THE LIPID-PEROXIDATION END-PRODUCT 4-HYDROXY-2,3-NONENAL UP-REGULATESTRANSFORMING-GROWTH-FACTOR BETA-1 EXPRESSION IN THE MACROPHAGE LINEAGE - A LINK BETWEEN OXIDATIVE INJURY AND FIBROSCLEROSIS

An increasing number of reports underscore the frequent association of fibrosclerotic diseases of lung, liver, arterial wall, brain, etc., w ith the accumulation of oxidatively modified lipids and proteins. A ca use-and-effect relationship has been proposed between cellular oxidati ve damage and increased fibrogenesis based on the fact that experiment al treatment with antioxidants either prevents or quenches the fibroti c process. With some peculiarities in the different organs, fibroscler osis is essentially the result of the interaction of macrophages and e xtracellular matrix-producing cells. The cross-talk is mediated by fib rogenic cytokines, among which the most important appears to be transf orming growth factor beta 1 (TGF-beta 1). This report describes treatm ent of different types of macrophage, of both human and murine origin, with 4-hydroxy-2,3-nonenal (HNE) a major aldehyde end product of memb rane lipid oxidation found consistently to induce both mRNA expression and synthesis of TGF-beta 1. Since increased HNE levels have been dem ostrated in the cirrhotic liver and in the oxidatively modified low-de nsity human lipoproteins associated with atherosclerosis, the up-regul ation of macrophage TGF-beta 1 by HNE appears to be involved in the pa thogenesis of these and similar diseases characterized by fibroscleros is.