Association of chronic alcohol consumption and increased susceptibility to and pathogenic effects of pulmonary infection with respiratory syncytial virus in mice.

Chronic alcohol abuse by human beings has been shown to be associated with increased susceptibility to pulmonary infections and severity of inflammatory responses associated with pulmonary infection. On the basis of the higher likelihood of exposure to respiratory viruses, people who abuse alcohol would logically be susceptible to respiratory viral infections. To test this hypothesis, mice were provided alcohol in drinking water for 13-16 weeks with the Meadows-Cook protocol and infected intranasally with respiratory syncytial virus. At various times after infection, severity of infection was determined by evaluation of cellular and cytokine composition of bronchoalveolar lavage fluid (BALF) and histologic evaluation of inflammation. Infection was associated with neutrophil infiltration in both groups, but the proportion and number of neutrophils in BALF were significantly greater in the alcohol consumption group than in the control group. Concentrations of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 in BALF in the alcohol consumption group were increased. Interferon (IFN)-gamma concentrations were lower in the alcohol consumption group at later times of infection. Pulmonary inflammation was cleared by 3-5 days after infection in the control group. In contrast, pulmonary inflammation was evident in the alcohol consumption group after 7 days of infection, and some mice showed severe inflammation with hemorrhage and edema. IFN-alpha/beta was evident in BALF at low concentrations in the alcohol consumption group for several days after infection, and increased mRNA for IFN-alpha/beta was also evident in the alcohol consumption group. This was accompanied by the presence of virus in this group at these times of infection. Chronic alcohol consumption increased severity of pulmonary infection with a virus that naturally infects hosts by an aerosol route. Infection of mice that had consumed alcohol chronically was more severe in terms of increased proinflammatory cytokine production, inflammation, and a failure to clear the virus from the lungs.

Alcoholic pancreatitis: mechanisms of viral infections as cofactors in the development of acute and chronic pancreatitis and fibrosis.

Acute and chronic pancreatitis is associated with alcohol abuse, but symptomatic pancreatitis develops in only a small proportion of persons (10-20%) who abuse alcohol. This apparent paradox has led to the notion that additional cofactors are involved in the development of alcoholic pancreatitis. Potential cofactors, such as diet and smoking, have been suggested, but there are no compelling epidemiologic data to support this idea. A number of viruses and some bacteria have been shown to infect the pancreas and produce pancreatitis. One important mediator of pancreatitis in persons with a compromised immune system is a viral infection. The increased susceptibility of immunocompromised persons to viral pancreatitis led to the hypothesis, described in this paper, that the well-known immunosuppression associated with alcohol abuse would result in a more severe viral pancreatitis in mice, which are provided ethanol, than in control animals. To test this hypothesis, C57BL/6 mice were infected with a virulent strain of coxsackievirus B3, which preferentially induces pancreatitis, or with a strain that is naturally avirulent. The study findings presented in this paper show that ethanol consumption alone does not produce pancreas damage but results in a more severe and prolonged pancreatitis after infection with a virulent virus and interestingly, after infection with the avirulent strain of virus. This was associated with an increased number of viruses in the pancreas and spleen, which correlated with decreased humoral immune responses to the virus.

Rescue of in vivo FAS-induced apoptosis of hepatocytes by corticosteroids either associated with alcohol consumption by mice or provided exogenously.

The pathogenic effects of many hepatic viral infections are mediated, at least in part, by the immune response to the infected hepatocyte. The immune response in the infected liver involves the interaction of cytotoxic T cells (CTL) with the hepatocytes through the interaction of FAS-ligand on the CTL and FAS on the hepatocyte. The initial hypothesis for this study was that alcohol consumption by mice would sensitize the liver to apoptosis induced by ligation of FAS. C57Bl/6 mice fed ethanol in a liquid diet did show an increased percentage of apoptotic cells 2 h after injection with anti-FAS as compared with the percentage in the control mice. However, 4 and 6 h after anti-FAS injection, control mice showed high percentages of apoptotic cells (20% to 41%) compared with 5% and 4% apoptotic cells in the ethanol-fed mice. The decreased apoptosis of ethanol-fed mice correlated closely with corticosterone levels in the sera. This was confirmed by the finding that adrenalectomized (ADX) mice provided a high level of corticosterone in drinking water were protected against FAS-induced hepatocyte apoptosis. Ethanol-fed mice showed a significant elevation of serum alanine aminotransferase (ALT) levels indicating the development of hepatitis in spite of the relatively low proportion of apoptotic cells in the liver. In conclusion, high levels of corticosterone protect hepatocytes from FAS-mediated apoptosis, but do not prevent the ultimate development of liver damage. In experiments where mice were provided ethanol chronically in drinking water, where stress is minimal, higher levels of ALT were noted in animals in the ethanol group as compared with animals in the control group. These data support the suggestion that ethanol increases hepatocyte sensitivity to FAS-mediated damage.