Microvascular endothelial response to cocaethylene exposure: morphological and molecular observations

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Title: Microvascular endothelial response to cocaethylene exposure: morphological and molecular observations
Author: Danyel Hermes Tacker
Abstract: Cocaethylene (CE ) is an active metabolite of cocaine and ethanol and is a toxicant of physiological relevance due to the high rate of cocaine and ethanol co -exposure ( ~80 % ) in cocaine abusers . It has prolonged action and increased potency on known physiological targets relative to the effect of cocaine . Since pathology in cocaine abusers is typically chronic and systemic , and CE persists in the body three to five times longer than cocaine , a link between CE and systemic disease in cocaine abusers was proposed . Consequently , this dissertation contains the studies that were used to test the hypothesis that the microvascular endothelium is a target tissue that is central in the pathogenic mechanism of cocaine -associated systemic disease , and that endothelial injury after CE exposure would result in dysregulation and altered barrier function due to changes in intracellular second messengers and signaling . To test this hypothesis , an in vitro model of CE exposure in human dermal microvascular endothelial cells (HMEC -1 ) was developed . Four Aims were designed to compartmentalize various components of the endothelial response to CE . The Aims included an array of methods to address cellular toxicity and dysfunction , including classical cytotoxicity and viability assays (Aim One ) , microscopic and electrical analyses of monolayer integrity (Aim Two ) , molecular analysis of second messengers , signaling molecule phosphorylation , and transcription factor DNA binding activity (Aims Three and Four ) . Aim One experiments demonstrated a lack of overt endothelial cytotoxicity caused by CE . Aim Two morphological analysis of endothelial intercellular borders and barrier integrity showed that CE exposure in the endothelial monolayers resulted in increased permeability , and hence a decrease in barrier integrity . These changes were observed temporally with alterations in cytosolic and total cellular free calcium ion (Aim Three ) , inositol 1 ,4 ,5 trisphosphate , and phosphorylated p38 mitogen -activated protein kinase concentrations , as well as changes in DNA binding activity and dimer composition of nuclear factor -kappaB (Aim Four ) . The observed changes suggest a distinct alteration of endothelial cell and monolayer function consistent with increased vascular permeability in vivo . Potential pathological outcomes of such effects include inflammation , vasculitis , systemic disease , and organ failure .
URI: http : / /hdl .handle .net /2152 .3 /262
Date: 2004-11-02

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Microvascular endothelial response to cocaethylene exposure: morphological and molecular observations. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /262 .

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