ETHANOL AND HOST DEFENSE RELATED HEPATIC FUNCTION

  • Gregory, Paula (PI)
  • MOLINA, PATRICIA (PI)
  • MOLINA, PATRICIA (PI)
  • SIMON, LIZ (PI)
  • EDWARDS, SCOTT (PI)
  • FERGUSON, TEKEDA (PI)
  • WELSH, DAVID (PI)
  • SIMON, LIZ (CoPI)
  • SPITZER, JOHN (PI)
  • NELSON, STEVE (PI)
  • GREENBERG, STANLEY (PI)
  • MASON, CAROL (PI)
  • MC DONOUGH, KATHLEEN (PI)
  • SHELLITO, JUDD (PI)
  • JERRELLS, THOMAS (PI)
  • MC DONOUGH, KATHLEEN (PI)
  • BAGBY, GREGORY (PI)
  • SPITZER, JOHN (PI)
  • NELSON, STEVE (PI)
  • GREENBERG, STANLEY (PI)
  • MASON, CAROL (PI)
  • MCDONOUGH, KATHLEEN (PI)
  • SHELLITO, JUDD (PI)
  • JERRELLS, THOMAS (PI)
  • BAGBY, GREGORY JOHN (PI)
  • NELSON, STEVE (PI)
  • BAUTISTA, ABRAHAM (PI)
  • PRAKASH, OM (PI)
  • LANCASTER, JACK (PI)
  • MOLINA, PATRICIA (PI)
  • BROWN, JULIE (PI)
  • BAGBY, GREGORY JOHN (PI)
  • KOLLS, JAY (PI)
  • GREENBERG, STANLEY (PI)
  • MASON, CAROL (PI)
  • MCDONOUGH, KATHLEEN (PI)
  • SHELLITO, JUDD (PI)
  • JERRELLS, THOMAS (PI)
  • NELSON, STEVE (PI)
  • KANTROW, STEPHEN (PI)
  • WINSAUER, PETER (PI)
  • SHELLITO, JUDD (PI)
  • AMEDEE, ANGELA (PI)
  • GUIDO, WILLIAM (PI)
  • NELSON, STEVE (PI)
  • KANTROW, STEPHEN (PI)
  • WINSAUER, PETER (PI)
  • SHELLITO, JUDD (PI)
  • BAGBY, GREGORY JOHN (PI)
  • KOLLS, JAY (PI)
  • NELSON, STEVE (PI)
  • Veazey, Ronald (PI)
  • AMEDEE, ANGELA (PI)
  • KOLLS, JAY (PI)
  • Zhang, Ping (PI)
  • BAGBY, GREGORY JOHN (PI)
  • THEALL, KATHERINE (PI)
  • GILPIN, NICHOLAS (PI)
  • SIMON PETER, LIZ (PI)
  • ZEA, ARNOLD (PI)
  • PARSONS, CHRISTOPHER (PI)

Project Details

Description

Ethanol is a potent immunosuppressive agent and the alcohol-consuming
patient is an immunocompromised host. Alcohol predisposes individuals
to bacterial and viral infections, and increases morbidity and mortality.
Within the liver, the Kupffer cells (resident macrophages) and
endothelial cells plays an essential role in surveillance against
bacteria or bacterial products The liver is also the primary location
for the metabolism of ethanol. Therefore, the long-term goal of the
present proposal is to elucidate the mechanisms for the functional and
metabolic alterations produced by acute and chronic alcohol intoxication
and LPS or the combination of these biological response modifiers in
Kupffer and hepatic endothelial cells, as well as in sequestered
neutrophils. Three hypotheses will be considered: (1) Ethanol alters
LPS-, cytokine- or hormone-induced changes in the uptake and
phosphorylation of glucose by hepatic nonparenchymal cells in a cell
specific manner; (2)Ethanol intoxication inhibit LPS-,cytokine-or
hormone-induced increased expression and synthesis of glucose
transporters and hexokinase and glucose-6-P-dehydrogenase in these cells;
and (3) The inhibitory effects of ethanol on the glucose metabolic
response lead to impairments of immune-competent functions and hamper the
protective mechanisms against oxidative hepatocellular injury.
Hypothesis #1 will be addressed by specific aims directed at determining
the effect of ethanol on the LPS, cytokine-or hormone-induced glucose
uptake in vivo and in vitro, and insulin and catecholamine binding.
Specific aims for hypothesis #2 will determine how ethanol and LPS or
cytokines modulate the mRNA expression and protein synthesis rate of the
key enzymes of glucose entry and subsequent metabolism in the pentose
cycle. The specific aims for hypothesis #3 focus on determining various
immune-competent functions of hepatic nonparenchymal cells dependent on
glucose catabolism by these cells. Alteration in nonspecific immune
functions of Kupffer and endothelial cells, and when possible sequestered
neutrophils, will be assessed by determining TNF, IL-1, IL-6 production,
superoxide anion and nitric oxide generation, phagocytosis, bactericidal
activity and hyaluronic acid uptake. Glutathione metabolism in various
hepatic cells types will be measured and it will be tested how ethanol
and LPS modify this important anti-oxidant mechanism. These studies will
provide novel information on the basic mechanisms regulating glucose
utilization and related immune functions in nonparenchymal cells, and how
two potent immunomodulatory agents, ethanol and LPS, interact to modulate
this pathway and control an important aspect of host defense.
StatusActive
Effective start/end date1/01/0130/11/21

Funding

  • National Institute on Alcohol Abuse and Alcoholism
  • National Institute on Alcohol Abuse and Alcoholism
  • National Institute on Alcohol Abuse and Alcoholism
  • National Institute on Alcohol Abuse and Alcoholism
  • National Institute on Alcohol Abuse and Alcoholism

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.