF expression in human gastric epithelial cells in response to H. pylori. METHODS: MIF mRNA and MIF protein expression was detected in human gastric epithelial cell lines after stimulation with proinflammatory cytokines or infection with H. pylori (cagA+/vacA+) using real-time reverse transcriptase-polymerase and enzyme-linked immunosorbent assay. Interleukin-8 secretion was measured as positive control. MIF mRNA and MIF protein expression was assessed in H. pylori-positive and -negative human gastric biopsy samples. RESULTS: While interleukin-8 mRNA expression and interleukin-8 secretion were upregulated in gastric epithelial cells in vitro after H. pylori infection, no changes in MIF mRNA expression and MIF secretion could be detected. We found no significant differences in MIF expression in total RNA extracted from gastric biopsy tissue when comparing H. pylori-positive to control patients. Likewise, MIF protein expression in gastric epithelium was unaffected by H. pylori infection as compared to uninfected tissue. CONCLUSIONS: While an increased MIF expression and positive effects of MIF blockade in ulcer healing have been shown in a rodent model and elevated numbers of MIF-positive cells have been found in H. pylori-infected human tissue, we herein could not confirm any differences in human gastric epithelial MIF expression and secretion after H. pylori infection in vitro and in vivo.

Biopsy↗
PubMed2006

Endoluminal gastroplasty (EndoCinch) versus endoscopic polymer implantation (Enteryx) for treatment of gastroesophageal reflux disease: 6-month results of a prospective, randomized trial.

OBJECTIVES: The aim of this study was to compare and determine the efficiency and safety of two newly introduced endoscopic antireflux procedures in the treatment of gastroesophageal reflux disease (GERD). METHODS: In a prospective, randomized trial, endoluminal gastroplasty (EndoCinch) was compared with polymer injection (Enteryx) employing 51 consecutive patients dependent on proton pump inhibitor therapy. Follow-up evaluation included drug consumption, symptoms, quality-of-life scoring, endoscopy, pH monitoring, manometry, and documentation of adverse events. RESULTS: Twenty-six patients were assigned to EndoCinch treatment, 23 patients received Enteryx implantation, and two patients dropped out before applying endoscopic therapy. At 6 months, proton pump inhibitor therapy could be stopped or dosage was reduced by > or =50% in 20 of 26 (77%) EndoCinch-treated patients and in 20 of 23 patients treated by Enteryx (87%, p= 0.365), which differed significantly in both groups compared to the pre-interventional status (p < 0.0001). Esophageal acid reflux (pH < 4) decreased from 14.5% to 9.6% in EndoCinch-treated patients (p= 0.071) and from 15.5% to 13.9% in patients treated by Enteryx (p= 0.930). Heartburn symptom score, modified DeMeester score, gastrointestinal life quality index, and SF-36 physical health survey score improved significantly in both groups postinterventionally (p < 0.0001). Approximately 25% of the patients in both groups required retreatment in an attempt to achieve symptom control. CONCLUSIONS: This is the first prospective, randomized study directly comparing two endoscopic anti-GERD techniques. EndoCinch and Enteryx seem to be equally successful in the treatment of GERD significantly reducing the proton pump inhibitor dosages, and also by improving symptoms of patients. Both endoluminal antireflux procedures may be promising therapeutic options; long-term evaluation will have to show if the positive initial results can be maintained.

Adult↗
PubMed2006

Apoptosis as a therapeutic tool in IBD?

Defective apoptosis of mucosal cell populations seems to be a relevant pathogenetic mechanism in inflammatory bowel disease (IBD). It has been suggested that the induction of apoptosis in various effector cells may be a relevant therapeutic mechanism in IBD. Indeed, it was shown that different drugs used for treatment of IBD have the capacity to induce apoptosis in T cells or monocytes in vitro and in vivo. However, it remains unclear whether these observations are related to clinical efficacy of these agents. TNF-alpha is one of the most relevant proinflammatory mediators in IBD and anti-TNF treatment has been shown to be of particular benefit for patients with IBD. It could subsequently be shown that various anti-TNF-alpha agents, such as infliximab and adalimumab, can induce apoptosis in activated monocytes and lymphocytes in vitro and in vivo. This mechanism requires reverse signaling via transmembranous TNF, thereby eliciting a signal transduction cascade that results in programmed cell death. Although other mechanisms might also contribute to the clinical effect of anti-TNF-alpha, current data suggest that apoptosis is a relevant mechanism that is associated with clinical efficacy of anti-TNF agents. Induction of apoptosis in activated monocytes or T cells may be regarded as therapeutic tool not only for anti-TNF agents, but also for other drugs used in IBD. Future strategies should focus on identification of mechanisms that prevent apoptosis in the mucosa of patients with IBD and in targeting apoptotic pathways as a therapeutic strategy in IBD.

