Increased inflammation in the liver is an important contributor to liver alcoholic liver disease (ALD). Kupffer cells, the resident macrophages in the liver, are particularly critical to the onset of ethanol-induced liver injury, producing a variety of inflammatory mediators, such as tumor necrosis factor-1 (TNF-1), that contribute to hepatocyte dysfunction, necrosis and apoptosis, as well as fibrosis. While many studies have documented a sensitization to pro-inflammatory signals in ALD, it is also likely that impaired resolution of the inflammatory process contributes to ALD. The resolution of inflammation is an active, highly coordinated response that can potentially be manipulated via therapeutic interventions to treat chronic inflammatory diseases. We have recently characterized a hemeoxygenase-1 (HO-1)/carbon monoxide (CO)-dependent pathway that is profoundly effective at decreasing chronic ethanol-induced inflammatory responses in primary cultures of Kupffer cells. Importantly, we find that induction of HO-1/CO also reduces inflammatory responses and hepatocellular apoptosis in an in vivo mouse model of chronic ethanol exposure. Therefore, the major objective of this proposal is to investigate the molecular mechanisms for the effective anti-inflammatory and anti-apoptotic effects of HO-1 in the liver after chronic ethanol exposure and to leverage these insights into the design of pre-clinical studies in mice to prevent and/or treat ethanol-induced liver injury.
In Specific Aim 1, we will make use of primary cultures of Kupffer cells to determine the molecular mechanisms for these anti-inflammatory effects of HO-1, indentifying the down-stream mediators and molecular targets of HO-1 activity.
In Specific Aim 2, we will interrogate the interactions between gut, liver and adipose in the protective effects of HO-1/CO in a pre-clinical in vivo model of ethanol-induced liver injury in mice. Here we will test the hypothesis that induction of HO-1 expression and/or the release of CO from CO- releasing molecules (CORMs) has pleiotropic protective effects on intestine and adipose tissue, as well as the composition of the immune cell "signature" in the liver. We hypothesize that this integrated physiological response to HO-1/CO culminates in protection from ethanol-induced liver injury. In mechanistic studies, we will determine the contribution of HO-1 expression by bone marrow vs stromally derived cells on ethanol-induced inflammation and hepatocyte apoptosis. Understanding the cellular targets of HO-1/CO will facilitate the rational design of therapeutic interventions for ethanol-induced liver injury. The studies carried out within our proposed studies will facilitate the development of therapeutic agents to regulate HO-1/CO-regulated pathways will enhance the resolution of inflammation during ALD.

Public Health Relevance

Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. The long-term goals of this research project are to investigate the mechanisms by which ethanol exacerbates inflammation in the liver. In this application, we will focus on investigating the anti-inflammatory effects of heme oxygenase-1 and carbon monoxide. Identification of anti- inflammatory pathways that are effective after alcohol exposure will provide the foundation for the future development of rationally designed therapeutic interventions to slow and/or reverse alcoholic liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA019673-02
Application #
8317548
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Radaeva, Svetlana
Project Start
2011-08-10
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$353,250
Indirect Cost
$128,250
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Bakhautdin, Bakytzhan; Das, Dola; Mandal, Palash et al. (2014) Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice. J Hepatol 61:1029-37