Thomas R. Jerrells

Alcohol Consumption by C57BL/6 Mice Is Associated with Depletion of Lymphoid Cells from the Gut-Associated Lymphoid Tissues and Altered Resistance to Oral Infections with Salmonella typhimurium

Studies were done to test whether ethanol (ETOH) consumption alters resistance to mucosal and systemic infections by Salmonella typhimurium. S. typhimurium-immune and -nonimmune mice were fed 1 of 3 diets (an ETOH-containing liquid diet, an isocaloric liquid diet equal in volume to that of the ETOH-treated group, or laboratory chow) in a pair-feeding design and were infected orally or intravenously with S. typhimurium. The number of bacteria in spleen and liver and the effect of ETOH feeding and infection on the number of lymphoid cells in the gut-associated lymphoid tissues (GALT) were determined. ETOH feeding resulted in profound loss of GALT lymphoid cells and an increased number of Salmonella organisms in the intestines, liver, and spleen of infected nonimmune, but not of immune, mice. These data show that ETOH consumption in this model impairs host defense mechanisms that control mucosal infections and inhibits the mechanisms that control levels of bacteria in the central organs.

Role of activated CD8+ T cells in the initiation and continuation of hepatic damage.

The cause of alcoholic liver disease (ALD) is multifactorial and poorly understood. It is clear that alcohol alone is not responsible for most of the changes associated with ALD and that cofactors are involved in initiation and production of ALD. One cofactor that has received a great deal of attention recently is the concomitant infection with hepatitis C virus (HCV) and alcohol abuse. The interactive effects of HCV and alcohol abuse are still unclear, but apparently they are the result of an inability of the immune system to control the viral infection and exaggerated hepatocyte damage mediated by either the cells of the inflammatory response or factors produced by the inflammatory cells. This review will focus on one aspect of the possible pathogenic effects associated with alcohol abuse and HCV infection: the possible role of the immune system, notably the cytotoxic T lymphocyte (CTL) response. It is clear that the development of a CTL response is critical for the control of HCV infections, and it is also likely that this response is involved in liver damage. In this review, the evidence that shows the importance of the CD8(+) CTL in viral clearance and the role for pathogenesis will be presented. Findings obtained from animal studies that support the suggestion that activated CD8(+) CTLs can induce liver damage will be presented, as will results of recent studies from my laboratory that provide evidence for an effect of alcohol to enhance the liver damage mediated by activated CD8(+) T cells.

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.

INHIBITION OF PROTEIN KINASE C EPSILON CAUSES CILIATED BOVINE BRONCHIAL CELL DETACHMENT

This study defines the in vitro phenomenon of ciliated bovine bronchial epithelial cell (BBEC) detachment from the basal epithelium and regulation of cilia motility mediated through protein kinase C epsilon (PKCε). The authors determined the time course of activation and downregulation of PKCε by the known PKC activator phorbol 12-myristate 13-acetate (PMA) and demonstrate that chemical inhibition of PKC by calphostin C or the novel PKC isoform inhibitor Ro 31-8220 induced striking detachment of ciliated BBECs from the basal cell monolayer within 1 hour, independent of apoptosis or necrotic cell death. The results of this study support a possible novel PKCε-mediated signaling pathway through which ciliated cell attachment is maintained.

Introducing the formation of the International Society of Addiction Journal Editors

In past editorials (Jerrells, 1999a, 1999b), I have indicated a strong commitment to publishing in Alcohol articles of the highest quality in terms of established criteria for the ethics of publishing scientific research findings. To that end, the editors of Alcohol have endorsed the tenets of The Farmington Consensus (see ‘‘Editorial,’’ Jerrells, 1999b, for details on The Farmington Consensus). The journal editors who, for the most part, were instrumental in framing The Farmington Consensus have taken their efforts to establish well-defined guidelines for publishing scientific reports in addiction journals to the most logical level; that is, to form an organized society of addiction journal editors. This was

Editorial on the special research focus

I am pleased to be able to introduce this Special Research Focus on Alcohol Biomarkers that has been organized by M. Raj Lakshman. This compendium of research articles is the result of a symposium that was held at The 10th Congress of the International Society for Biomedical Research on Alcoholism in July 2000, which was chaired by Dr. Lakshman and Dr. Mikihiro Tsutsumi. The papers published in this Special Research Focus are expanded versions of the talks presented at this symposium. As such, they present in more detail the important findings of these investigators in terms of current knowledge of various markers of alcohol consumption and abuse. As Editor-in-Chief of Alcohol, I have encouraged scientists to prepare this type of collection of research articles with a common focus. As you will note, some of the articles published in this Special Research Focus provide an in-depth review of the specific field the authors are involved with, whereas in other articles new data are presented. To encourage authors to consider being a part of this type of publication I have established an editorial policy to have these articles peer reviewed. To this end, Dr Lakshman, in collaboration with the editorial office of Alcohol, arranged to have all these articles peer reviewed. This review process was essentially coordinated by Dr. Lakshman, and he made the final editorial decision to accept the manuscripts, which I believe is an appropriate approach. I, of course, read the manuscripts and the reviews. It should also be noted that the Managing Editor, Ms. Janice Jerrells, RN, BA, ELS, provided expert copyediting for each manuscript, as well as ensured that the references provided by the authors for each paper were complete and accurate. I would like to take this opportunity to thank Drs. Lakshman and Tsutsumi for organizing the symposium and Dr. Lakshman for organizing the Special Research Focus that is published in this issue of Alcohol. I am sure the readers of Alcohol will find this an informative compilation of manuscripts and research data.