Osório Miguel Parra

Enhancement of liver size by stimulation of intact rat liver with exogenous hepatotrophic factors

In mammals, liver size is related to animal body weight at the 2.5 to 3% proportion, a ratio mediated by the afflux of hepatotrophic factors. Formulas capable of modifying this ratio have been developed in previous studies on the rat, with enhancement of liver size brought about by intraperitoneal (portal) infusion of exogenous factors such as glucose, amino acids, insulin, glucagon, vitamins, electrolytes, and triiodothyronine. However, the efficacy of these formulations was accompanied by increased animal mortality (PARRA et al.). The present study, which was carried out with small methodological modifications on a larger number of rats using daily intraperitoneal injections of a solution of exogenous hepatotrophic factors (40 ml/kg) for seven days, confirms the previous findings, with a 114.16 +/- 7.90% enhancement of liver size beyond the expected value for the body weight of the animal. However, the problem of animal mortality was not fully resolved.

Experimental studies on the response of the fish ( Notothenia coriiceps Richardson, 1844) to parasite ( Pseudoterranova decipiens Krabbe, 1878) and other irritant stimuli at Antarctic temperatures

Abstract In order to better understand the immune response of Notothenia coriiceps to Pseudoterranova decipiens larvae and other irritant stimuli, we implanted a catgut suture thread, killed P. decipiens larvae and macerated P. decipiens larvae in the hepatic and muscle tissues of the fish. The response varied according to the tissue concerned and the extent of the lesion. The most noticeable immune response occurred with the implant of parasite larvae macerate in the liver, which indicates immunological memory, since all the captured fish were found infected with P. decipiens. An intense response also occurred after macrophages had infiltrated the cuticle of the implanted dead parasite in the liver, which confirms that the cuticle acts as a physical barrier to the immune system. Nevertheless, the immune response of N. coriiceps does not appear able to eliminate the infection and the fish in nature appear to suffer no adverse clinical effects.

Hepatotrophic factors reduce hepatic fibrosis in rats

CONTEXT Hepatic fibrosis occurs in response to several aggressive agents and is a predisposing factor in cirrhosis. Hepatotrophic factors were shown to stimulate liver growth and to restore the histological architecture of the liver. They also cause an improvement in liver function and accelerate the reversion of fibrosis before it progresses to cirrhosis. OBJECTIVE To test the effects of hepatic fibrosis solution composed by amino acids, vitamins, glucose, insulin, glucagon and triiodothyronine on hepatic fibrosis in rats. METHODS Fibrosis was induced in rats by gastric administration of dimethylnitrosamine (10 mg/kg) for 5 weeks. After liver biopsy, the rats received either hepatotrophic factors solution (40 mg/kg/day) or saline solution for 10 days by intraperitoneal injection. Blood samples and liver fragments were collected for hepatic function analysis, standard histopathology evaluation, and morphometric collagen quantification. RESULTS Rats in the hepatotrophic factors group showed a decrease of the histopathological components of fibrosis and an increase of their hepatic mass (12.2%). There was no development of neoplasic lesions in both groups. Compared with the saline group, the hepatotrophic factors group also had a decrease of blood levels of hepatic-lesion markers (AST, ALT) and a decrease of collagen content in the portal spaces (31.6%) and perisinusoidal spaces (42.3%), as well as around the hepatic terminal vein (57.7%). Thus, hepatotrophic factors administration in the portal blood promoted a regenerative hepatic response, with an overall reduction of the volumetric density of collagen, improved hepatic function, and a general improvement in the histopathological aspects of fibrosis. CONCLUSION Taken together, these results suggest the potential therapeutic use of this hepatotrophic factors solution to treat chronic liver diseases.

Parenteral Solution of Nutritional Hepatotrophic Factors Improves Regeneration in Thioacetamide-induced Cirrhotic Livers after Partial Hepatectomy

