Hepatic regeneration and growth factors

Francavilla, A.; Polimeno, Lorenzo; Barone, M.; Azzarone, Alessandro; Starzl, Thomas E.

doi:10.1002/jso.2930530503

Cited by 34 publications

(26 citation statements)

References 28 publications

(43 reference statements)

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“…7,8 On the other hand, the present findings confirm that, in vivo, UDC does not act as an initiator of hepatocyte proliferation but operates as an augmenter. 24 In this case, hepatocyte HBV-related protein accumulation represents the event that triggers proliferation that, in turn, is susceptible to amplification by UDC.…”

Section: Discussionmentioning

confidence: 99%

Influence of ursodeoxycholate-enriched diet on liver tumor growth in HBV transgenic mice

Barone¹,

Maiorano

Ladisa³

et al. 2003

Hepatology

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Hepatitis B virus (HBV) transgenic mice (official designation, Tg [Alb-1 HBV] Bri 44) invariably develop macroscopically evident tumors within the 20th month of life. Sustained proliferative activity seems to play an important role in the development of these lesions. We previously showed that ursodeoxycholate (UDC) stimulates hepatocyte proliferation in various experimental settings. Herein, we tested the assumption that biological factors able to further increase liver cell proliferation, such as UDC, could accelerate tumor development in this animal model. For this study, 22 eight-week-old male transgenic mice were divided into 2 groups; 11 animals received a standard diet, and 11 received a UDC-enriched diet. The 2 groups were further divided into 2 subgroups of 5 and 6 animals each and were sacrificed at 3 and 15 months of age, respectively. These different times were chosen to exclude diet-related toxicity (in 3-month-old mice) and evaluate tumor growth (in 15-month-old mice). In addition, hepatocyte proliferation was assessed in all animals. In 3-month-old mice receiving UDC, cholestatic and cytolytic indices as well as liver histology were comparable to those in controls. At 15 months, all UDC-treated mice showed large multinodular tumors whereas only 33% of controls developed smaller uninodular neoplasms. Hepatocyte proliferation was increased in all animals receiving UDC compared with controls. In conclusion, the increase in serum UDC (undetectable in mice fed a standard diet), in the absence of any toxic effect on the liver, suggests the involvement of this bile salt in the stimulation of hepatocyte proliferation and tumor growth. (HEPATOLOGY 2003;37:880-886.) T ransgenic mice with hepatitis B virus (HBV) sequences encoding for viral proteins pre-S, S, and X (official designation, Tg [Alb-1 HBV] Bri 44) develop progressive hepatocyte damage due to intracellular accumulation of these proteins. 1-5 During the first months of life, the hepatic damage consists of degenerative alterations. 2 Later, an active inflammatory response commences that induces a marked damage-related compensatory proliferative reaction. 3,5 Such a condition should be considered precancerous because it is constantly followed after the 8th to 9th month of life by the development of dysplastic hepatic lesions 3,4 that progress to overt liver cancer after the 12th month of life. 3 The progressive growth of these neoplastic lesions leads to macroscopic nodules that are invariably observed in all transgenic mice within the 20th month of life. 4 Interestingly, these transgenic mice, harboring hepatocellular carcinomas, do not manifest any specific alteration of known oncogenes or tumor suppressor genes at any stage of neoplastic transformation. 6 It has therefore been suggested that the damage-related sustained proliferative activity observed in the liver of these animals could play an important role in tumor development. 5 We have already shown that bile salts can stimulate proliferation in cultured hepatocytes and augment the regene...

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Section: Discussionmentioning

confidence: 99%

Influence of ursodeoxycholate-enriched diet on liver tumor growth in HBV transgenic mice

Barone¹,

Maiorano

Ladisa³

et al. 2003

Hepatology

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“…24 Because HSS activity was not species-restricted, 8,25 and was so precisely measurable, increasingly purified rat HSS could be identified with certainty with a single canine Eck fistula experiment. 8,[25][26][27] Eventually, the peptide purified from HSS was renamed augmenter of liver regeneration (ALR) 8 and cloned. 28,29 The cDNA for rat ALR encodes a protein containing 198 amino acid residues and has a molecular weight of about 22 kd.…”

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confidence: 99%

A fresh look at augmenter of liver regeneration in rats

et al. 1999

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Augmenter of liver regeneration (ALR) is a hepatotrophic protein originally identified by bioassay in regenerating rat and canine livers following partial hepatectomy and in the hyperplastic livers of weanling rats, but not in resting adult livers. The ALR gene and gene product were subsequently described, but little is known about the cellular/subcellular sites of ALR synthesis in the liver, or about the release and dissemination of the peptide. To obtain this information in rats, we raised antibodies in rabbits against rat ALR for development of an enzyme-linked immunosorbent assay (ELISA). ALR concentrations were then determined in intact livers of unaltered weanling and adult rats; in regenerating residual liver after partial hepatectomy; in cultured hepatocytes and nonparenchymal cells (NPCs); and in culture medium and serum. ALR in the various liver cells was localized with immunohistochemistry. In addition, hepatic ALR and ALR mRNA were assayed with Western blotting and reversetranscriptase polymerase chain reaction (RT-PCR), respectively. The hepatocyte was the predominant liver cell in which ALR was synthesized and stored; the cultured hepatocytes secreted ALR into the medium in a timedependent fashion. Contrary to previous belief, the ALR peptide and ALR mRNA were present in comparable concentrations in the hepatocytes of both weanling and resting adult livers, as well as in cultured hepatocytes. A further unexpected finding was that hepatic ALR levels decreased for 12 hours after 70% hepatectomy in adult rats and then rose with no corresponding change in mRNA transcripts. In the meantime, circulating (serum) ALR levels increased up to 12 hours and declined thereafter. Thus, ALR appears to be constitutively expressed in hepatocytes in an inactive form, and released from the cells in an active form by unknown means in response to partial hepatectomy and under other circumstances of liver maturation (as in weanling rats) or regeneration. (HEPATOLOGY 1999;29:1435-1445.)The control of hepatic growth and regeneration has interested experimentalists for much of the 20th century. 1 Soon after the classical description in 1931 by Higgins and Anderson 2 of liver regeneration in rats following 70% hepatectomy, a search began for growth factors within the liver itself. McJunkin and Breuhaus 3 observed that the modest mitotic response to a 30% to 40% hepatectomy in rats was enhanced with an intraperitoneal injection 2 days postoperatively of homogenized homologous rat liver. Two decades later, Teir and Ravanti 4 and Blomquist 5 noted that this ''augmentation'' effect was demonstrable only when the injected homogenates were prepared from regenerating liver fragments following hepatectomy or from weanling rat livers that have a naturally heightened mitotic index. Subsequently, LaBrecque and Pesch 6 reported the same prerequisite of a hyperplastic liver source for cytosol extracts containing a putative ''hepatic stimulatory substance'' (HSS).Importantly, however, a cocondition for demonstrating a mitosis-augmenting a...

