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PubMed1998

Increased nitric oxide production in the liver in the perioperative period of partial hepatectomy with Pringle's maneuver.

BACKGROUND/AIMS: There is no evidence that nitric oxide is produced in the liver during ischemia/reperfusion injury. This study examined the production of nitric oxide and inducible nitric oxide synthase in patients undergoing partial hepatectomy. METHODS: Twenty patients undergoing partial hepatectomy with only Pringle's maneuver were included. Peripheral blood was taken 1 day before the operation, during the operation (just after laparotomy and the first and last Pringle's maneuver) and 1 and 3 days after the operation, for measurement of plasma nitrate/nitrite, endotoxin and cytokine levels. Blood was also sampled from hepatic veins after Pringle's maneuver. Two liver specimens were taken from each patient, one before ischemia and one after partial hepatectomy, for the detection of inducible nitric oxide synthase. RESULTS: Average nitrate reached a maximum (33.5+/-3.4 micromol/l) after the final clamp (hepatic venous level). The increase in nitrate level during the operation correlated with the total duration of clamping. Endotoxin and interleukin-6 levels increased in a similar manner to nitrate levels, but tumor necrosis factor-alpha and interleukin-1 beta levels did not. In liver specimens taken after partial hepatectomy from patients, inducible nitric oxide synthase mRNA and protein were detected. CONCLUSIONS: Nitric oxide was produced in livers during ischemia/reperfusion injury and inducible nitric oxide synthase was involved in nitric oxide production.

Adult↗
PubMed1995

Expression of S14 protein gene in rat liver in response to partial hepatectomy, and its regulation with T3 and sucrose.

In rat liver a significant decrease in the expression of the protein S14 gene was observed 4 h after partial hepatectomy compared to sham operation performed after overnight fasting. After 24 h a decrease was recorded after partial hepatectomy or sham operation and this low level persisted for 120 h. A single i.p. dose of 3,5,3,'-L-triiodothyronine (10 micrograms/100 g body wt), a potent inducer of gene S14, reversed the inhibition of gene expression at each time interval studied in both the partially hepatectomized and sham-operated rats. Sucrose administration to rats 24 h after partial hepatectomy or to sham-operated rats restored the induction of hepatic mRNA S14 gene expression in approx. 60% of controls as recorded after 4 and 24 h. These data suggest that the expression of gene S14 was altered in the liver after partial hepatectomy or sham operation by food restriction, and no compensatory effect of the increased lipid metabolism was found in rat remnant liver. Our findings indicate that thyroid hormone and sucrose administration exert similar effects on hepatic expression of the protein S14 gene both in the regenerating liver and in the intact liver of sham-operated animals. In spite of the increased lipid metabolism of the liver after resection, sensitivity of mRNA S14 expression to triiodothyronine and sucrose was unchanged and its regulation was operative in a positive manner. These results also suggest that the treatment of a regenerating liver containing both the parent and the daughter hepatocytes with sucrose and/or triiodothyronine resulted in a fully restored response.

Animals↗
PubMed2006

Is there any effect of renal failure on the hepatic regeneration capacity following partial hepatectomy in rats?

The effects of renal dysfunction on liver regeneration capacity have not been fully elucidated before, although many patients with renal failure are subjected to hepatectomy due to hepatobiliary diseases. In this study, we sought to determine the effects of renal dysfunction on the hepatic regeneration capacity using rat chronic renal failure model. After establishing chronic renal failure (CRF group) by semi-total renal resection, the rats were subjected to 70% partial hepatectomy (PHx). Rats without renal failure were used as control (Sham group). The hepatic regeneration rate, histology of the liver, clearance of indocyanine green into the bile, and the expression of hepatic regeneration-associated genes in the liver were evaluated. The hepatic regeneration rate was lower in CRF group as compared to Sham group on day 1 after PHx. Mitotic index evaluated by histologic examination on day 1 after PHx was also significantly lower in CRF group. However, no difference in these indices was observed on day 2 and 7 between Sham and CRF. Indocyanine green clearance rate was almost identical between Sham and CRF on day 7 following PHx. The baseline expressions of the hepatic regeneration-associated genes, such as IL-6, TNF-alpha, HGF, c-fos, and c-jun, in the liver of CRF were significantly lower than those of Sham. However, the rate of upregulation of these genes was not significantly different between Sham and CRF. These results clearly demonstrate that the renal dysfunction, although initially delays the onset, does not suppress the total hepatic regeneration capacity following partial hepatectomy. The function of the regenerated liver on day 7 after PHx also was not different. Our results provide a possibility that the hepatectomy can be indicated even for the patient with a chronic renal failure.

