Inflammation can be up-regulated by microglia and macrophages through the release of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α). Excess production of TNF-α can lead to a variety of diseases and even tissue necrosis. Recently, the expression of alpha seven acetylcholine receptors (α7AChR) by microglia have been shown to decrease the amount of TNF-α released. This anti-inflammatory pathway has been studied extensively where researchers are able to reduce TNF-α concentration through α7AChR expression and increases in the concentration of its ligand. I have shown that Neuregulin is able to increase the expression of α7AChR in microglia and macrophages. Using three immortalized cell lines, BV-2, EOC-20 and RAW 264.7, and primary microglial cells harvest from mice I investigated the role that neuregulin plays in the anti-inflammatory process. Neuregulin signals through the ErbB receptors, a family of tyrosine kinase receptors, to facilitate the effects on ACh expression. My results show that ErbB4 is expressed in BV-2, EOC-20 and RAW 264.7 cell lines while ErbB2-4 receptors are expressed in primary microglia. As well, I was able to show that ErbB4 became phosphorylated upon binding to NRG in immortalized cell lines. Using an Enzyme Linked Immunsorbent Assay to analyze TNF- α concentration in microglia and macrophages, I was able to demonstrate that increased levels of α7AChRs did not result in a reduction in TNF-α concentration. These results showed that NRG is able to increase α7AChRs in microglia and macrophages after the phosphorylation of the ErbB4 receptors. As well, this increase in α7AChR does not relate to a reduction in TNF-α, thus under these experimental conditions does not have an effect on the anti-inflammatory pathway.

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Inflammation can be up-regulated by microglia and macrophages through the release of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α). Excess production of TNF-α can lead to a variety of diseases and even tissue necrosis. Recently, the expression of alpha seven acetylcholine receptors (α7AChR) by microglia have been shown to decrease the amount of TNF-α released. This anti-inflammatory pathway has been studied extensively where researchers are able to reduce TNF-α concentration through α7AChR expression and increases in the concentration of its ligand. I have shown that Neuregulin is able to increase the expression of α7AChR in microglia and macrophages. Using three immortalized cell lines, BV-2, EOC-20 and RAW 264.7, and primary microglial cells harvest from mice I investigated the role that neuregulin plays in the anti-inflammatory process. Neuregulin signals through the ErbB receptors, a family of tyrosine kinase receptors, to facilitate the effects on ACh expression. My results show that ErbB4 is expressed in BV-2, EOC-20 and RAW 264.7 cell lines while ErbB2-4 receptors are expressed in primary microglia. As well, I was able to show that ErbB4 became phosphorylated upon binding to NRG in immortalized cell lines. Using an Enzyme Linked Immunsorbent Assay to analyze TNF- α concentration in microglia and macrophages, I was able to demonstrate that increased levels of α7AChRs did not result in a reduction in TNF-α concentration. These results showed that NRG is able to increase α7AChRs in microglia and macrophages after the phosphorylation of the ErbB4 receptors. As well, this increase in α7AChR does not relate to a reduction in TNF-α, thus under these experimental conditions does not have an effect on the anti-inflammatory pathway.

In order to search for bioactive compounds, we have studied the chemical constituents from the organic extracts of five soft corals including Sinularia lochmodes, Sinularia nanolobata, Sinularia grandilobata, Sinularia depressa and Lobophytum crassum. This study had led to the isolation of eighteen natural compounds 1¡Ð18, including seven new compounds, lochmolins A ¡Ð G (1 ¡Ð 7) from S. lochmodes, a new compound nanolobatolide (8) featuring with a new carbon skeleton from S. nanolobata, two new compounds grandilobatin G (9) and sinugrandisterol E (10) from S. grandilobata, a new compound depressoloide A (11) and a known compound sarcophytol L (12) from S.depressa, and three new compounds crassumolides G¡ÐI (13¡Ð15) along with three known compounds durmolides B and C (16 and 17) and sinularolide C (18) from L. crassum. The structures of compounds 1¡Ð18 were established by detailed spectral data analysis (IR, MS, 1D & 2D NMR) and by comparison with the spectral data of the related known compounds. The relative stereochemistries of compound 8 was further confirmed by X-ray single-crystal diffraction analysis. Among them, compounds 13¡Ð15 and 16¡Ð17 were found to show significant activity against the accumulation of the pro-inflammatory iNOS and COX-2 proteins at 10 £gM.

