Screening for candidate hepatic growth factors by selective portal infusion after canine Eck’s fistula

Abstract

Completely diverting portacaval shunt (Eck's fistula) in dogs causes hepatocyte atrophy, disruption of hepatocyte organelles, fatty infiltration and low-grade hyperplasia. The effect of hepatic growth regulatory substances on these changes was assessed by constantly infusing test substances for four postoperative days after Eck's fistula into the detached left portal vein above the shunt. The directly infused left lobes were compared histopathologically with the untreated right lobes. In what has been called an hepatotrophic effect, stimulatory substances prevented the atrophy and increased hepatocyte mitoses. Of the hormones tested, only insulin was strongly hepatotrophic; T 3 had a minor effect, and glucagon, prolactin, angiotensin II, vasopressin, norepinephrine and estradiol were inert. Insulin-like growth factor, hepatic stimulatory substance, transforming growth factor-α and hepatocyte growth factor (also known as hematopoietin A) were powerfully hepatotrophic, but epidermal growth factor had a barely discernible effect. Transforming growth factor-β was inhibitory, but tamoxifen, interleukin-1 and interleukin-2 had no effect. The hepatotrophic action of insulin was not altered when the insulin infusate was mixed with transforming growth factor-β or tamoxifen. These experiments show the importance of in vivo in addition to in vitro testing of putative growth control factors. They illustrate how Eck's fistula model can be used to screen for such substances and possibly to help delineate their mechanisms of action.Regulation of liver mass and the control of hepatic regeneration are poorly understood and presumably related processes. Hormones, soluble mediators and other substances that can influence hepatocyte size, proliferation or both have been identified with in vitro or in vivo models of testing (1-10). Both test systems are important because no assurance exists that agents with in vitro activity are physiologically important. Moreover, substances with potent physiological activity in the intact animal may be inert when tested in vitro (11).An in vivo canine model of portacaval shunt (Eck's fistula) has been used previously to demonstrate striking hepatotrophic qualities of insulin (3,4), crude (12) and partially purified (13) hepatic stimulatory substance (HSS) in the cytosol of regenerating livers and the immunosuppressive drugs cyclosporine (14) and FK 506 (15). In this study, the same technique has been used to test most other growth factors that have been reported to influence hepatocyte proliferation. Copyright © 1991, MATERIALS AND METHODS Experimental ModelConditioned female beagle dogs weighing 8.3 to 13 kg were anesthetized with intravenous sodium pentobarbital, halothane and nitrous oxide. The experimental model was as described previously (3,4,12,14,15). Side-to-side portacaval shunt was performed and converted to a functional end-to-side shunt by ligation of the portal vein above the anastomosis ( Figure 1A). The main right and left portal veins were isolated, and the right vein w...

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“…HSS protects the liver from the hepatic agent CCl 4 and galactosamine against fibrosis (Gao and Zhou, 2005; Li et al, 2011). The liver regeneration enhancer ALR can inhibit liver atrophy induced by Eck’s fistula (portal vein and inferior vena cava anastomosis) (Rosemurgy et al, 2002; Francavilla et al, 2010; Zeng et al, 2010; Xi et al, 2013). The results of the study showed that these factors can effectively protect the liver from further damage in vivo and improve animal survival by promoting hepatocyte DNA synthesis and liver regeneration.…”

Liver Regeneration in Surgical Animal Models – A Historical Perspective and Clinical Implications

“…Francavilla et al [35] utilized a canine Eck fistula model in 1991, infusing T 3 , glucagon, prolactin, angiotensin II, vasopressin, norepinephrine, estradiol, IGF-II, HSS, TGF-α, HGF (also termed hepatopoietin-A), EGF, TGF-β, tamoxifen, IL-1, IL-2 and insulin into one of the detached portal vein branches above the shunt [35]. Insulin and partly T 3 , IGF-II, HSS, TGF-α and HGF inhibited liver atrophy.…”