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The role of oxygen free radicals in the endotoxic shock induced myocardial dysfunction and cellular injury

by Pattanaik, Uttara

Abstract (Summary)
The pathophysiology of endotoxemia is complex. Endotoxic shock (ET-shock) is associated with increased levels of cytokines [interleukin-1 (IL-1) and tumour necrosis factor (TNF) 1, platelet activating factor (PAF), activated complement (C,,, C ) and norepinephrine in the blood. Activated complement, 1 , TNF and PAF are known to activate polymorphonuclear leukocytes (PMhlLs), which on activation lead to increased production of oxygen free radicals (OFRs) and hypochloroue acid (HOC1). During ET-shock, OFRs could also be produced from other sources including auto-oxidation of catecholamines, xanthine-xanthine oxidase enzyme system during ischemia, and arachidonic acid metabolism. An increase in the levels of OFRs could also be due to a decrease in the activity of the antioxidant enzymes and antioxidant reserve. However the changes in these parameters are not known. OFRs depress cardiac function and contractility and produce tissue injury. We hypothesized that decreases in cardiac function and contractility, and cellular injury during endotoxemia are due to increased levels of OFRs because of increased production and/or decreased destruction and that the agents which prevent the production and/or scavenge OFRs, would prevent the ET-induced cardiac depression and tissue injury. To test this hypothesis experiments were carried out on anaesthetized dogs. The dogs were assigned to the following groups : (a) Sham Control (b) Endotoxin (ET)-treated (ET-shock group) (c) ET+Antioxidants [purpurogallin (PPG), dimethylthiourea (DMTU), MCI-1861 (d) ET+HOCl quencher (methionine) (e) ET+PAF antagonist (flax seed) (f) ET+cytokine inhibitor [pentoxifylline (PTF)]. Hernodynamic parameters were measured before and at various times after ET administration to determine myocardial function and contractility andmyocardial oxygen consumption. Blood samples were collected at similar intervals as above for the measurements of OFR producing activity of PMNLs (PMNL-CL), and plaama creatine kinase (CK) and lactate levels ( an indicators of cellular damage). At the end of the experiments hearts were removed for the estimation of malondialdehyde (MDA) - a lipid peroxidation product (an indirect measure of the level of OFRs), muscle chemiluninescence (an index of tissue antioxidant reserve), and the activity of antioxidant enzymes (superoxidedismutase, catalase and glutathione peroxidase). ~ndotoxin-induced depression in cardiac function and contractility were associated with increased production of oxyradicals by PMNLs, increased levels of left ventricular MDA, plasma CK and lactate, and decreased activity of the antioxidant enzymes and antioxidant reserve. Pre-treatment with OFR scavangers, HOCl quencher, PAF antagonist and cytokine inhibitor, completely prevented ET-induced depression in cardiac contractility, but offered only partial protection iii of the depressed myocardial function. These effects were associated with restoration of antioxidant enzyme activities, antioxidant reserve, cardiac MDA levels and PMNL-CL, to the control values. Additionally these treatments showed partial protection of the ET-induced rise in plasma CK end lacfate levels. These results suggest that ET-induced cardiac depression and cellular injury was due to increased levels of OFRs as a result of increased production and decreased antioxidant reserve and antioxidant enzymes. I would like to express my sincere gratitude to my supervisor, Dr. K. Prasad, for his constant support, guidance and patience throughout the project and during the preparation of my thesis. I would also like to extend my sincere appreciation to my advisory committee members, Drs. B. Blakley, C. Sisodia, S. Hdngs, L. Hiebert and J. Tuchek for their valuable suggestions, and help. The technical assistance of Mr. P.K. Chattopadhyay, MS. Jackie Andrews, Dr. .Xing Yu, . Hike Ring and Mr. Robert Hutchinson was highly appreciated. I extend my sincere thanks to the members of our laboratory, Dr. Rakesh Kapoor, Mr. Paul Lee, Ms. Barbara Raney and MS. Lalita Bharadwaj, for their friendship and support. I would like to take this opportunity to express my deepest appreciation to my husband, Kushal, whose patience, understanding, support and constant encouragement has made the completion of this project possible. I also owe a debt of gratitude to my loving parents, Mr. Radharanjan Pattanaik and Mrs. Sorojini Pattanaik and my wonderful sister, Ms. Lulabi Pattanaik, who supported and guided me in every way throughout the years. This research project was supported by the Heart and Stroke Foundation of Saskatchewan. 1.2 Oxygen Free R ~ d i ~ ~ l ~ ~ ~ . ~ . TABLE: OF CO#TE#TS
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Source Type:Master's Thesis

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Date of Publication:01/01/1996

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