The only effective treatment for advanced alcohol liver disease (ALD) is liver transplantation. It is imperative to better understand the pathogenesi in order to advance therapeutic development. Evidence suggests that hepatic macrophages (Macs) play an important role;however research to date has not distinguished resident Macs, Kupffer cells (KCs), from infiltrating bone marrow-derived myeloid cells (BMMCs), which replenish KCs during pathological conditions. We detected BMMCs and distinguished them from KCs in the liver of mice treated with alcohol. We hypothesize that the BMMCs recruited into the liver during ALD assume different phenotypes and functions, depending on the microenvironment and severity of ALD.
The Specific Aims of the proposed studies are:
(Aim 1), investigate the mechanisms of hepatic BMMC accumulation as result of alcohol treatment. a) Livers from ethanol-fed mice will be harvested to examine message expression levels of IL-1b, IL-6, S100A8/A9, HSP72, and COX-2. b) The specific involvement of IL-1b and S100A8/A9 in hepatic accumulation of BMMCs will be investigated by using neutralizing antibodies and IL-1R-/- mice. c) The STAT3hep/- mice will be utilized to examine the role of hepatocyte-specific STAT3 signaling in BMMC accumulation in the liver after alcohol exposure.
(Aim 2), Determine the phenotypes and functions of BMMCs in mild and advanced ALD. a) Chronic feeding of mice with 5% ethanol-containing Lieber-Decarli diet simulates mild ALD. Using this model, we will investigate the function of BMMCs in promoting the repair of alcohol-induced microcirculation disorder, and examine the roles of VEGF and MMPs in mediating such function. The CD11b-DTR mice and anti-Gr-1 antibody will be employed to deplete BMMCs in these studies. b) A hybrid model, in which mice are fed ad libitum with "Western diet" and intragastrically infused with ethanol, shares characteristics of alcoholic steatohepatitis (ASH) and liver fibrosis found in patients with advanced ALD. This model will be employed to examine the phenotype of BMMCs, and investigate their contribution to liver injury.
(Aim 3), Dissect the molecular regulations of BMMC phenotypes in mild and advanced ALD. a) The systemic and hepatic levels of endotoxin and damage-associated molecular pattern (DAMP) molecules will be measured in the hybrid model of ALD. b) The contributions of endotoxin and DAMPs to pro-inflammatory activation of BMMCs and liver damage in the hybrid model will be investigated by administering mice with rifaximin antibiotic, and inhibitors of DAMPs. c) STAT3 activation and STAT1/NF-kB activation in BMMCs associated with mild ALD and ASH, respectively, will be investigated.
Alcoholic liver disease (ALD) affects more than 2 million people in the U.S. Nearly 20 - 30% of alcoholics develop advanced forms of the disease, such as steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma, for which the only effective cure is liver transplantation. Evidence suggests that hepatic macrophages (Macs) play an important role in the progression of ALD. However, research to date has not distinguished resident Macs, Kupffer cells (KCs), from infiltrating bone marrow-derived myeloid cells (BMMCs), which replenish KCs during pathological conditions. The proposed study will be the first to distinguish resident KCs from infiltrating BMMCs and to focus on investigating the role of BMMCs in ALD. We hypothesize that the BMMCs assume different phenotypes and functions, depending on the microenvironment and severity of ALD. This hypothesize will be examined by employing a widely used mouse model of mild ALD and a new model that recapitulates several salient features seen in ASH patients. Successful completion of the proposed project will not only lead to a better understanding of the pathogenesis of ALD but also identification of targets for effective pharmaceutical treatment of the disease.
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