Animals↗
PubMed2006

The clinical value of hepatocyte growth factor and its receptor--c-met for liver cancer patients with hepatectomy.

BACKGROUND: To study the dynamic change of hepatocyte growth factor after hepatectomy in patients with primary liver cancer, and to analyse the prognostic value of hepatocyte growth factor and c-met for these patients. METHODS: Thirty-one consecutive patients undergoing partial hepatectomy for liver cancer were studied. Serum hepatocyte growth factor level was determined by using enzyme-linked immunosorbent assay kit before and after operation, respectively. C-met protein and MRNA expressions in cancerous and paracancerous tissues were examined by immunohistochemical and RT-PCR methods, respectively. The correlations between clinical-pathologic parameters and the expressions of hepatocyte growth factor in serum and c-met in cancerous tissues were analysed, respectively. RESULTS: Liver cancer patients had a significantly higher level of serum hepatocyte growth factor than normal controls (1.0424+/-0.498 ng/ml versus 0.685+/-0.115 ng/ml, p=0.008). Serum hepatocyte growth factor level was positively affected by tumour size, node cirrhosis, portal vein tumour thrombi, cholangiocarcinoma (including combined hepatocellular carcinoma), poorly differentiated hepatocellular carcinoma and tumour recurrence or metastases. After hepatectomy, serum hepatocyte growth factor level peaked on the third postoperative day, and then declined, but did not return to normal level on the postoperative day 10. From the preoperative day to postoperative day 10, the level of serum hepatocyte growth factor had a decrease of percent (85.33+/-10.2%) in the group with large tumours (>5 cm), but an elevation of percent (121.9+/-10.3%) in the group with small tumours (<or=5 cm). From the preoperative day to postoperative day 3, the level of serum hepatocyte growth factor had a higher elevation in the group with major resection than in the group with local resection (p=0.016). Moderately or strongly positive expression of c-met protein was observed in 27 cancerous regions (27/31), and only in 5 paracancerous regions. The intensive expression of c-met MRNA was 100% (31/31) detectable in the cancerous tissues, but only 22.6% (7/31) in the paracancerous tissues. C-met protein expression in cancerous tissues was correlated with portal vein tumour thrombi, cholangiocarcinoma and tumour recurrence or metastases, and the expression in paracancerous tissues was correlated with node cirrhosis. No significant correlation was observed between the hepatocyte growth factor in serum and c-met in cancerous tissues. CONCLUSION: The over-expressions of the hepatocyte growth factor and c-met indicates an adverse prognosis for patients with liver cancer. The sustained high level of serum hepatocyte growth factor after hepatectomy may be a factor related to early tumour recurrence and metastasis. Liver regeneration may be a main factor leading to high level of serum hepatocyte growth factor in early postoperative stage.

Adult↗
PubMed2006

Trans-metastasis hepatectomy: results of a 21-case study.

AIM: The aim of this study was to report the feasibility and efficiency of a new approach, called post-RF trans-metastasis hepatectomy (PRFTMH). This technique consists in using RF to first ablate an ill-located liver metastasis (LM) along the planned hepatectomy resection line, the only one possible for volumetric reasons, and then to perform the hepatectomy passing via this initially ablated LM. MATERIAL AND METHODS: Twenty-one patients were treated with PRFTMH between January 2000 and May 2004. Thirteen of them had a primary colorectal tumour, four had a primary endocrine tumour and four had miscellaneous primaries. The mean number of LMs per patient was 13.8 (10.7 for primary colorectal tumours and 22.2 for primary endocrine tumours). Pre-operative hypertrophy of the future remaining liver was obtained by selective portal vein embolisation in 11 patients. RESULTS: One patient died post-operatively (4.7%) and five developed complications (24%). No local recurrence has occurred at the site of PRFTMH after a median follow-up of 19.4 months (range: 47-7), demonstrating the efficacy of this technique. All patients, except the patient who died post-operatively, are currently alive, and the median survival rate has not yet been attained, after a median follow-up of 19.4 months. CONCLUSION: PRFTMH combining RF ablation and trans-metastasis hepatectomy is a new and safe technique, allowing a curative approach to be proposed to some patients with unresectable bilateral LMs.

