Type beta transforming growth factor reversibly inhibits the early proliferative response to partial hepatectomy in the rat.
Type beta transforming growth factor (TGF-beta), a factor produced by many cell types, is a potent inhibitor of hepatocyte DNA synthesis in vitro. To determine whether TGF-beta can influence hepatocyte proliferation in vivo, its effects were examined on the regenerative response of liver to partial hepatectomy (PH) in the rat. Porcine platelet-derived TGF-beta 1 (0.5 micrograms), administered intravenously at the time of PH and 11 hr later, reduced the fraction of hepatocytes engaged in DNA synthesis 22 hr after PH by 67% and inhibited the rate of hepatic [3H]thymidine incorporation by 50%. TGF-beta 2 produced a similar effect. A single dose of 0.5 micrograms of TGF-beta 1 given 11 hr after PH reduced liver [3H]thymidine incorporation by 32%; 4.5 micrograms of TGF-beta 1 or TGF-beta 2 inhibited DNA synthesis by 88% and the labeling index by 86%. Although sensitive to TGF-beta administered 11 hr after PH, late in the G1 phase of the cell cycle, a single dose of 0.5 micrograms given at the time of PH did not significantly influence DNA synthesis 22 hr after PH. The inhibitory effects of TGF-beta were transient; rats treated with two 0.5-microgram doses of TGF-beta at 0 and 11 hr had completely restored their original liver DNA mass 8 days after PH. Administration of 0.5 microgram of either TGF-beta 1 or TGF-beta 2 every 12 hr for 5 days failed to suppress the recovery of hepatic DNA mass. However, the nuclear labeling index of the TGF-beta-treated animals was significantly higher than that of the controls. There was no evidence of cytotoxicity from TGF-beta, as determined by liver histology and plasma concentrations of glucose, insulin-like growth factor I, and two hepatic enzymes. Thus, TGF-beta 1 and TGF-beta 2 reversibly inhibit the proliferative response of liver to PH and may be important in the modulation of normal liver growth and repair.
Russell
W E
WE
Endocrine-Metabolic Unit of the Children's Service, Massachusetts General Hospital, Boston.
Coffey
R J
RJ
Ouellette
A J
AJ
Moses
H L
HL
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis*; D006133:Growth Substances; D006498:Hepatectomy; D007334:Insulin-Like Growth Factor I / Q000097:blood; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D015291:Transforming Growth Factors
D001786:Blood Glucose; D006133:Growth Substances; D010455:Peptides; D007334:Insulin-Like Growth Factor I; D015291:Transforming Growth Factors; D004247:DNA; D001219:Aspartate Aminotransferases; D000469:Alkaline Phosphatase