There are a lot of inflammatory agents, such as substance P, histamine, capsaicin, and lipopolysaccharide¡]LPS¡^. LPS is the component of all gram-negative bacterial cell wall that can stimulate the immune cells to release pro-inflammatory cytokines that can induce systemic acute inflammation and sepsis. The present study sought to investigate the location of leaky microvessels and magnitude of plasma leakage in the rat stomach secretory and non-secretory portions after an intravenous injection of high dose of LPS¡]15 mg/kg¡^. India ink¡]1 ml/kg¡^ and Evans blue¡]30 mg/ml¡^were used as tracer dyes to measure the magnitude of plasma leakage after LPS application. In the whole mounts of the stomach secretory and non-secretory portions with silver staining, the boundaries of endothelial cells and gaps between endothelial cells for plasma leakage in the blood vessels of microcirculation were made visible. Tissue sections were stained with Alcian blue and periodic acid-Schiff reagent to reveal the mucosubstance present in the mucous cells of the stomach secretory tissue. The result of study demonstrated that the magnitude of LPS-induced plasma leakage in the rat stomach secretory and non-secretory portions was larger than that of the vehicle control. Extensive plasma extravasation was found from 5 min to 30 min after LPS injection. Numerous endothelial gaps formed in both postcapillary venules and collecting venules in the rat stomach secretory portion at 5 min and 30 min after LPS, but the number of gaps declined strikingly 60 min after LPS. Endothelial gaps were rare in the stomach of vehicle control. Histological sections of the stomach secretory portion showed that the leaky vessels were present in the serosa and muscularis externa. Administration of LPS also resulted in release of mucus in gastric gland cells. It is concluded that endotoxin-induced increase in plasma leakage correlated with the formation of endothelial gaps, and associated with depletion of mucosubstance from the mucous cells.

Inflammatory bowel disease (IBD) is a chronic disease which steadily increases worldwide with the highest prevalence in Canada. Genetic susceptibility is considered to be an important factor in causing IBD. Organic cation transporters, SLC22A4 and SLC22A5 have been associated to IBD multiple times. Recently, SLC22A23, a novel gene that encodes for an organic cation membrane transporter protein has also been associated to IBD however; neither its gene structure nor its functions has been characterized. The aim of this study was to characterize the genomic structure of SLC22A23 gene using bioinformatics analysis, determine the tissue expression, characterize the location of the protein and perform functional studies using Liquid Chromatography-Quadrupole Time of Flight-Mass Spectrometry. We have identified the chromosomal location, the gene neighborhood and the genomic structure of human SLC22A23.The result of this study indicates that SLC22A23 gene is a membrane transporter and it is abundantly expressed in the intestine. / October 2015

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Inflammatory Bowel Disease (IBD) is an umbrella term used to describe a group of chronic, relapsing/remitting disorders of the gastrointestinal tract (GIT). While the precise aetiology of IBD is unknown, it is believed to be a result of the interaction of genetics, the immune system and the enteric microbiota. Thus, the search for potentially pathogenic microbial residents of the GIT is a current research focus. Fusobacterium nucleatum (Fn) is a member of the normal human microflora, including the GIT and has a well-characterized role in periodontitis in the oral setting. We have determined that Fn can be frequently recovered from human intestinal biopsies and furthermore, there is a positive correlation between recovery of Fn and the IBD status of the host. Fn strains from IBD patients were more invasive in vitro than strains from healthy controls and also demonstrated the ability to survive and proliferate inside host cells. Furthermore, while Fn strains from both IBD patients and healthy controls were able to induce expression of the pro-inflammatory cytokine IL-8 in vitro, in comparison to strains from controls, Fn strains from IBD patients resulted in decreased levels of IL-8 protein outside the host cells, suggesting that these strains may utilize sophisticated tactics to promote their survival. Thus, differences in virulence determinants among strains may be key to understanding a potential role for Fn in IBD. Characterization of virulence mechanisms utilized by Fn isolates from IBD patients could define a potentially important aspect of microbe/host interactions in this devastating disease, and indicate future therapeutic targets. / Canadian Institutes of Health Research, Canadian Digestive Health Foundation, Crohn's and Colitis Foundation of Canada

Gamma-interferon stimulates human macrophages to produce of 7,8-dihydroneopterin (7,8-NP). 7,8-NP and its oxidation product neopterin are excellent inflammatory markers for a variety of chronic conditions, including atherosclerosis. The biological significance of 7,8-NP in atherosclerosis is not fully understood, but 7,8-NP has been shown to protect macrophage cells from oxidised low density lipoprotein (oxLDL). Cellular accumulation of oxLDL-derived lipids and oxLDL-induced cytotoxicity are major drivers of atherosclerotic plaque progression. This thesis investigated the mechanisms of 7,8-NP-mediated protection against oxLDL-induced damage to macrophage cells. The research assessed the relative contribution of the previously identifyed antioxidant capacity of 7,8-NP and its ability to down-regulate oxLDL uptake. OxLDL cytotoxicity was characterised by high intracellular oxidative stress within the first 12 hours of exposure, which was critical to oxLDL toxicity. Exogenously added 7,8-NP effectively scavenged the intracellular oxidants generated in response to oxLDL, shown by the oxidation of 7,8-NP to neopterin. The ability of 7,8-NP to alleviate oxidative stress during the critical time-frame of acute toxicity was the primary mechanism of protection. 7,8-NP was also found to down-regulate the levels of intracellular oxysterol esters in oxLDL-treated macrophages. This decrease was associated with the reduction of CD36 scavenger receptor protein and mRNA expression. The late onset of these processes in the second half of the 24 hour incubation highlighted their potential role in foam cell formation. Research indicated that 7,8-NP may play a role in the reverse cholesterol transport in these cholesterol ester-loaded cells. The CD36 down-regulation by 7,8-NP did not protect macrophages from acute oxLDL cytotoxicity. This research reveals novel detail about the mechanism of 7,8-NP protection of macrophages from cytotoxic effects of oxLDL. It is suggested that 7,8-NP may protect macrophage cells in the atherosclerotic plaques by scavenging ROS produced during acute cytotoxicity and alleviate oxysterol ester accumulation, thus stabilising macrophage cells during chronic oxLDL exposure.

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