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Inflammation in Innate and Adaptive Immune Mechanisms October 28 – 30, 2012 Hilton Grand Wailea Resort | Maui, Hawai’I Organizers: Tom Hamilton and Xiaoxia Li

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Inflammation in Innate and Adaptive Immune Mechanisms October 28 – 30, 2012 Hilton Grand Wailea Resort | Maui, Hawai’I Organizers: Tom Hamilton and Xiaoxia Li 45th Annual Meeting of The Society for Leukocyte Biology InflammatIon In Innate and adaptIve Immune mechanIsms October 28 – 30, 2012 Hilton Grand Wailea Resort | Maui, Hawai’i Organizers: Tom Hamilton and Xiaoxia Li abstracts Journal of Leukocyte Biology, Supplement 2012 www.leukocytebiology.org 45th AnnuAl Meeting of the Society for leukocyte Biology inflAMMAtion in innAte And AdAptive iMMune MechAniSMS grAnd WAileA, MAui, hAWAi’i ~ octoBer 28-30, 2012 Thank you to the supporters of the 2012 SLB Meeting! Journal of Leukocyte Biology Supplement 2012 ABSTRACTS 1 2 Alcohol and Drugs of Abuse Interaction with HIV/AIDS: Chronic Alcohol Consumption Increases Mortality in Sepsis Systems Biology Approach in the SIV-Infected Macaque Benyam P. Yoseph, Zhe Liang, Elise Breed, Kevin McConnell, Patricia E. Molina David M. Guidot, Michael Koval, Craig M. Coopersmith Comprehensive Alcohol Research Center, Louisiana State Emory University School of Medicine University Health Sciences Center, NOLA Introduction: Excessive alcohol abuse is a problem of particular The two most commonly used and abused drugs are alcohol concern in the intensive care unit (ICU), as the rate of morbidity and the cannabinoids. Alcohol and drugs of abuse have been and mortality in all patients admitted to ICU is 2-4 times greater demonstrated to alter host response to human immunodeficiency than in non-alcoholics. Sepsis is the leading cause of death in ICU. (HIV) infection; by affecting progression of infection, tissue The purpose of this study was to examine the pathophysiology of injury, and time to death. Several factors can be involved in chronic alcohol abuse in sepsis. this, those pertaining to the host response, as well as those Methods: FVB/N mice were given liquid ethanol diet (20% w/v) or related to the ability of the virus to integrate itself into the host water for 12 weeks. Twelve weeks later all mice underwent 2X25 genome. Alcohol use disorders frequently coexist with infection. cecal ligation and puncture (CLP). Mice were sacrificed seven-days Cannabinoid use is frequent in HIV-infected individuals, both as or 24 h after CLP. Gut apoptosis was quantified in 100 crypts/mouse a recreational agent and a therapeutic adjuvant, in its synthetic by caspase-3 staining. Villus length was measured from the crypt form of Δ9-tetrahydrocannabinol. The biomedical consequences neck to villus tip in 12 villi/mouse. Permeability was measured by of alcohol abuse are multi-systemic. While considerable advances gavaging mice with 22mg/ml FITC-dextran 19hrs post-CLP. The have been made in our understanding of alcohol-induced injury FITC concentration in the plasma was determined at 24hrs. Blood, of hepatic, behavioral, and neural substrates; the metabolic peritoneal fluid (PF), and bronchoalveolar lavage (BAL) levels consequences of chronic alcohol abuse have been previously of TNF-α, IL-6, IL-10, IL-1β, IL-13, MCP-1, G-CSF, IFN-γ, and neglected. Cannabinoids, the principal chemical constituents of TGF- β concentration were evaluated using a multiplex assay. Data marijuana, exert neurobehavioral effects and in addition have the were compared using Mann-Whitney tests. potential of affecting the immune system. Viral entry, integration Results: Septic alcoholic (SA) mice had a significant higher and replication, and cell injury involve numerous cellular signaling mortality than septic non-alcoholic (SNA) mice (74% vs 41%, and effector mechanisms determining the overall systemic p=0.01). SA mice had increased in gut apoptosis compared with response to the infection. The multiplicity and interconnectedness SNA mice (25 ± 1 vs 14 ± 1cells, p=0.0001, n=9-10/group). SA mice of factors cannot be effectively reconciled using isolated organ, had shorter villi than SNA mice (178 ± 8 vs 246 ± 7µm, p=0.0002, cellular, or molecular approaches. Using an integrated systems n=9/group). SA mice had higher permeability than SNA mice (632 biology analysis our studies have identified salient cellular and ± 57 vs 372 ± 38 pg/ml, p=0.0009, n=13-15/group). SA mice had molecular signatures prevailing during the infection and their significantly lower levels of IL-6 in serum, significantly higher modulation by chronic alcohol and cannabinoid administration levels of MCP-1 in PF, and significantly higher levels of G-CSF in the Simian Immunodeficiency Virus (SIV)-infected rhesus and TGF- β in BAL compared to SNA mice (Table 1). macaque. Our findings suggest that chronic alcohol and cannabinoid administration differentially modulate key interconnected and tissue-specific mechanisms responsible for control