Improvement in liver fibrosis, functionality and hemodynamics in CCI4-cirrhotic rats after injection of the Liver Growth Factor.
OBJECTIVE
Most substances used in experimental models of cirrhosis are chosen either as protectors of lipid peroxidation, as antifibrogenic agents or as vitamins, among others. In this report, we analyze the improvement produced, in established cirrhosis (CCl4 plus phenobarbital) in rats, by intraperitoneal injection of Liver Growth Factor, a hepatic mitogen with activity both in vivo and in vitro.


METHODS
Following confirmation of CCl4-induced cirrhosis, Liver Growth Factor (4.5 microg per ratx2 injections/week for 3 weeks) was administered to one group of rats (Cirr+LGF). The remaining rats (Cirr) received saline. The groups were compared in terms of serum enzymes, tissue damage, total liver collagen, collagenase activity, microsomal enzyme activities, splanchnic and systemic hemodynamics and portosystemic shunting.


RESULTS
Treatment of rats presenting CCl4-induced cirrhosis with Liver Growth Factor decreased serum aminotransferase levels and increased levels of serum albumin and total protein. The Liver collagen content was lower in rats treated with Liver Growth Factor (2.96 vs. 4.32 mg/g liver, p<0.01). Microscopic studies revealed that the livers of rats receiving Liver Growth Factor showed decreases in fibrosis, necrosis and inflammatory infiltration, as well as a recovery of architectural integrity. Liver function was improved after treatment with Liver Growth Factor, as indicated by the rate constant for elimination of aminopyrine, which increased from 0.0063 to 0.0170 (p<0.05). This increase was accompanied by a higher total amount of cytochrome P-450 as well as of certain P-450 isoenzymes, especially those that are hormone-dependent, such as P-450 3A. The improved liver histology and function observed in Cirr+LGF rats was associated with decreases in portal pressure (14.4 vs. 9.4 mm Hg, p<0.01) and portosystemic shunting (55.8 vs. 11.5%, p<0.01), as well as increases in mean arterial pressure and systemic vascular resistance, and a reduction in ascites.


CONCLUSIONS
Administration of the hepatic mitogen, Liver Growth Factor, to CCl4-cirrhotic rats decreased liver collagen and reorganized the hepatic extracellular matrix, resulting in an improvement in liver function, reduced portal pressure and amelioration of ascites.
Laboratorio de Hepatología Experimental (Servicio de Bioquímica Experimental), Clínica Puerta de Hierro, Madrid, Spain.
J J
JJ
Díaz-Gil
J
J
Muñoz
A
A
Albillos
C
C
Rúa
C
C
Machín
R
R
García-Cañero
R M
RM
Cereceda
M C
MC
Guijarro
C
C
Trilla
P
P
Escartín
D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D001663:Bilirubin / Q000008:administration & dosage / Q000494:pharmacology*; D001798:Blood Proteins / Q000032:analysis; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D003094:Collagen / Q000032:analysis; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D006133:Growth Substances / Q000008:administration & dosage / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D007249:Inflammation; D007274:Injections, Intraperitoneal; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D009336:Necrosis; D011168:Portal System / Q000502:physiology; D011170:Portasystemic Shunt, Surgical; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000008:administration & dosage / Q000032:analysis / Q000494:pharmacology*; D000075462:Serum Albumin, Human; D000637:Transaminases / Q000097:blood
D001798:Blood Proteins; D006133:Growth Substances; D012709:Serum Albumin; C053498:albumin-bilirubin complex; D000632:Aminopyrine; D003094:Collagen; D003577:Cytochrome P-450 Enzyme System; D000637:Transaminases; D001663:Bilirubin; D000075462:Serum Albumin, Human