rodents, 2,3,9 and formation of pathological lesions in rodents 4,5 tion, suggesting that it inhibits a critical step common to different forms of inflammation. We showed previously and humans, [11][12][13][14] demonstrate that quasiclonal or truly clonal proliferation of hepatocytes leading to lineage clustering is a that a-MSH inhibits nitric oxide (NO) production in cultured macrophages. To determine how a-MSH acts in prototypical pattern. Quasiclonal or fractal proliferation of hepatocytes occurring uniformly throughout the liver allows vivo, we induced acute hepatic inflammation by administering endotoxin (LPS) to mice pretreated with Coryne-rapid replacement of the original tissue pattern (as after partial hepatectomy). In contrast, focal, unevenly distributed, bacterium parvum a-MSH prevented liver inflammation even when given 30 min after LPS administration. To quasiclonal or clonal proliferation of hepatocytes appears to underlie the development of the wide variety of pathological determine the mechanisms of action of a-MSH, we tested its influence on NO, infiltrating inflammatory cells, cyto-nodular lesions that affect the liver. True clonality of some or all of these lesions also provides a cellular pathway that kines, and chemokines. a-MSH inhibited systemic NO production, hepatic neutrophil infiltration, and in-may link neoplasms and preneoplastic precursor cells. Availability of methods of genomic tagging, both experimental (us-creased hepatic mRNA abundance for TNFa, and the neutrophil and monocyte chemokines (KC/IL-8 and ing engineered retroviral constructs) and naturally occurring (from chronic infection with HBV), will ultimately enable a MCP-1). We conclude that a-MSH prevents LPS-induced hepatic inflammation by inhibiting production of che-more complete understanding of hepatocyte lineages and of the genesis of various pathological nodular lesions.
moartractant chemokines which then modulate infiltration of inflammatory cells. Thus, a-MSH has an effect very early in the inflammatory cascade.