Liver resection is a suitable option for the treatment of certain hepatic conditions, particularly hepatocarcinomas, in patients with cirrhosis. However, this disease impairs liver regeneration, which increases the risk of liver failure and postoperative death. Supportive treatments for regeneration of the remaining liver may be useful for the recovery of these patients. We demonstrated that nutritional hepatotrophic factors (NHF) is an effective regenerative stimulus for cirrhotic livers in rats subjected to partial hepatectomy (PH). The rats with thioacetamide-induced cirrhosis were subjected to PH, and they were divided into 2 groups. One group received intraperitoneal administration of NHF, and the other group received saline solution. After 12 days, biometric data, collagen content, hepatocyte regeneration (proliferation cell nuclear antigen immunochemistry), and profibrotic gene expression (Collagen-α1, matrix metalloproteinase 2, tissue inhibitor of metalloproteinase 1, and transforming growth factor beta 1) were assessed. The results indicated that the rats treated with NHF after PH had an increased liver size, a reduced amount of collagen, and a higher hepatocyte proliferation index compared with the rats that underwent PH alone. In addition, collagen-α1 gene expression was decreased in the NHF-treated rats. Thus, postoperative improvement in the liver morphology following NHF treatment may cause a significant decrease in the risk of liver failure and mortality after hepatic resection.

Fatores hepatotróficos e regeneração hepática. Parte II: fatores de crescimento

Several identifyed substances are involved with liver proliferative process, somatomedines (growth factors) among them. The most of them show different actions, stimulating or inhibiting cell division, depending on their concentrations. The following factors play important role on the liver: HGF; EGF; TGF-alpha; TGF b ; Interleucin-6; IGF; FGF; VEGF; KGF; HSS e ALR. The combined action of HGF, TGF-alpha, IL-6, TNF-alpha, norepinephrin and EGF, allows insulin, glucagon and also EGF to express their effects. HGF seems to be essential and constitutes, maybe, the main trigger of this process, generating endocrine signal wich strongly ativates mitogenesis in the hepatocytes primmed by EGF, IL-6, insulin, remainig matrix matriz and others, leading to DNA synthesis. EGF probably participates of initial events imediately after partial hepatectomy. Besides their actions upon the liver, FGF, VEGF and KGF propably play role in the tissue recovering processes.

Fatores hepatotróficos e regeneração hepática. Parte I: o papel dos hormônios

No complexo processo de proliferacao celular, os hormonios agem de diferentes maneiras ao atingirem seus receptores nos tecidos-alvo. Os principais fatores ligados ao crescimento hepatico sao HGF, TGF-alpha, IL-6, TNF-alpha, norepinefrina, EGF e insulina. O GH estimula tanto o figado a produzir fatores de crescimento, como a expressao genetica do HGF e a sintese de DNA. Hormonios tireoideanos aumentam a capacidade proliferativa dos hepatocitos. A insulina age sinergicamente com GH e glucagon. Nao tem potencial mitogenico primario mas intensifica o estimulo regenerativo iniciado pela epinefrina e norepinefrina. Esta amplifica os sinais mitogenicos do EGF e HGF, induz a secrecao de EGF e antagoniza os efeitos inibitorios do TGF-beta 1. O glucagon isoladamente nao produz efeitos mas provavelmente participa na sintese de DNA e da resposta homeostasica pela qual a glicemia e mantida estavel durante a regeneracao. Tambem ha indicios de acao hepatotrofica da gastrina.

Modelo de suplementação nutricional com fatores hepatotróficos aumenta proliferação celular em fígado de ratos sadios

ABSTRACT Two protocols of hepatotrophic factors (HF) administration, in solution composed by aminoacids, vitamins, mineral salts, glucose, insulin, glucagon, and triiodothyronine were evaluated in healthy rats. This solution was administered for 10 days, (40mg/kg/day) i.p., in two (group 2xFH; n=15) or three daily doses (group 3xFH n=15). The effects on hepatocytes cell proliferation, angiogenesis, and hepatic extracellular matrix, and also possible adverse reactions were analyzed. Animals of groups 2xFH and 3xFH presented an increase in hepatic mass of 30.1% and 22.5%, respectively, when compared rats of control group (CT; n=15). Hepatocellular proliferation index was higher in rats of groups 2xFH (1.4%) and 3xFH (1.2%) when compared to CT group animals (0.53%), and the relative densitometry of the vascular endothelial growth factor analyzed with immunoblot did not show a significant difference among the three groups. Rats of groups 2xFH and 3xFH showed a reduction of interstitial collagen when compared to CT rats. HF solution stimulated hepatic growth and reduced the volume of perisinusoidal collagen. Administration in three daily doses resulted in 26.7% mortality, possibly due to excessive stress from manipulation and lower physiological adaptation of rats, which did not occur in rats of groups 2xFH and CT. The more appropriate and safer experimental procedure for this approach in rats with higher chance of animal adaptation and significant results is the application of HF in two daily doses. Keywords: rat, collagen, hepatotrophic factors, experimental model, parenteral nutrition