Imaging the neuroimmune response to alcohol exposure in adolescent baboons: a TSPO PET study using 18 F-DPA-714.

The effects of acute alcohol exposure to the central nervous system are hypothesized to involve the innate immune system. The neuroimmune response to an initial and acute alcohol exposure was investigated using translocator protein 18 kDa (TSPO) PET imaging, a non-invasive marker of glial activation, in adolescent baboons. Three different alcohol-naive adolescent baboons (3-4 years old, 9 to 14 kg) underwent 18 F-DPA-714 PET experiments before, during and 7-12 months after this initial alcohol exposure (0.7-1.0 g/l). The brain distribution of 18 F-DPA-714 (VT ; in ml/cm3 ) was estimated in several brain regions using the Logan plot analysis and the metabolite-corrected arterial input function. Compared with alcohol-naive animals (VTbrain  = 3.7 ± 0.7 ml/cm3 ), the regional VT s of 18 F-DPA-714 were significantly increased during alcohol exposure (VTbrain  = 7.2 ± 0.4 ml/cm3 ; p < 0.001). Regional VT s estimated several months after alcohol exposure (VTbrain  = 5.7 ± 1.4 ml/cm3 ) were lower (p < 0.001) than those measured during alcohol exposure, but remained significantly higher (p < 0.001) than in alcohol-naive animals. The acute and long-term effects of ethanol exposure were observed globally across all brain regions. Acute alcohol exposure increased the binding of 18 F-DPA-714 to the brain in a non-human primate model of alcohol exposure that reflects the 'binge drinking' situation in adolescent individuals. The effect persisted for several months, suggesting a 'priming' of glial cell function after initial alcohol exposure.

Chronic Alcohol Consumption Promotes Diethylnitrosamine-Induced Hepatocarcinogenesis via Immune Disturbances.

Chronic alcohol consumption increases the risk of hepatocellular carcinoma (HCC). However, little is known about the potential immunological mechanisms by which ethanol affects tumor progression. Here, adult male mice were administered multiple doses of diethylnitrosamine (DEN). Four and a half months later, the DEN-treated mice were placed on a liquid Lieber-DeCarli control diet or diet containing 5% ethanol for 2.5 months. At the end of the study, liver tissue samples were obtained to analyze pathology, gene expression, and hepatic mononuclear cells (MNCs). Results showed that ethanol feeding exacerbates the progression of hepatic tumors (characterized by the ratio of liver weight to body weight, and the tumor volume and diameter) in DEN-treated mice. Mechanistically, chronic alcohol consumption decreased the number of antitumor CD8+ T cells but increased the number of tumor-associated macrophages (TAMs) in the liver in DEN-initiated tumorigenesis. Besides, TAMs were prone to be M2 phenotype after alcohol consumption. Moreover, chronic alcohol consumption aggravated inflammation, fibrosis, and epithelial-mesenchymal transition (EMT) in the pathological process of HCC. These data demonstrate that chronic alcohol consumption exacerbates DEN-induced hepatocarcinogenesis by enhancing protumor immunity, impairing antitumor immunity and aggravating hepatic pathological injury. Targeting the immune system is a potential therapeutic regimen for alcohol-promoted HCC.

Epigenetic targets for reversing immune defects caused by alcohol exposure.

Alcohol consumption alters factors that modify gene expression without changing the DNA code (i.e., epigenetic modulators) in many organ systems, including the immune system. Alcohol enhances the risk for developing several serious medical conditions related to immune system dysfunction, including acute respiratory distress syndrome (ARDS), liver cancer, and alcoholic liver disease (ALD). Binge and chronic drinking also render patients more susceptible to many infectious pathogens and advance the progression of HIV infection by weakening both innate and adaptive immunity. Epigenetic mechanisms play a pivotal role in these processes. For example, alcohol-induced epigenetic variations alter the developmental pathways of several types of immune cells (e.g., granulocytes, macrophages, and T-lymphocytes) and through these and other mechanisms promote exaggerated inflammatory responses. In addition, epigenetic mechanisms may underlie alcohol's ability to interfere with the barrier functions of the gut and respiratory systems, which also contribute to the heightened risk of infections. Better understanding of alcohol's effects on these epigenetic processes may help researchers identify new targets for the development of novel medications to prevent or ameliorate alcohol's detrimental effects on the immune system.

Alcoholism causes alveolar macrophage zinc deficiency and immune dysfunction.

