[Show abstract][Hide abstract] ABSTRACT: Chronic inflammation has a major role in the development and propagation of endothelial dysfunction, which can lead to coronary artery disease. Endothelial dysfunction has been described in patients with various and diverse chronic inflammatory conditions. Altered vascular flow has been proposed to mediate inflammation in inflammatory bowel disease (IBD), although the role of endothelial dysfunction remains obscure. The purpose of our study was to assess endothelial function in patients with IBD.
Ninety-eight subjects were included in this study; 48 with IBD (17 with ulcerative colitis and 31 with Crohn's disease) and 50 healthy controls. Endothelial function was assessed by pulse arterial tonometry (PAT) and brachial ultrasound to determine flow-mediated dilation and shear stress reactive hyperemia. The impact of disease activity, disease duration, and IBD therapy also was assessed.
Baseline demographic characteristics, including cardiovascular risk factors, were similar in all groups. IBD patients showed microvascular endothelial dysfunction, with lower PAT indices (P < .01) and shear stress reactive hyperemia (P < .05) compared with controls. There was no relationship between microvascular endothelial dysfunction, disease duration, underlying therapy, or clinical disease activity. There was a positive association between lower PAT scores and recent abdominal pain (P < .05).
This was a large study assessing endothelial dysfunction in IBD. Both ulcerative colitis and Crohn's disease patients showed evidence of microvascular endothelial dysfunction. Future research could determine whether endothelial dysfunction is involved in the pathogenesis of IBD or increases the risk of cardiovascular events in this patient population.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 10/2008; 7(2):175-82. DOI:10.1016/j.cgh.2008.10.021 · 7.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mechanisms responsible for microbially induced epithelial apoptosis and increased intestinal permeability remain unclear. This study assessed whether purified bacterial lipopolysaccharide (LPS) increases epithelial apoptosis and permeability and whether these changes are dependent on caspase-3 activation. In nontumorigenic epithelial monolayers, Escherichia coli O26:B6 LPS increased apoptosis, as shown by nuclear breakdown, caspase-3 activation, and PARP cleavage, and induced disruption of tight junctional ZO-1. Apical, but not basolateral, exposure to LPS increased epithelial permeability. Addition of a caspase-3 inhibitor abolished the effects of LPS. The findings describe a novel mechanism whereby apical LPS may disrupt epithelial tight junctional ZO-1 and barrier function in a caspase-3-dependent fashion.
Canadian Journal of Physiology and Pharmacology 11/2006; 84(10):1043-50. DOI:10.1139/y06-056 · 1.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Helicobacter pylori is a spiral, gram-negative bacterium that specifically and persistently infects the human stomach. In some individuals, H. pylori-induced chronic gastritis may progress to gastroduodenal ulcers and gastric cancer. Currently, the host-microbe interactions
that determine the clinical outcome of infection are not well defined. H. pylori strains capable of disrupting the gastric epithelial barrier may increase the likelihood of developing serious disease. In
this study, H. pylori strain SS1 increased gastric, but not small intestinal, permeability in C57BL/6 mice. H. pylori strain SS1 was able to directly increase paracellular permeability, in the absence of host inflammatory cells, by disrupting
the tight-junctional proteins occludin, claudin-4, and claudin-5 in confluent nontransformed epithelial cells. H. pylori SS1 also reduced claudin-4 protein levels in human gastric AGS cells. The ability of H. pylori SS1 to increase permeability appeared to be independent of the well-characterized virulence factors vacuolating cytotoxin
and CagA protein. H. pylori activated myosin light-chain kinase in epithelial cells to phosphorylate myosin light chain and increase permeability by
disrupting claudin-4 and claudin-5. The bacterial factor responsible for increasing epithelial permeability was heat sensitive,
membrane bound, and required apical contact with monolayers. In conclusion, disruptions of the tight junctions observed in
this study implicate host cell signaling pathways, including the phosphorylation of myosin light chain and the regulation
of tight-junctional proteins claudin-4 and claudin-5, in the pathogenesis of H. pylori infection.