Apoptosis↗
PubMed2006

Induction of intestinal lymphoid tissue: the role of cryptopatches.

The intestinal immune system includes several organized structures, such as Peyer's patches, isolated lymphoid follicles (ILFs), cryptopatches (CPs) as well as mesenteric lymph nodes (MLNs) that constitute an extensive network with other nonorganized parts, such as intraepithelial and lamina propria lymphocytes. CPs are small clusters of lymphoid cells with an immature lymphocyte phenotype and dendritic cells. Initial observations in transfer experiments suggested that the immature lymphocytes are T cell precursors and CPs are a potential site of extrathymic intraepithelial lymphocyte (IEL) differentiation. This feature has recently been challenged particularly by the observation that CP cells express the orphan receptor RORgammat and are phenotypically indistinguishable from lymphoid tissue-inducer (LTi) cells, suggesting that CP cells are the adult counterpart of fetal LTi cells. In addition, the chemokine receptor CCR6 is specifically expressed by precursor cells within CPs and its deletion inhibits the development of ILFs. Therefore, it is likely that ILFs derive from CPs under the control of CCR6 under inflammatory conditions and might constitute a valuable target for anti-inflammatory therapies.

Animals↗
PubMed2006

Role of the melanocortin system in inflammation.

In recent years, scientific interest in melanocortins (MC) has progressively increased due to their wide range of effects and expression on various tissues. Primarily discovered as mediators of skin pigmentation, recent research has shown their important roles in various body functions, such as energy homeostasis, sexual function, and inflammation. The anti-inflammatory and immunomodulatory properties discovered so far have led to the hypothesis that alpha-melanocyte-stimulating hormone (MSH) and its cognate receptors might present potential anti-inflammatory treatment options.

Animals↗
PubMed2006

Role of lymphotoxins in the development of Peyer's patches and mesenteric lymph nodes: relevance to intestinal inflammation and treatment.

Hallmarks of the adaptive immune system are antigen-specific cellular and humoral immune responses. Secondary lymphoid organs serve as sites of contact between antigen-presenting cells (APCs) and immune effector T and B lymphocytes. The gut-associated lymphatic system (GALT) as the intestinal branch of the immune system provides different mechanisms to protect organisms against pathogens. Simultaneously, immune activation secondary to genetic factors and/or environmental signals can induce detrimental autoimmunity. The effector pathways in host defense and autoimmunity use similar cytokines and chemokines. Unlike few other cytokines, lymphotoxin (LT) alpha/beta regulates the development of intestinal lymphoid organs, including Peyer's patches (PPs) and mesenteric lymph nodes (MLNs). In addition, intestinal inflammation is suppressed by inhibition of LTbeta signalling, an observation which has initiated clinical studies using this treatment principle. Conversely, the course of Citrobacter rodentium-induced infectious colitis is more severe in mice with impaired LTbeta-receptor-mediated signalling. This report provides an overview on the role of the different organs of the GALT in intestinal inflammation. Moreover, it describes the role of the LTbeta-receptor-mediated signalling in intestinal inflammation as encountered in autoimmune and infectious pathology. The contribution of LT to the delicate balance of immune effector functions in host defense and autoimmunity is discussed.

Crohn Disease↗
PubMed2005

Absence of CCR6 inhibits CD4+ regulatory T-cell development and M-cell formation inside Peyer's patches.

The chemokine Mip3alpha is specifically expressed by the follicle-associated epithelia (FAE) covering intestinal Peyer's patches (PPs) and is the only known chemokine ligand for the chemokine receptor CCR6. Although CCR6-deficient mice are known to have a perturbed intestinal immune system, little is known about the specific impact of this interaction for Peyer's patch formation. To elucidate the effect of Mip3alpha on PP lymphocyte development, we used a CCR6/enhanced green fluorescent protein (EGFP) knock-in mouse model and analyzed lymphocyte development by immunohistochemistry and flow cytometry. PPs of CCR6-/- mice were significantly size-reduced with a proportional loss of B cells and T cells, whereas T-cell subsets were disturbed with a decreased CD4/CD8 ratio paralleled with a loss of regulatory CD4+ CD45Rb(low) T cells. The analysis of cytokine production by CCR6-expressing cells could demonstrate that CCR6 is involved in the regulation of cytokine secretion such as interleukin-12 by dendritic cells. Quantification of UEA-1+ cells inside the FAE showed reduced M-cell numbers in CCR6-deficient mice. These results suggest that the interaction of CCR6 with its ligand Mip3alpha is important for immune responses generated inside the PPs, particularly for the generation of regulatory CD4+ T cells residing inside PPs and for the formation of M cells.

Animals↗
PubMed2005

Activation of epithelial CD98 glycoprotein perpetuates colonic inflammation.

