The major function of liver sinusoidal endothelial cells (SECs) is in host defense and homeostasis via their so-called """"""""scavenger"""""""" function whereby they recognize, internalize and degrade a variety of extracellular matrix components and modified proteins. In fact, recent reports from our laboratory have shown that a variety of aldehyde modified proteins are removed by SECs, including the recently described malondialdehyde-acetaldehyde adduct (MAA). Preliminary data have demonstrated that a family of receptors, commonly known as scavenger receptors, appears to mediate the biological functions of SECs in response to MAA-modified proteins. Under normal conditions, MAA-modified proteins bind to scavenger receptors on SECs and are degraded. However, following chronic ethanol consumption, it has been shown that there is a 50-60% decrease in the degradation of these adducts. Thus, we hypothesize that following chronic ethanol consumption, MAA-modified hepatocyte proteins are released into the surrounding tissues. The receptor(s) that bind these MAA-modified proteins are altered with respect to the level of cell activation, the number of receptors bound, the types of receptors bound, and the ability of the SECs to respond. This results in the stimulation of pro-inflammatory and pro-fibrotic responses that may play a prominent role in the development and/or progression of alcoholic liver disease (ALD). Therefore, the principal objective of this research project is to better define and characterize the receptor(s) on SECs responsible for the binding of MAA modified proteins, and determine the effects of chronic ethanol consumption on their normal biological functions. Initial studies will begin to delineate the receptors that bind MAA modified proteins using molecular and immunological techniques. Further in vitro studies will attempt to determine the mechanism(s) by which SECs are activated through the identified scavenger receptors to produce pro-inflammatory and pro-fibrotic responses. Finally, studies will be initiated to assess the effects of the binding of MAA-modified proteins to different receptors on SECs and result in the initiation of antigen-driven immune responses. Thus, these studies will continue to investigate the role of SECs, MAA-modified proteins, and chronic ethanol consumption in the development and/or progression of the inflammatory and fibrotic responses observed in ALD. ? ? ?
