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Summary The cause of chronic rejection is clearly multifactorial and relates to both immunologic and nonimmunologic factors. Most likely, the final effector molecules are the growth factors expressed, in response to immune injury, by endothelial and vascular SMCs. Many of the known growth factors may interact in this process. Several studies show a significant role of IGF-I, PDGF-BB, TGF-β, aFGF, bFGF, EGF, and VEGF, concomitantly with the induction of intimal SMC proliferation and intimal thickening. Our results suggest that the IGF-I ligand and receptor genes are rate limiting in smooth muscle proliferation in the development of transplant arteriosclerosis. Blocking growth factor ligands or receptors could be effective strategies for the prevention or treatment of transplant arteriosclerosis. We consistently find chronic estradiol treatment of transplant recipients to inhibit arteriosclerosis by attenuating both IGF-I expression and immune response, particularly MHC class II expression. Thus an estrogen with minimal feminizing properties like Raloxifen (Eli Lilly, Indianapolis, IN) may be an ideal drug for prevention of one of the major causes of loss of transplant function. |
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