The sympathetic nervous system promotes carbon tetrachloride-induced liver cirrhosis in rats by suppressing apoptosis and enhancing the growth kinetics of regenerating hepatocytes.
Norepinephrine is considered to possess potent anti-apoptotic action in regenerating hepatocytes. To clarify the role of the sympathetic nervous system in apoptosis that occurs in chronic liver damage and following the promotion of liver cirrhosis, we studied a carbon tetrachloride (CCl4)-induced liver injury model, using spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), and chemically sympathectomized WKY. At 24 h after CCl4 administration. acute damage, characterized by vacuolated hepatocytes in the centrilobular zone, was greater in SHR than in WKY. This vacuolated change in WKY hepatocytes was significantly reduced by chemical sympathectomy with 6-hydroxydopamine (6-OHDA). After 48 h, the acute damage was dramatically improved in each animal, without significant differences between the three groups. In chronic damage after weekly repetition of CCl4 treatment for 4 weeks, fibrosis was evident in SHR, while in the other groups there was only scant fibrosis in the centrilobular zone. After 8 weeks' repetition of CCl4, liver cirrhosis was seen only in SHR. The incidence of apoptotic cells in areas of both acute and chronic damage in WKY, detected by terminal deoxynucleotidyl transferase-dUTP nick end labeling, was significantly increased in comparison with that in SHR, and was further increased by 6-OHDA pretreatment. In contrast, there was significantly greater enhancement of the growth of hepatocytes in SHR than in WKY in both acute and chronic damage. Moreover. hepatocyte growth kinetics in WKY was significantly inhibited after sympathectomy in acute injury, as evidenced by immunohistochemistry for proliferating cell nuclear antigen (PCNA). In vitro, the amount of hepatocellular apoptosis induced by transforming growth factor-beta1 was significantly decreased by incubation with norepinephrine. These findings suggest that the anti-apoptotic effect of the sympathetic nervous system increases cell growth kinetics and promotes liver cirrhosis in this animal model.
Department of Molecular Pathology, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Japan.
K
K
Hamasaki
M
M
Nakashima
S
S
Naito
Y
Y
Akiyama
A
A
Ohtsuru
Y
Y
Hamanaka
C T
CT
Hsu
M
M
Ito
I
I
Sekine
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002251:Carbon Tetrachloride; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002455:Cell Division; D022781:Hepatocytes / Q000166:cytology*; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000473:pathology*; D008115:Liver Regeneration; D008297:Male; D023421:Models, Animal; D009638:Norepinephrine / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013562:Sympathectomy; D013564:Sympathetic Nervous System / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured
D018809:Proliferating Cell Nuclear Antigen; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D002251:Carbon Tetrachloride; D009638:Norepinephrine