Mechanisms of Endotoxin-driven Artherosklerosis

Atherosclerosis is a chronic inflammation of the vascular wall, which progression has been correlated to microbial infection and activation of the innate immune system. Endotoxin (LPS) from gram negative bacteria is one potent stimulator of this system via recently discovered Toll-like receptors (TLR). Preliminary data from our lab suggest that lipopolysaccharide binding protein (LBP), which serum levels are elevated upon infection, is actively transporting LPS into endothelial cells and presumably into atherosclerotic lesions. Since atherosclerotic plaques are typically found at sites of turbulent blood flow, we will investigate LPS-uptake mechanisms in human and murine endothelial cells under static and flow conditions in vitro and in mouse models in vivo. Experiments will also include other TLR ligands. Finally, the effects of microbial products on the initiation and propagation of atherosclerosis will be investigated in mice with deficiencies at distinct levels of the innate immune system (knockout mice). By determining whether mediators of innate immunity have roles in the chronic inflammation of atherosclerosis, we will significantly broaden our basic understanding of this aspect in vascular biology and may also uncover the potential role of selective inhibitors of these pathways. Inasmuch as atherosclerosis continues to be a serious medical problem, novel approaches to its treatment are necessary.