Recently we observed the massive accumulation of polymorphonuclear neutrophils (PMN) in the liver during reperfusion after ischemia and also during acetaminophen (AAP)-induced injury. Preliminary data suggest that PMN may actively contribute to the tissue damage in these two models of hepatic injury. The chemotactic signal recruiting the PMN appears to be reactive oxygen in both models. The main objectives of this proposal therefore are to confirm that reactive oxygen is the signal, to identify the source(s) of the reactive oxygen, to confirm the direct relationship between PMN accumulation and tissue damage by various pharmacological interventions, and to quantify the metabolic and physiologic contributions to the liver injury of PMN accumulation itself versus the ischemic insult or the direct damage by AAP. In a model of hepatic ischemia and reperfusion the effect of selective pharmacological interventions on organ, cell, and mitochondrial injury will be studied in vivo and compared with the similar model in the isolated blood-free rat perfused liver. Drugs include oxyradical and radical scavengers, xanthine oxidase inhibitors, Kupffer cell inhibitors and simulators, iron and iron chelators (to study the involvement of lipid peroxidation) and lipoxygenase inhibitors (to study the involvement of eicosatetraenoic acid- derived mediators in the recruitment of PMN during reperfusion injury). The contribution of PMN in AAP-induced injury will be investigated in an in vivo model using similar pharmacological interventions as described above and compared quantitatively with the effects of these drugs on AAP-induced injury in the blood-free perfused mouse liver. Our hypothesis is that injury produced by the reactive metabolite of AAP leads to PMN accumulation, secondary alteration of the hepatic microvascular circulation, and an extension of the AAP injury by the PMN-mediated low blood flow ischemia. The studies should clarify the role of PMN in the pathophysiology of ischemia-reperfusion and AAP-induced hepatic injury and provide rationales for new therapeutic interventions in various liver diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29GM042957-03
Application #
3467845
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1989-07-01
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Jaeschke, Hartmut (2002) Neutrophil-mediated tissue injury in alcoholic hepatitis. Alcohol 27:23-7
Jaeschke, H; Smith, C W; Clemens, M G et al. (1996) Mechanisms of inflammatory liver injury: adhesion molecules and cytotoxicity of neutrophils. Toxicol Appl Pharmacol 139:213-26
Liu, P; McGuire, G M; Fisher, M A et al. (1995) Activation of Kupffer cells and neutrophils for reactive oxygen formation is responsible for endotoxin-enhanced liver injury after hepatic ischemia. Shock 3:56-62
Wang, Y; Mathews, W R; Guido, D M et al. (1995) Inhibition of nitric oxide synthesis aggravates reperfusion injury after hepatic ischemia and endotoxemia. Shock 4:282-8
Essani, N A; Fisher, M A; Farhood, A et al. (1995) Cytokine-induced upregulation of hepatic intercellular adhesion molecule-1 messenger RNA expression and its role in the pathophysiology of murine endotoxin shock and acute liver failure. Hepatology 21:1632-9
Mathews, W R; Guido, D M; Fisher, M A et al. (1994) Lipid peroxidation as molecular mechanism of liver cell injury during reperfusion after ischemia. Free Radic Biol Med 16:763-70
Liu, P; Vonderfecht, S L; McGuire, G M et al. (1994) The 21-aminosteroid tirilazad mesylate protects against endotoxin shock and acute liver failure in rats. J Pharmacol Exp Ther 271:438-45
Liu, P; Fisher, M A; Farhood, A et al. (1994) Beneficial effects of extracellular glutathione against endotoxin-induced liver injury during ischemia and reperfusion. Circ Shock 43:64-70
Liu, P; Vonderfecht, S L; Fisher, M A et al. (1994) Priming of phagocytes for reactive oxygen production during hepatic ischemia-reperfusion potentiates the susceptibility for endotoxin-induced liver injury. Circ Shock 43:9-17
Jaeschke, H; Farhood, A; Smith, C W (1994) Contribution of complement-stimulated hepatic macrophages and neutrophils to endotoxin-induced liver injury in rats. Hepatology 19:973-9

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