Chronic inflammation is considered strongly influence the morbidity and mortality of patients with end-stage renal disease (ESRD) through its multiple pathogenic roles, in association with oxidative stress, accelerated aging, endothelial dysfunction and atherosclerosis, malnutrition, dialysis-related amyloidosis, anaemia, and immune dysfunction . Hemodialysis ¡]HD¡^ is widely used for kidney failure patients,it is a method for removing waste products such as creatinine and urea. However, at present it is well known the course of hemodialysis can create obvious inflammation condition and oxidation pressure. The oxidation stress of HD can arise from the osmosis pressure and oxidative environment of dialysis tube. The oxidative stresses will finally modify proteins which turn out initiate the short term and long term complications related to renal diseases of HD patients. We identified oxidated proteins in the hemodialysis tube of 16 HD patients. The protein oxidation level was determined by Oxyblot assay. The oxidation proteins were further identified by LC/MS detection. Many serum proteins were detected to be oxidized including albumin, apoA, immunoglobin,beta-globin, hemoglobin, etc. It has been well documented that albumin is quite vulnerable to ROS and elevated levels of carbonyl groups of albumin have been reported in plasma of dialysis patients. Inflammatory effects were further tested. The oxidation proteins of HD patients induce pro-inflammatory factor TNF-alpha expression of HEK293T and HEK293 cells. These results indicate HD induce protein oxidation, and inflammatory response which may responsible for complications of End-stage kidney disease (ESRD). Keywords¡GHemodialysis, oxidative stress, ESRD, HEK293, inflammatory

Burns often leads to infection, due to damage to the skin's protective barrier. Burn injury has been repeatedly shown to induce considerable inflammatory and immune dysfunction. The innate immune system is a universal and ancient form of host defense against infection. Activation of innate immunity constitutes the first line of host defense against infection. Neutrophils are white blood cells and part of the immune system. They are the most common PMN (polymorphonuclear neutrophils) and accounted for 70% of all leukocytes. Neutrophils provided the first line of defense of the innate immune system by phagocytosing, killing, and digesting bacteria and fungi. Priming means a process whereby the response of neutrophils to an activating stimulus is potentiated, sometimes greatly, by prior to exposure to priming agents such as tumor necrosis factor-alpha(TNF-alpha), platelet-activating factor (PAF). Neutrophil priming causes a dramatic increase in the response of these cells to an activating agent; this process has been shown to be critical for neutrophil-mediated tissue injury both in vitro and in vivo. However, the intracellular signaling pathways used by neutrophil in response to pro-inflammatory stimuli have not been elucidated. The discovery of TLRs has made us understanding of the mechanisms of innate immune recognition. The innate immune system detectes the invasion of microorganism through TLRs, which recognize microbial components and trigger inflammatory responses. Severe burn injury produces shock and induces acute gastrointestinal derangement that may disrupt gastrointestinal mucosa integrity and facilitate the bacterial translocation (BT) to Mesenteric lymph node (MLN), liver, and spleen. Hypertonic saline (HTS) has been advocated in thermal injury resuscitation because of the possibility of giving less total volume of resuscitation fluid, with a resulting decrease in edema and the need for escharotomy. In this study, I found that priming effect of BM neutrophils is TNF-alpha and p38 dependent and TLRs play a critical role to the innate immunity by recognizing bacteria and HTS enhance host response to bacterial challenge by increasing TLRs of inflammatory cells.

Inflammatory response in the airway may lead to asthma. Asthma may develop during the childhood in some asthmatic patients. Both environmental and genetic factors may influence the onset and progress of asthma. It is well-known that there may be complex neural innervation and reflex mechanisms between trachea and esophagus. Intraesophgeal infusion of 1N HCl could lead to tracheal inflammation by activating neural reflex pathway and cause tachykinin-like substance to release. In this study, we first sensitized rats with 1ml of OVA-Al［OH］3 mixture containing 200£gg OVA via intraperitoneal injection on days 1, 2, 3 and 11, then perform intraesophageal infusion of ovalbumin to see whether stimulation of esophagus in sensitized rat model could involve inflammatory response in the lower airways. Animals were perfused with saline and fixative at various time points and the esophagus and airway tissues were processed for the subsequent analysis. We observed the extent of plasma leakage and migration of leukocytes in the lower airway. India ink was used to label the leaky blood vessels.The magnitude of plasma leakage was expressed by the area density of India ink-labeled blood vessels. The results showed that the intraesophageal infusion of ovalbumin 75 mg/kg caused an increase in plasma leakage in the lower airways. The plasma leakage peaked at 30 min, the area density of plasma leakage in trachea was 22.43 ¡Ó 3.34¢H; and 20.57 ¡Ó 4.91¢H in right bronchus; 18.47 ¡Ó 5.03¢H in left bronchus and 27.85 ¡Ó 2.71¢H in epiglottis. The extent of leakage gradually diminished 3 hours after ovalbumin infusion. However, a second increased plasma leakage peaked at about 4 hours of ovalbumin infusion. Tissue sections clearly showed degranulation of mast cells in OVA infusion group. Experimental data showed that pretreatment with either bilateral vagotomy, or mepyramine, the histamine H1 receptor antagonist, significantly inhibited the inflammatory response in the lower airways induced by intraesophageal infusion of OVA. In conclusion, there were clearly two phases, early and late phase responses, in inflammatory response in OVA-sensitized rats receiving intra-esophageal OVA challenge. The underlying mechanisms may involve vagal C-fibers and histamine H1 receptors.

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Thesis (M.S.)--University of North Texas, Aug., 2009. / Title from title page display. Includes bibliographical references.

Thesis (M.A.) - Simon Fraser University, 2006. / Theses (Dept. of Sociology/Anthropology) / Simon Fraser University. Also issued in digital format and available on the World Wide Web.