Another abstract; I'll stop when you say when. In any case, from the material below I think it is possible to see several steps where blocking a signal or two may interfere with disease progress. I also think the step-by-step summary below connects the "biologist's view" (e.g. that implicit in MLNM press release) and the "standard" view.
Diabetes Res Clin Pract 30 Suppl: 1-11 (Feb 1996)
Cellular mechanisms in the development of atherosclerosis.
Rosenfeld ME
Department of Pathobiology, University of Washington, Seattle 98195, USA.
Morphologic and immunocytochemical studies of hypercholesterolemic animal models have now clearly established the chronological patterns of cellular interactions that occur during the initial and transitional phases of the atherogenic process. These include: adherence of leukocytes to the endothelial surface, chemotactic attraction of the leukocytes into the arterial intima, conversion of monocytes to foam cells, stimulation of smooth muscle cell migration, connective tissue synthesis and proliferation, inflammatory and immune activation of macrophages and T lymphocytes, and the necrosis or apoptosis of cells within the developing lesions. Recent studies have begun to provide-mechanistic explanations for these observed cellular events. For example, the adherence of leukocytes to the endothelium appears to be dependent on the increased expression of adherence molecules by endothelial cells. The formation of foam cells is likely dependent on an increase in the expression of modified lipoprotein receptors. An increase in the migration and proliferation of macrophages, T lymphocytes, and smooth muscle cells appears to be in response to the inflammatory activation of cells with a resulting increase in the secretion of cytokines, chemoattractants, and growth regulatory molecules. However, it is still unclear how cells within atherosclerotic lesions initially become activated and whether there are common stimulatory factors. In this regard, immunocytochemical staining of human and rabbit lesions with antibodies recognizing oxidation-specific epitopes suggests that many of the cells involved in these key events in the atherogenic process contain these lipid-protein adducts and that it is these products of oxidation that activate the cells. Furthermore, we have also recently demonstrated that components of oxidized LDL maximally induce the production of IL-1 by macrophage-derived foam cells. These observations suggest that there may be a common intracellular signal transduction pathway that is responsive to oxidative mechanisms and which underlies some of the key cellular events in the atherogenic process. |