Infection and Immunity 01/2006; 73(12):7844-52. DOI:10.1128/IAI.73.12.7844-7852.2005 · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Infection of the human stomach with Helicobacter pylori may develop into gastritis, ulceration, adenocarcinoma and mucosal lymphomas. The pathogenic mechanisms that determine the clinical outcome from this microbial-epithelial interaction remain poorly understood. An increasing number of reports suggests that disruptions of epithelial barrier function may contribute to pathology and postinfectious complications in a variety of gastrointestinal infections. The aim of this review is to critically discuss the implications of H pylori persistence on gastric disease, with emphasis on the role of myosin light chain kinase, claudins and matrix metalloproteinases in gastric permeability defects, and their contribution to the development of cancer. These mechanisms and the associated signalling events may represent novel therapeutic targets to control disease processes induced by H pylori, a microbial pathogen that colonizes the stomach of over 50% of the human population.
Canadian journal of gastroenterology = Journal canadien de gastroenterologie 10/2005; 19(9):543-52. · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vibrio parahaemolyticus is a leading cause of seafood-borne gastroenteritis worldwide. Virulence is commonly associated with the production of two toxins, thermostable direct hemolysin (TDH) and TDH-related hemolysin (TRH). Although the majority of clinical isolates produce TDH and/or TRH, clinical samples lacking toxin genes have been identified. In the present study, we investigated the effects of V. parahaemolyticus on transepithelial resistance (TER) and paracellular permeability in Caco-2 cultured epithelial cells. We found that V. parahaemolyticus profoundly disrupts epithelial barrier function in Caco-2 cells and that this disruption occurs independently of toxin production. Clinical isolates with different toxin genotypes all led to a significant decrease in TER, which was accompanied by an increased flux of fluorescent dextran across the Caco-2 monolayer, and profound disruption of actin and the tight junction-associated proteins zonula occludin protein 1 and occludin. Purified TDH, even at concentrations eightfold higher than those produced by the bacteria, had no effect on either TER or paracellular permeability. We used lactate dehydrogenase release as a measure of cytotoxicity and found that this parameter did not correlate with the ability to disrupt tight junctions. As the effect on barrier function occurs independently of toxin production, we used PCR to determine the toxin genotypes of V. parahaemolyticus isolates obtained from both clinical and environmental sources, and we found that 5.6% of the clinical isolates were toxin negative. These data strongly indicate that the effect on tight junctions is not due to TDH and suggest that there are other virulence factors.
Infection and Immunity 04/2005; 73(3):1275-83. DOI:10.1128/IAI.73.3.1275-1283.2005 · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the effects of oral administration of tilmicosin in piglets experimentally infected with Actinobacillus pleuropneumoniae.
Forty 3-week-old specific-pathogen free piglets.
Piglets were assigned to 1 of 4 groups as follows: 1) uninfected sham-treated control piglets; 2) infected untreated piglets that were intratracheally inoculated with 10(7) CFUs of A pleuropneumoniae; 3) infected treated piglets that were intratracheally inoculated with A pleuropneumoniae and received tilmicosin in feed (400 ppm [microg/g]) for 7 days prior to inoculation; or 4) infected treated piglets that were intratracheally inoculated with A pleuropneumoniae and received chlortetracycline (CTC) in feed (1100 ppm [microg/gl) for 7 days prior to inoculation. Bronchoalveolar lavage (BAL) fluid and lung tissue specimens of piglets for each group were evaluated at 3 or 24 hours after inoculation. For each time point, 4 to 6 piglets/group were studied.
Feeding of CTC and tilmicosin decreased bacterial load in lungs of infected piglets. Tilmicosin delivered in feed, but not CTC, enhanced apoptosis in porcine BAL fluid leukocytes. This was associated with a decrease in LTB4 concentrations in BAL fluid of tilmicosin-treated piglets, compared with untreated and CTC-treated piglets, and also with a significant decrease in the number of pulmonary lesions. Tilmicosin inhibited infection-induced increases in rectal temperatures, as measured in untreated and CTC-treated piglets. Pulmonary neutrophil infiltration and prostaglandin E2 concentrations in the BAL fluid were not significantly different among groups at any time.
Oral administration of tilmicosin to infected piglets induces apoptosis in BAL fluid leukocytes and decreases BAL fluid LTB4 concentrations and inflammatory lung lesions.
American Journal of Veterinary Research 02/2005; 66(1):100-7. DOI:10.2460/ajvr.2005.66.100 · 1.34 Impact Factor