Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S., and there is still no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentrations of tumor necrosis factor (TNF-) and TNF--inducible proinflammatory cytokines/chemokines, such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis, and levels correlated with markers of the acute phase response, reduced liver function, and poor clinical outcome. The focus of this application is the delivery of an available drug using a unique carrier system that targets liver, and corrects the dysregulated cytokine production. Preliminary studies in isolated cells indicate that cyclic AMP (cAMP) decreases when cells are exposed to alcohol, and is associated with an increase in pro- inflammatory cytokine levels. Increased cellular cAMP levels were observed to attenuate alcohol-mediated upregulation in pro-inflammatory cytokines. We also have preliminary data demonstrating the causal role of increased expression of phosphodiesterase 4 (PDE4) in the decreased cAMP concentrations observed in alcohol-exposed cells. Our working hypothesis is that altered PDE4 and cAMP metabolism cause abnormal cytokine production/activity which plays a critical role in the development and perpetuation of ALD. Our long-term goal is to develop therapeutic interventions based on this research in order to provide much needed drug therapy for ALD. We have identified a highly effective PDE4 inhibitor to treat ALD, but in humans systemic administration of the inhibitor induces severe nausea when the drug crosses the blood-brain-barrier. The goal of this proposal is to develop a carrier system that targets liver, and minimizes release of free drug systemically while circulating in route to the organ. We will evaluate efficac of low-doses of PDE4 inhibitor in blocking cytokine production in the liver after challenging with lipopolysaccharide, and we will evaluate efficacy of therapy in reducing alcohol induced liver injury in a rat model. We predict that our carrier system "loaded" with PDE4 inhibitor will not block PDE4 activity in brain, but will concentrate in the liver. This will increase local bioavailability of inhibitor (blocking PDE4 activity in liver cells and selectively inhibiting production of pro-inflammatory cytokines) and will greatly enhance the protective effect, albeit with a smaller amount of drug that does not cause toxic side effects.
Public Health Relevance: Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S., and there is still no FDA-approved therapy. We have identified a highly effective inhibitor of proinflammatory factors to treat ALD, but in humans oral systemic administration of the inhibitor induces severe nausea when it reaches the brain. We propose to develop a carrier system that minimizes release of free-drug while circulating, and concentrates drug in the liver, thereby maximizing the therapeutic effect while minimizing severe side effects.
Public Health Relevance Statement: Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S., and there is still no FDA-approved therapy. We have identified a highly effective inhibitor of proinflammatory factors to treat ALD, but in humans oral systemic administration of the inhibitor induces severe nausea when it reaches the brain. We propose to develop a carrier system that minimizes release of free-drug while circulating, and concentrates drug in the liver, thereby maximizing the therapeutic effect while minimizing severe side effects.
NIH Spending Category: Alcoholism; Chronic Liver Disease and Cirrhosis; Digestive Diseases; Hepatitis; Liver Disease; Substance Abuse
Project Terms: Abstinence; Acute-Phase Reaction; Adverse effects; alcohol exposure; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcohols; Anti-Tumor Necrosis Factor Therapy; Antibodies; Attenuated; base; bile duct; Biological Availability; Blood; Blood - brain barrier anatomy; Brain; Cause of Death; Cells; chemokine; Chronic; Cirrhosis; Clinical; Complex; cost; Crohn's disease; Cross Circulation; Cyclic AMP; cytokine; Data; Development; Devices; Disease; Dose; Drug usage; Endotoxins; Enteral; Enzymes; Ethanol; FDA approved; feeding; France; Goals; Hepatic; Hepatocyte; Hepatotoxicity; Human; IL8 gene; Inflammation; Inflammatory; inhibitor/antagonist; injured; Injury; Interleukin-10; Interleukin-18; Intestines; Kupffer Cells; Label; Ligation; Lipids; Lipopolysaccharides; Liver; Liver diseases; liver function; Liver Regeneration; macrophage; Mediating; Metabolism; Modeling; monocyte; Mortality Vital Statistics; Multicenter Trials; Mus; Nausea; Nausea and Vomiting; novel; nutrition; Oral; Organ; Outcome; Patients; PDE4B; Peripheral; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phosphodiesterase Inhibitors; phosphodiesterase IV; Physicians; Play; Prednisone; Process; Production; protective effect; Psoriasis; Rattus; receptor; Reporting; Research; response; Rheumatoid Arthritis; Role; Rolipram; Route; Serum; Severity of illness; Staging; Stimulus; Stomach; Surrogate Markers; Survival Rate; System; Testing; Therapeutic Effect; Therapeutic Intervention; Therapeutic Uses; TLR4 gene; TNF gene; TNFR-Fc fusion protein; Treatment Efficacy; Tumor Necrosis Factor-alpha; Up-Regulation (Physiology); Vesicle; Work