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“…In contrast to these results obtained by the whole animal treatment, the three molecules had no effect on NK cell functions when added to cultures of MNL from the livers, spleens, or blood of untreated rats. These data support and extend our previously advanced hypothesis that ALR and other hepatotrophic factors play an important role in liver regeneration by regional regulation of NK cells through some as-yet-unknown intermediary mechanism.Hepatotrophic factors (Table 1) have been so characterized [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] by virtue of their ability to augment the hyperproliferative response induced by partial hepatectomy (PH) in rats 3,6 or dogs, 5 and to prevent the atrophy as well as augment the heightened cell renewal caused by portacaval shunt (Eck's fistula) in dogs. 2,4 Only two of the eight known hepatotrophic factors (hepatocyte growth factor [HGF] and transforming growth factor [TGF]-α) are primary mitogens capable of stimulating de novo hepatocyte proliferation in vitro without the requisite precondition of preexisting commitment to heightened cell renewal.…”

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confidence: 99%

The in vivo effect of hepatotrophic factors augmenter of liver regeneration, hepatocyte growth factor, and insulin-like growth factor-II on liver natural killer cell functions

Francavilla

1997

Hepatology

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Fine balanced sequential changes of the levels of circulating hepatotrophic factors are essential for normal liver regeneration. Our recent studies have indicated that liver-resident natural killer (NK) cells are important regulators of liver regeneration and have raised the possibility that hepatotrophic factors might mediate their activities through NK cells. In the present study, we assessed the effects of in vivo administration of three hepatotrophic factors (augmenter of liver regeneration [ALR], insulin-like growth factor-II [IGF-II], and hepatocyte growth factor [HGF]) on NK cells in normal rats. Each of the three, given over a 1-day period in doses known to produce hepatotrophic activity, induced inhibition of NK cell cytotoxic activities in the population of mononuclear leukocytes (MNL) in the liver, but not in MNL from the spleen or peripheral blood. In contrast to these results obtained by the whole animal treatment, the three molecules had no effect on NK cell functions when added to cultures of MNL from the livers, spleens, or blood of untreated rats. These data support and extend our previously advanced hypothesis that ALR and other hepatotrophic factors play an important role in liver regeneration by regional regulation of NK cells through some as-yet-unknown intermediary mechanism.Hepatotrophic factors (Table 1) have been so characterized [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] by virtue of their ability to augment the hyperproliferative response induced by partial hepatectomy (PH) in rats 3,6 or dogs, 5 and to prevent the atrophy as well as augment the heightened cell renewal caused by portacaval shunt (Eck's fistula) in dogs. 2,4 Only two of the eight known hepatotrophic factors (hepatocyte growth factor [HGF] and transforming growth factor [TGF]-α) are primary mitogens capable of stimulating de novo hepatocyte proliferation in vitro without the requisite precondition of preexisting commitment to heightened cell renewal. Molecules with opposite effects have been called "antihepatotrophic." [16][17][18] After PH, there is an acute temporary increase in the circulating levels of several of the endogenous hepatotrophic factors 1,2,4,5,19 and multiple gene expression in the liver. 20 have speculated that the hepatocyte stimulatory activity of augmenter of liver regeneration (ALR) and the other hepatotrophic factors may be mediated through or by nonparenchymal cells. 1,9,21 This possibility was reinforced by the observation during the acute phase of regeneration after PH in rats of temporary suppression of natural killer (NK) cell functions of liver mononuclear leukocytes (MNL), followed by their recovery at the termination of regeneration. 21 These changes occurred contemporaneously with mirror-image susceptibility of the regenerating hepatocytes to NK-induced lysis.To test this immunologic hypothesis, we have determined in the present study whether the changes of NK cell function occurring after PH could be reproduced in unoperated naive rats by their treatment with three pot...

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Hepatic regeneration and growth factors

Cited by 34 publications

References 28 publications

Influence of ursodeoxycholate-enriched diet on liver tumor growth in HBV transgenic mice

Influence of ursodeoxycholate-enriched diet on liver tumor growth in HBV transgenic mice

A fresh look at augmenter of liver regeneration in rats

The in vivo effect of hepatotrophic factors augmenter of liver regeneration, hepatocyte growth factor, and insulin-like growth factor-II on liver natural killer cell functions

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