Anomalies in the regulation and function of integrins have been implicated in the etiology of various pathologic conditions, including inflammatory disorders such as irritable bowel disease. Several classes of cell surface glycoproteins such as CD98 have been shown to play roles in integrins-mediated events. Here, we investigated the role of CD98 in intestinal inflammation using both in vivo and in vitro approaches. We found that in Caco2-BBE monolayers and colonic tissues, expression of CD98 was upregulated by the proinflammatory cytokine, interferon gamma (INF gamma). Furthermore, CD98 was highly upregulated in colonic tissues from mice with active colitis induced by dextran sodium sulfate (DSS), but not in DSS-treated INF gamma -/- mice. Administration of an anti-CD98 antibody worsened DSS-induced colitis in mice but had no effect on untreated control mice. Finally, we used Caco2-BBE cell monolayers to model intestinal epithelial wound healing, and found that activation of epithelial CD98 in DSS-treated monolayers inhibited monolayer reconstitution, but had no affect on untreated control monolayers. Our data collectively indicate that (i) CD98 upregulation is mediated by INF gamma during intestinal inflammation and (ii) activation of epithelial CD98 protein aggravates intestinal inflammation by reducing intestinal epithelial reconstitution. Overall, our data suggest that epithelial CD98 plays an important role in the perpetuation of intestinal inflammation.

Animals↗
PubMed2005

Ischaemic colitis mimicking inflammatory bowel disease in a young adult receiving oral anticoagulation.

Ischaemic colitis (IC) is the most frequent form of gastrointestinal ischaemia. Discrepancy between non-specific symptoms and objective findings is a hallmark of IC. Thus delay of diagnosis is common due to its often subtle and unpredictable presentation. In particular, the clinical symptoms and signs of IC can overlap with those of inflammatory bowel disease. We present a case of a young man with known factor-V-Leiden mutation in whom IC developed during effective therapy with oral anticoagulants, presenting with symptoms and endoscopic findings suggestive of inflammatory bowel disease.

Abdominal Pain↗
PubMed2004

Human intestinal microvascular endothelial cells express Toll-like receptor 5: a binding partner for bacterial flagellin.

Bacterial flagellin has recently been identified as a ligand for Toll-like receptor 5 (TLR5). Human sites known to specifically express TLR5 include macrophages and gastric and intestinal epithelium. Because infection of intestinal epithelial cells with Salmonella leads to an active transport of flagellin to the subepithelial compartment in proximity to microvessels, we hypothesized that human intestinal endothelial cells functionally express TLR5, thus enabling an active inflammatory response upon binding of translocated flagellin. Endothelial expression of TLR5 in human macro- and microvascular endothelial cells was examined by RT-PCR, immunoblot analysis, and immunofluorescence. Endothelial expression of TLR5 in vivo was verified by immunohistochemistry. Endothelial modulation of ICAM-1 expression was quantitated using flow cytometry, and leukocyte transmigration in vitro was assessed by an endothelial transmigration assay. Epithelial-endothelial cellular interactions upon infection with viable Salmonella were investigated using a coculture system in vitro. We found that Salmonella-infected intestinal epithelial cells induce endothelial ICAM-1 expression in cocultured human endothelial cells. Both macro- (HUVEC) and microvascular endothelial cells derived from human skin (human dermal microvascular endothelial cell 1) and human colon (human intestinal microvascular endothelial cells) were found to express high constitutive amounts of TLR5 mRNA and protein. These findings were paralleled by strong immunoreactivity for TLR5 of normal human colonic microvessels in vivo. Furthermore, incubation of human dermal microvascular endothelial cells with flagellin from clinical isolates of Escherichia and Salmonella strains led to a marked up-regulation of ICAM-1, as well as to an enhanced leukocyte transendothelial cell migration. These results suggest that endothelially expressed TLR5 might play a previously unrecognized role in the innate immune response toward bacterial Ags.

Caco-2 Cells↗
PubMed2004

Thalidomide induces apoptosis in human monocytes by using a cytochrome c-dependent pathway.

Thalidomide has been shown to be an effective treatment in various immunologic diseases such as Crohn's disease and rheumatoid arthritis. Its major effect is thought to be mediated by the inhibition of TNF-alpha, but the exact mechanism of action is still uncertain. Recent observations could demonstrate that the induction of monocyte apoptosis is a common feature of a variety of anti-inflammatory agents. Therefore, we investigated the role of thalidomide on monocyte apoptosis. Treatment with thalidomide resulted in apoptosis of human peripheral blood monocytes in a time- and dose-dependent manner as demonstrated by annexin V staining. Monocyte apoptosis required the activation of caspases, as combined stimulation by thalidomide together with the broad caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone markedly prevented monocyte cell death. Apoptosis was triggered by a CD95/CD95 ligand, TNF-RI, and TRAIL-R1 independent pathway with an inhibition of AKT-1 kinase and consecutive mitochondrial release of cytochrome c, followed by the proteolytic activation of initiator caspase-9 and effector caspase-3. Our data suggest that thalidomide-induced monocyte apoptosis is at least partially mediated by a mitochondrial signaling pathway and might contribute to the complex immunomodulatory properties of the drug.