RATIONALE: Alcohol use disorders cause oxidative stress in the lower airways and increase susceptibility to pneumonia and lung injury. Currently, no therapeutic options exist to mitigate the pulmonary consequences of alcoholism. OBJECTIVES: We recently determined in an animal model that alcohol ingestion impairs pulmonary zinc metabolism and causes alveolar macrophage immune dysfunction. The objective of this research is to determine the effects of alcoholism on zinc bioavailability and alveolar macrophage function in human subjects. METHODS: We recruited otherwise healthy alcoholics (n = 17) and matched control subjects (n = 17) who underwent bronchoscopy for isolation of alveolar macrophages, which were analyzed for intracellular zinc, phagocytic function, and surface expression of granulocyte-macrophage colony-stimulating factor receptor; all three of these indices are decreased in experimental models. MEASUREMENTS AND MAIN RESULTS: Alcoholic subjects had normal serum zinc, but significantly decreased alveolar macrophage intracellular zinc levels (adjusted means [SE], 718 [41] vs. 948 [25] RFU/cell; P < 0.0001); bacterial phagocytosis (adjusted means [SE], 1,027 [48] vs. 1,509 [76] RFU/cell; P < 0.0001); and expression of granulocyte-macrophage colony-stimulating factor receptor ß subunit (adjusted means [SE], 1,471 [42] vs. 2,114 [35] RFU/cell; P < 0.0001]. Treating alveolar macrophages with zinc acetate and glutathione in vitro increased intracellular zinc levels and improved their phagocytic function. CONCLUSIONS: These novel clinical findings provide evidence that alcohol abuse is associated with significant zinc deficiency and immune dysfunction within the alveolar space and suggest that dietary supplementation with zinc and glutathione precursors could enhance airway innate immunity and decrease the risk for pneumonia or lung injury in these vulnerable individuals.

Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice.

BACKGROUND & AIMS: Short-chain fatty acids (SCFAs), the most abundant microbial metabolites in the intestine, activate cells via G-protein-coupled receptors (GPRs), such as GPR41 and GPR43. We studied regulation of the immune response by SCFAs and their receptors in the intestines of mice. METHODS: Inflammatory responses were induced in GPR41(-/-), GPR43(-/-), and C57BL6 (control) mice by administration of ethanol; 2, 4, 6-trinitrobenzene sulfonic-acid (TNBS); or infection with Citrobacter rodentium. We examined the effects of C rodentium infection on control mice fed SCFAs and/or given injections of antibodies that delay the immune response. We also studied the kinetics of cytokine and chemokine production, leukocyte recruitment, intestinal permeability, and T-cell responses. Primary colon epithelial cells were isolated from GPR41(-/-), GPR43(-/-), and control mice; signaling pathways regulated by SCFAs were identified using immunohistochemical, enzyme-linked immunosorbent assay, and flow cytometry analyses. RESULTS: GPR41(-/-) and GPR43(-/-) mice had reduced inflammatory responses after administration of ethanol or TNBS compared with control mice, and had a slower immune response against C rodentium infection, clearing the bacteria more slowly. SCFAs activated intestinal epithelial cells to produce chemokines and cytokines in culture and mice after administration of ethanol, TNBS, or C rodentium. These processes required GPR41 and GPR43 and were required to recruit leukocytes and activate effector T cells in the intestine. GPR41 and GPR43 activated extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase signaling pathways in epithelial cells to induce production of chemokines and cytokines during immune responses. CONCLUSIONS: SCFAs activate GPR41 and GPR43 on intestinal epithelial cells, leading to mitogen-activated protein kinase signaling and rapid production of chemokines and cytokines. These pathways mediate protective immunity and tissue inflammation in mice.

Association of alcohol consumption with total serum immunoglobulin E levels and allergic sensitization in an adult population-based survey.

BACKGROUND: Chronic alcoholism is associated with increased total serum IgE levels. OBJECTIVE: The study aimed to investigate the relationship between alcohol intake and both total serum IgE levels and allergic sensitization in a general adult population. MATERIALS AND METHODS: A total of 720 subjects was randomly selected (stratified by age) from the population older than 18 years of A-Estrada (Spain) and invited to participate in the study. From 697 eligible subjects, 469 (67%, median age 54 years, range 18 to 92 years, 44% males, 75% of cases from a rural environment) agreed to participate. A battery of 13 skin prick tests to common aeroallergens was performed in all subjects. Cases with at least one positive test (n = 121, 26%) were considered to have allergic sensitization. The most frequent sensitisers were mites and pollens (24% and 10% of subjects, respectively). Total serum IgE was measured in 465 subjects (99%). Alcohol consumption was registered as the number of standard (approximately 10 g) drinking units habitually consumed per week. A total of 244 subjects (52%) were alcohol consumers (median intake, 14 units/week, range 1 to 147 units/week). Abstainers (n = 225, 48%) constituted the reference category. RESULTS: Alcohol consumption of more than 14 units/week was associated with an increase in serum IgE levels after adjusting for age, gender, allergic sensitization and smoking (P = 0.02). Alcohol consumption was not significantly associated with either overall allergic sensitization or mite sensitization after adjusting for age, gender and smoking. However, alcohol consumption of more than 14 units/week was associated with an increased prevalence of pollen sensitization (adjusted OR 3.15, 95% CI 1.19 to 8.34, P = 0.02). CONCLUSION: Alcohol consumption above a certain threshold is associated with an increase in total serum IgE levels. Alcohol consumption may also be associated with an increased prevalence of pollen sensitization.

Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease.

Autoimmune reactions are often associated with alcoholic liver disease; however, the mechanisms responsible are largely unknown. This study investigates the potential role of the immune response against hydroxyethyl free radical (HER)-derived antigens and of polymorphisms in immunoregulatory genes in the development of anti-cytochrome P4502E1 (CYP2E1) autoantibodies in alcohol abusers. Immunoglobulin G (IgG) recognizing human CYP2E1 and HER-derived epitopes were measured by microplate immunosorbent assay in the sera of 90 patients with alcoholic fibrosis/cirrhosis (ALD), 37 heavy drinkers without liver disease or steatosis only (HD), and 59 healthy subjects. Single nucleotide polymorphisms in the interleukin 10 (IL-10) promoter and in exon 1 of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. The titers and frequency of anti-CYP2E1 autoantibodies were significantly higher in ALD than in HD subjects or controls. ALD patients with anti-HER IgG had higher titers and a 4-fold increased risk (OR: 4.4 [1.8-10.9]) of developing anti-CYP2E1 autoantibodies than subjects without anti-HER antibodies. The mutant CTLA-4 G allele, but not the IL-10 polymorphism, was associated with an enhanced risk of developing anti-CYP2E1 IgG (OR: 3.8 [1.4-10.3]). CTLA-4 polymorphism did not influence antibody formation toward HER-antigens. ALD patients with concomitant anti-HER IgG and the CTLA-4 G allele had a 22-fold higher (OR: 22.9 [4.2-125.6]) risk of developing anti-CYP2E1 autoreactivity than subjects negative for these factors. In conclusion, antigenic stimulation by HER-modified CYP2E1 combined with an impaired control of T-cell proliferation by CTLA-4 mutation promotes the development of anti-CYP2E1 autoantibodies that might contribute to alcohol-induced liver injury.

Choque anafiláctico por ingestión de alcohol etílico / Anaphylactic shock after drinking an alcoholic beverage

Se comunica un caso raro de una paciente de 34 años de edad que sufrió un choque anafiláctico casi mortal 15 minutos después de ingerir una bebida alcohólica. La paciente refiere que seis años antes, con diferentes clases de bebidas alcohólicas manifestaba siempre urticaria generalizada, que desaparecía espontáneamente sin medicamantos. Aunque no se pudo demostrar el mecanismo de la reacción de nuesta paciente, la amplia variedad de bebidas alcoholicas que lo provocan sugiere que el etanol o sus metabolitos son el antígeno ofensor que actúa como hepteno

Aflatoxin removal from peanut meals with commercial aqueous ethyl alcohol

A remoçäo de aflatoxinas (AF), com álcool etílico aquoso comercial (carburante), de farelo de amendoim contaminado em vaso extrator de escala real foi testada em 2 experimentos (testes 1 e 2) realizados numa indústria de extraçäo de óleo no Estado de Säo Paulo, Brasil. No teste 1, álcool 90oGL (diluído a partir do 96oGL) aquecido a 75oC, foi utilizado para fazer 3 extraçöes de uma hora cada (sempre com álcool novo), tendo sido retiradas amostras após cada extraçäo, para análise de AF e de proteína. No teste 2, álcool 96oGL foi utilizado em 4 extraçöes de uma hora, nas mesmas condiçöes porém, sem parar o processo para retirada de amostras intermediárias mas, introduzindo um período de 30 minutos de maceraçäo entre as extraçöes. Neste experimento, pedaços de cerca de 2 cm de espessura e farelo grosseiramente moído, foram utilizados para testar a influência do tamanho da partícula na eficiência da extraçäo de AF pelo solvente. Vinte amostras (10 de cada tipo) foram retiradas no fim do processo para anólises de AF. Os resultados mostraram que a extraçäo de AF com álcool etílico aquoso carburante, em escala real, é dependente do tempo e tecnicamente possível. Alcool 96oGL removeu, em média 87,3 por cento do farelo em pedaços e 95,3 por cento do moído, após 4 extraçöes de uma hora. Houve uma melhor extraçäo na parte inferior do que na parte superior do vaso. O conteúdo de proteína foi avaliado antes e durante o TESTE 1 e mostrou um pequeno aumento de 60,19 por cento para 63,79 por cento