Adult↗
PubMed2004

Laparoscopic right hepatectomy: surgical technique.

The objective of this study was to demonstrate the safety of laparoscopic right hepatectomy for benign or malignant disease. Many reports document the success of minor or segmental liver resections performed laparoscopically. Major hepatic resection has rarely been reported. This report documents our experience with 12 laparoscopic right hepatectomies. Ten patients had suspected malignancy, but all had lesions well clear of the midplane of the liver. The surgery followed three distinct phases: (1). Portal dissection during which diathermy and harmonic shears are used, clips are applied to the right hepatic duct and right hepatic artery, and a vascular stapler is used to divide the right portal vein; (2). dissection of the vena cava, which is usually done by tunneling below the liver using harmonic shears, clips, and a linear stapler to divide the right hepatic vein; and (3). parenchymal division during which harmonic shears and multiple firings of linear staplers are used to divide the liver substance. In five patients the procedure was completed totally laparoscopically, five patients had a laparoscopic-assisted procedure, and two patients had to be converted to formal open hepatectomy. Four patients required blood transfusion. There were no deaths and two cases of major morbidity-bile leakage in one and wound dehiscence in one. The average hospital stay was 8 days, but for those whose operations were completed totally laparoscopically, 4 days was the average. Two of the nine patients with documented cancer have since died-one with widespread intrahepatic hepatocellular carcinoma and another with widespread metastatic melanoma after resection of a colorectal metastasis. Seven patients with colorectal cancer are alive and disease free with follow-up of 6 to 24 months. Laparoscopic right hepatectomy is feasible in selected patients. It is technically demanding but can be safely accomplished by surgeons who have experience in advanced laparoscopic procedures and open hepatic surgery.

Adult↗
PubMed2006

Outcomes and recurrence of initially resectable hepatocellular carcinoma meeting milan criteria: Rationale for partial hepatectomy as first strategy.

BACKGROUND: Partial hepatectomy and liver transplantation are considered curative treatments for small hepatocellular carcinoma (HCC) meeting the Milan criteria (solitary tumor <5 cm or up to 3 nodules <3 cm). This study was designed to clarify whether partial hepatectomy can be the first option in patients eligible for both treatments. STUDY DESIGN: All patients (n = 152) underwent curative surgical operation for primary HCC during 2000 to 2005 at our hospital. Eighty-seven patients met Milan criteria and the remaining 65 did not. Outcomes were examined according to Milan criteria. RESULTS: After partial hepatectomy, 3-year survival rate was 89.6% for the group that met Milan criteria, compared with 60.8% for the group that did not (p = 0.0044). Among patients with HCC who initially met the criteria, tumor recurrences were observed in 30 patients; 23 patients met criteria and 7 patients exceeded the criteria at first diagnosis of recurrence. Patients with recurrence within the criteria showed a higher 3-year survival rate compared with patients with recurrence exceeding the criteria (100% versus 19.8%; p < 0.0001). Analysis of clinicopathologic variables to predict mode of recurrence revealed tumor size (p < 0.0001) and lower histologic differentiation (p = 0.0326) as positive factors for recurrence exceeding Milan criteria. CONCLUSIONS: Our results suggest that it is an appropriate strategy to treat HCC patients who meet Milan criteria with partial hepatectomy. It should be noted that approximately one-tenth of patients who initially met Milan criteria experienced postoperative recurrence that exceeded the criteria.

Adult↗
PubMed2004

Pirfenidone prevents endotoxin-induced liver injury after partial hepatectomy in rats.