Apoptosis↗
PubMed2004

The lymphotoxin-beta receptor is critical for control of murine Citrobacter rodentium-induced colitis.

BACKGROUND AND AIMS: Lymphotoxin is a tumor necrosis factor-family cytokine. Blocking of lymphotoxin alpha 1 beta 2 /lymphotoxin-beta receptor interactions prevents experimental colitis in mice, and this suggests a potential treatment principle of human inflammatory bowel disease. Infection of mice with Citrobacter rodentium serves as an animal model for human infectious colitis induced by enteropathogenic Escherichia coli . We studied the role of lymphotoxin alpha 1 beta 2 /lymphotoxin-beta receptor signaling in Citrobacter rodentium -induced colitis. METHODS: Mice with disrupted lymphotoxin alpha 1 beta 2 /lymphotoxin-beta receptor interactions secondary to gene defects (lymphotoxin-alpha -/- , lymphotoxin-beta -/- , and lymphotoxin-beta receptor -/- ) or treatment with the antagonist lymphotoxin-beta receptor-immunoglobulin G fusion protein were infected with Citrobacter rodentium . Body weight, fecal excretion of Citrobacter rodentium , and disease-related mortality were monitored. Spleen and liver organ cultures of mice assessed systemic infection. Intestinal inflammation and lymphoid architecture were histologically recorded in the large intestine, mesenteric lymph nodes, and spleen of infected mice. RESULTS: Inhibition of lymphotoxin alpha 1 beta 2 /lymphotoxin-beta receptor interactions was associated with increased severity of Citrobacter rodentium -induced colitis, as indicated by increased disease-related mortality, more severe weight loss, intestinal bacterial abscesses, and a higher burden of Citrobacter rodentium in the spleen and liver of -/- and lymphotoxin-beta receptor-immunoglobulin G-treated mice. There was a reduction of CD11c + dendritic cells in the spleen of naive and infected -/- and lymphotoxin-beta receptor-immunoglobulin G-treated mice. In infected lymphotoxin-beta receptor -/- mice, anti- Citrobacter rodentium immunoglobulin G2a levels were decreased, whereas immunoglobulin G1 levels were increased. Citrobacter rodentium -induced interleukin-4 secretion was increased in lymphotoxin-beta receptor -/- mice. CONCLUSIONS: Lymphotoxin alpha 1 beta 2 /lymphotoxin-beta receptor interactions are critical for immunity against Citrobacter rodentium in mice. Impaired anti-enteropathogenic Escherichia coli immunity may be anticipated in anti-lymphotoxin-beta receptor-directed therapy for human inflammatory bowel disease.

Animals↗
PubMed2003

Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms.

It is well known that inflammatory conditions of the intestinal mucosa result in compromised barrier function. Inflammation is characterized by an influx into the mucosa of immune cells that influence epithelial function by releasing proinflammatory cytokines such as IFN-gamma and TNF-alpha. Mucosal barrier function is regulated by the epithelial apical junctional complex (AJC) consisting of the tight junction and the adherens junction. Since the AJC regulates barrier function, we analyzed the influence of IFN-gamma and TNF-alpha on its structure/function and determined the contribution of apoptosis to this process using a model intestinal epithelial cell line, T84, and IFN-gamma and TNF-alpha. AJC structure/function was analyzed by confocal microscopy, biochemical analysis, and physiologic measurement of epithelial gate/fence function. Apoptosis was monitored by determining cytokeratin 18 cleavage and caspase-3 activation. IFN-gamma induced time-dependent disruptions in epithelial gate function that were potentiated by coincubation with TNF-alpha. Tight junction fence function was somewhat disrupted. Cytokine treatment was associated with internalization of AJC transmembrane proteins, junction adhesion molecule 1, occludin, and claudin-1/4 with minimal effects on the cytoplasmic plaque protein zonula occludens 1. Detergent solubility profiles of junction adhesion molecule 1 and E-cadherin and their affiliation with "raft-like" membrane microdomains were modified by these cytokines. Inhibition of cytokine-induced apoptosis did not block induced permeability defects; further emphasizing their primary influence on the epithelial AJC structure and barrier function. Our findings for the first time clearly separate the proapoptotic effects of IFN-gamma and TNF-alpha from their abilities to disrupt barrier function.

Adherens Junctions↗