of disease progression. The systemic pathophysiological effects of alcohol have been identified to adversely affect the course and progression of HIV infection. The significant multi-systemic pathophysiological mechanisms including; but not limited, to nutritional, metabolic, oxidative, and disruption of neuroendocrine pathways have all been implicated as modulators of disease progression. In contrast, our data suggests that cannabinoids may exert an overall protective effect. Although these effects are multisystemic, specific organ systems have been identified to be central to disease progression; including the central nervous system, the immune system, and gut mucosa. We hypothesize that the contrasting disease phenotype resulting from chronic alcohol and cannabinoid administration to SIV-infected non-human primates provides a unique opportunity for systems biology analysis of the epigenetic, genetic, and proteomic profiles prevailing during SIV infection that are translatable to HIV disease progression. Supported by NIDA-020419, NIDA030053, AA-09803, AA-07577, AA-11290. S1 Journal of Leukocyte Biology Supplement 2012 ABSTRACTS Conclusions: These results indicate that chronic alcohol abuse 4 causes higher mortality in septic mice compared to previously Chronic Alcohol Effects on Oxidative Stress Markers in the healthy mice subject to the same insult. This was associated with Rat Heart increased gut apoptosis, decreased villus length, and increased gut Robin Walker, George Haddad permeability. Among the cytokines, systemic IL-6, local MCP-1, Howard University and BAL G-CSF and TFG- β were the predominant cytokines affected by chronic use of alcohol in sepsis. Cardiovascular disease is among the major causes for increased morbidity and mortality rates. High alcohol consumption may 3 lead to cardiomyopathy, cardiac arrhythmias, and a suite of Inhibition of Myosin Light Chain Kinase Prevents Gut other disorders. Previous studies in our lab have linked the AKT/ Inflammation and Alterations in Tight Junction Proteins PI3K pathway to cardiovascular disease. Alcohol consumption Following Binge Ethanol Exposure and Burn Injury induces oxidative stress and increases the risk of liver disease, Anita Zahs1, Luis Ramirez1, Jerrold R. Turner2, Mashkoor A. heart disease, certain cancers, brain damage and several other Choudhry1, Elizabeth J. Kovacs1 complications involving metabolic disturbances and organ 1Loyola University Medical Center Stritch School of Medicine; damage. Clinical features of the consequences of prolonged and 2Department of Pathology University of Chicago excessive ethanol consumption encompass defects in myocardial contractility and derangement of cellular architecture, including Elevated myosin light chain kinase (MLCK) activity has been disarray of the contractile elements. Although the incidence of attributed to intestinal permeability following numerous diseases heart muscle abnormalities in alcohol misusers is generally higher and insults. Burn injury or ethanol exposure alone induces greater than previously considered, the mechanisms are only just being MLCK activity, specifically in the intestine. As nearly 50% of the elucidated. Oxidative stress has been reported to be the major adult burn patient population has a positive blood alcohol content at contributor for these alcohol induced pathologies. In the present the time of admission, we examined the role of MLCK in intestinal study, our aim is to investigate the effects of chronic alcohol barrier dysfunction in a mouse model of ethanol exposure and burn treatments on expression of NRF2, a core regulator of antioxidant injury. Two hours after the combined insult both tumor necrosis machinery on oxidative stress markers of alcohol induced factor α (TNFα) and interleukin-6 (IL-6), two major activators of cardiomyopathy; as well as other phase II oxidative stress genes. MLCK, are 10 times higher in the serum of mice exposed to burn Our preliminary results show that with increasing concentrations injury alone or the combined insult as compared to either sham of alcohol from low (5mM Ethanol) to high (100mM Ethanol) we group. By 3 hours post injury, mice exposed to binge ethanol and increase NRF2 and SOD-3 gene expression. Our data suggest that burn injury have twice as much MLCK and significantly more NRF2 may act as a molecular switch to control the oxidative balance phospho-myosin light chain (pMLC) in intestinal epithelial cells during chronic alcohol consumption in the heart. We will use this than all other groups. This increase in pMLC was associated data to continue to examine the link between NRF2 signaling and with elevated villus blunting, bacterial translocation, and ileum the AKT/PI3K pathway in alcohol-induced cardiomyopathy. This levels of IL-1β at 6 hours post insult. Furthermore, tight junction work was supported in part by grants 1R15AA19816-01A1 NIH/ proteins, ZO-1 and occludin, were no longer localized with actin
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