BACKGROUND/AIMS: Massive liver resection causes a variety of complications including endotoxemia. Pirfenidone (PFD) is a new experimental drug used as antifibrotic agent. Studies were performed to investigate whether PFD influences the survival rate of animals with endotoxin-induced liver injury after partial hepatectomy, and the mechanisms involved. METHODS: Rats were treated with lipopolysaccharide (LPS) 48 h after 70% hepatectomy. PFD was administered orally before LPS injection. RESULTS: PFD improved the survival rate of LPS-treated rats after hepatectomy. PFD prevented increases in serum enzymes and total bilirubin related to liver injury. Histopathological analysis revealed that PFD inhibited the enhancement in hepatic necrosis and apoptosis. Further, PFD inhibited increases of inflammatory cytokines and cytokine-induced neutrophil chemoattractant (CINC) in serum and liver, followed by decreases of number of infiltrating neutrophils into liver. Electrophoretic mobility shift assay revealed that PFD inhibited the activation of transcription factor nuclear factor-kappa B (NF-kappa B) induced by LPS. PFD also reduced the induction of inducible nitric oxide synthase (iNOS) in the liver of LPS-treated rats. CONCLUSIONS: These results indicate that PFD inhibits the productions of inflammatory cytokines, CINC and iNOS in part through the inhibition of NF-kappa B activation, resulting in the prevention of endotoxin-induced liver injury after hepatectomy.

Animals↗
PubMed2004

Effect of vascular endothelial growth factor on functional recovery after hepatectomy in lean and obese mice.

BACKGROUND/AIMS: Liver regeneration is dependent upon coordinated proliferation of hepatocytes and endothelial cells. Vascular endothelial growth factor (VEGF) promotes angiogenesis. Hepatic steatosis delays regeneration and increases liver resection morbidity. We hypothesized that VEGF overexpression stimulates hepatic regeneration. METHODS: Recombinant adenovirus expressing human VEGF165 or adenovirus control-vector (LacZ) were administered before 2/3 hepatectomy in lean and ob/ob mice. Galactose elimination capacity, a quantitative liver function test, was repeatedly measured before and after hepatectomy. Expression of VEGF receptors (flt1, flk1), endoglin and hypoxia inducible factor-1alpha (HIF-1alpha) was assessed by quantitative RT-PCR and for endoglin also by immunohistochemistry. RESULTS: After 2/3 hepatectomy, VEGF gene transfer increased galactose elimination capacity in lean and ob/ob mice. HIF-1alpha, endoglin and VEGF receptor mRNA increased during regeneration in lean but not in obese mice. Staining of endothelial cells by endoglin immunohistochemistry returned to baseline reactivity in lean mice by day 6 and remained decreased in ob/ob mice. VEGF treatment decreased HIF-1alpha and increased flk1 response in lean mice. CONCLUSIONS: Hepatic resection elicits an angiogenic response in the remnant liver, which is impaired in case of steatosis. Adenovirus-mediated transfer of VEGF hastens functional hepatic recovery in lean, and more importantly also, in obese mice after partial hepatectomy.

Adenoviridae↗
PubMed2005

Sexual dimorphism in endotoxin susceptibility after partial hepatectomy in rats.

BACKGROUND/AIMS: Liver failure due to endotoxemia after hepatectomy is a fatal complication. Little is known regarding the gender influence on this pathophysiological condition. This study was conducted to investigate whether a gender difference exists in the endotoxin susceptibility after hepatectomy. METHODS: Sexually mature male and female rats received an intravenous administration of lipopolysaccharide (LPS), as endotoxin, 48h after a two-thirds hepatectomy. RESULTS: The 24-h survival rate after LPS administration was significantly higher in females (75%) than in males (38%). Ovariectomy reduced the survival rate in females to 44%. Plasma tumor necrosis factor-alpha levels 1h after LPS were significantly elevated in males and ovariectomized females. The inducible nitric oxide synthase (iNOS) gene expression in liver and spleen, and consequent nitric oxide production 3h after LPS were significantly enhanced in males and ovariectomized females when compared to females, in addition to less functional and structural liver damage in females. CONCLUSIONS: Our results indicate a gender difference in the susceptibility to endotoxemia in the early phase after hepatectomy. Female tolerance to these conditions may be mediated by an inhibition of excessive inflammatory response in the liver and the spleen, partially via the suppression of iNOS gene up-regulation.

Animals↗
PubMed2005

Protective effect of fibronectin for endotoxin-induced liver injury after partial hepatectomy in rats.

