Laboratory Models Available to Study Alcohol‐Induced Organ Damage and Immune Variations: Choosing the Appropriate Model

El-Guindy, Nympha B. D'Souza; Kovacs, Elizabeth J.; Witte, Philippe De; Spies, Claudia; Littleton, John M.; Villiers, Willem J.S. de; Lott, Amanda J.; Plackett, Timothy P.; Lanzke, Nadine; Meadows, Gary G.

doi:10.1111/j.1530-0277.2010.01234.x

Cited by 80 publications

(75 citation statements)

References 310 publications

(399 reference statements)

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“…Although concentrated ethanol is believed to be more effective in promoting cancer than diluted ethanol, one major limitation in animal studies is poor tolerance of lab animals to concentrated ethanol. ~20% (w/v, or 25% v/v) or ~32% (w/v, or 40% v/v) is the upper limit of ethanol concentration in drinking water for mice or rats, respectively [189]. In addition, ethanol passes the oral cavity and esophagus quickly, thus its effects on the oro-esophageal squamous epithelial cells in vivo tend to be weak and transient.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma

et al. 2015

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Alcohol drinking is a major etiological factor of oro-esophageal squamous cell carcinoma (OESCC). Both local and systemic effects of ethanol may promote carcinogenesis, especially among chronic alcoholics. However, molecular mechanisms of ethanol-associated OESCC are still not well understood. In this review, we summarize current understandings and propose three mechanisms of ethanol-associated OESCC: (1) Disturbance of systemic metabolism of nutrients: during ethanol metabolism in the liver, systemic metabolism of retinoids, zinc, iron and methyl groups is altered. These nutrients are known to be associated with the development of OESCC. (2) Disturbance of redox metabolism in squamous epithelial cells: when ethanol is metabolized in oro-esophageal squamous epithelial cells, reactive oxygen species are generated and produce oxidative damage. Meanwhile, ethanol may also disturb fatty-acid metabolism in these cells. (3) Disturbance of signaling pathways in squamous epithelial cells: due to its physico-chemical properties, ethanol changes cell membrane fluidity and shape, and may thus impact multiple signaling pathways. Advanced molecular techniques in genomics, epigenomics, metabolomics and microbiomics will help us elucidate how ethanol promotes OESCC.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma

et al. 2015

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“…Further, nutritional composition is important in determining the extent of ethanol-induced liver damage. It is well known that a high fat diet exacerbates alcohol-induced fatty liver in rodents (D’Souza El-Guindy et al, 2010; Fisher et al, 2002). However, we observe fatty liver in C57 mice fed the Dytes low fat Lieber-DeCarli diet (Liangpunsakul et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Chronic Free‐Choice Drinking in Crossed High Alcohol Preferring Mice Leads to Sustained Blood Ethanol Levels and Metabolic Tolerance Without Evidence of Liver Damage

Matson

Liangpunsakul

Crabb

et al. 2012

Alcoholism Clin & Exp Res

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Background Crossed High Alcohol Preferring (cHAP) mice were selectively bred from a cross of the HAP1xHAP2 replicate lines, and demonstrate blood ethanol concentrations (BECs) during free-choice drinking that are reminiscent of those observed in alcohol-dependent humans. Therefore, this line may provide an unprecedented opportunity to learn about the consequences of excessive voluntary ethanol consumption, including metabolic tolerance and liver pathology. Cytochrome p450 2E1 (CYP 2E1) induction plays a prominent role in driving both metabolic tolerance and ethanol-induced liver injury. In this report, we sought to characterize cHAP drinking by assessing whether pharmacologically relevant BEC levels are sustained throughout the active portion of the light-dark cycle. Given that cHAP intakes and BECs are similar to those observed in mice given an ethanol liquid diet, we assessed whether free-choice exposure results in metabolic tolerance, hepatic enzyme induction, and hepatic steatosis. Methods In Experiment 1, blood samples were taken across the dark portion of a 12:12 light-dark cycle to examine the pattern of ethanol accumulation in these mice. In Experiments 1 and 2, mice were injected with ethanol following 3–4 weeks of access to water or 10% ethanol and water, and blood samples were taken to assess metabolic tolerance. In Experiment 3, 24 mice had 4 weeks access to 10% ethanol and water or water alone, followed by necropsy and hepatological assessment. Results In experiment 1, cHAP mice mean BEC values exceeded 80 mg/dl at all sampling points, and approached 200 mg/dl during the middle of the dark cycle. In experiments 1 and 2, ethanol-exposed mice metabolized ethanol faster than ethanol-naïve mice, demonstrating metabolic tolerance (p < .05). In experiment 3, ethanol-drinking mice showed greater expression of hepatic CYP 2E1 than water controls, consistent with the development of metabolic tolerance (p < .05). Ethanol access altered neither hepatic histology nor levels of ADH and ALDH. Conclusions These results demonstrate that excessive intake by cHAP mice results in sustained BECs throughout the active period, leading to the development of metabolic tolerance and evidence of CYP 2E1 induction. Together these results provide additional support for the cHAP mice as a highly translational rodent model of alcoholism.

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“…(Garcia-Lavandeira et al, 2016). Absolute ethanol was purchases from Sigma-Aldrich and used for all ethanol treatments (D’Souza El-Guindy et al, 2010). …”

Section: Methodsmentioning

confidence: 99%

Alcohol exposure differentially effects anti-tumor immunity in females by altering dendritic cell function

Thompson

Navarro

Chitsike

et al. 2016

Alcohol

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Dendritic cells (DCs) are a critical component of anti-tumor immunity due to their ability to induce a robust immune response to antigen (Ag). Alcohol was previously shown to reduce DC ability to present foreign Ag and promote pro-inflammatory responses in situations of infection and trauma. However the impact of alcohol exposure on generation of an anti-tumor response, especially in the context of generation of an immune vaccine has not been examined. In the clinic, DC vaccines are typically generated from autologous blood, therefore prior exposure to substances such as alcohol may be a critical factor to consider regarding the effectiveness in generating an immune response. In this study we demonstrate for the first time that ethanol differentially affects DC and tumor Ag-specific T cell responses depending on sex. Signaling pathways were found to be differentially regulated in DC in females compared to males and these differences were exacerbated by ethanol treatment. DC from female mice treated with ethanol were unable to activate Ag-specific cytotoxic T cells (CTL) as shown by reduced expression of CD44, CD69, and decreased production of granzyme B and IFNγ. Furthermore, although FOXO3, an immune suppressive mediator of DC function, was found to be upregulated in DC from female mice, ethanol related suppression was independent of FOXO3. These findings demonstrate for the first time differential impacts of alcohol on the immune system of females compared to males and may be a critical consideration for determining the effectiveness of an immune based therapy for cancer in patients that consume alcohol.

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Laboratory Models Available to Study Alcohol‐Induced Organ Damage and Immune Variations: Choosing the Appropriate Model

Cited by 80 publications

References 310 publications

Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma

Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma

Chronic Free‐Choice Drinking in Crossed High Alcohol Preferring Mice Leads to Sustained Blood Ethanol Levels and Metabolic Tolerance Without Evidence of Liver Damage

Alcohol exposure differentially effects anti-tumor immunity in females by altering dendritic cell function

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