BACKGROUND: Endotoxemia may occur after hepatectomy and become the cause of post-operative death. Fibronectins (Fns) are involved in a number of biological processes, such as cellular adhesion, motility, differentiation, apoptosis, hemostasis, wound healing, and ischemic injury. Studies were performed to determine whether Fn influences the survival rate of rats subjected to endotoxin-induced liver injury after partial hepatectomy. MATERIALS AND METHODS: Lipopolysaccharide (LPS) was administered intravenously to male Sprague-Dawley rats within 48 h of 70% hepatectomy. Before LPS administration, plasma Fn or bovine serum albumin was given intravenously. RESULTS: The survival rate of the Fn-treated group was markedly improved compared with that of the controls. Fn prevented increases in the concentrations of serum enzymes and total bilirubin related to liver injury. The levels of inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1beta, and cytokine-induced neutrophil chemoattractant, in serum and liver tissue, also were significantly lower in the Fn-treated group than in the control group. Furthermore, the degree of apoptosis and necrosis in remnant liver was significantly decreased in the Fn-treated rats compared with the controls. CONCLUSIONS: These results indicate that Fn prevents endotoxin-induced liver injury after partial hepatectomy, at least in part through the inhibition of production of inflammatory cytokines, necrosis and apoptosis in the remaining liver.

Animals↗
PubMed2005

The practical value of applying chemical biliary duct embolization to chemical hepatectomy for treatment of hepatolithiasis.

BACKGROUND: The high recurrence rate of hepatolithiasis, together with the high operative risk of hepatectomy for specifically located stones, has not been effectively settled until now. Thus, the aim of this study was to investigate the feasibility and effectiveness of using chemical biliary duct embolization (CBDE) to achieve chemical hepatectomy in a rabbit model of hepatolithiasis. MATERIALS AND METHODS: The animal model of hepatolithiasis was established using the methods of obstruction plus infection. Seven days later, the left hepatic ducts were embolized using phenol plus cyanoacrylate or absolute ethanol plus cyanoacrylate. Subsequently, the influence of CBDE on bile duct, liver, and stone formation was analyzed by histology, RT-PCR for procollagen, biochemistry, and enzymatic histochemistry for beta-glucuronidase (beta-G). RESULTS: CBDE resulted in the entire ablation of the diseased biliary duct mucosa and the complete occlusion of the diseased biliary duct lumen, thus effectively eradicating chronic proliferative cholangitis and preventing stone formation. More importantly, CBDE also resulted in the complete fibrosis and "self-cut" in the periphery of the embolized lobe, thus achieving chemical hepatectomy. Also of note, the embolized lobe exhibited a much lower level of endogenous beta-G than the nonembolized lobe, indicating an inhibitory effect of CBDE on beta-G. Besides, the mRNA level of procollagen I in the embolized bile duct wall of phenol embolization group was significantly higher than the ethanol embolization group. CONCLUSION: Chemical biliary duct embolization, especially using phenol plus cyanoacrylate, may prevent the recurrence of intrahepatic stone and concurrently achieve the effect of chemical hepatectomy.

Animals↗
PubMed2006

Single dose of anti-transforming growth factor-beta1 monoclonal antibody enhances liver regeneration after partial hepatectomy in biliary-obstructed rats.

BACKGROUND: Transforming growth factor (TGF) beta is a potent inhibitor of hepatocyte DNA synthesis and liver regeneration. TGF-beta(1) expression progressively increases in obstructive jaundice. We investigated the effect of TGF-beta(1) blockage on liver regeneration in rats induced with obstructive jaundice. MATERIALS AND METHODS: Male Wistar-albino rats were divided into three groups: sham, control, and study groups. In the study and control groups, the common bile duct was ligated and divided, and 7 days later a partial hepatectomy was performed. In the study group, anti-TGF-beta(1) monoclonal antibody (10-microg single dose) was administered immediately after the 70% hepatectomy. In the control group, those rats in which obstructive jaundice was induced received normal saline after the 70% hepatectomy, and nonjaundiced rats received anti-TGF-beta(1) monoclonal antibody after the 70% hepatectomy. Rats were sacrificed after 48 or 72 h. Relative liver weight, AST, ALT, total and conjugated bilirubin, and TGF-beta(1) levels were measured. The mitotic index and proliferating cell nuclear antigen (PCNA) labeling index were evaluated as histopathologic parameters. RESULTS: At 72 h, the TGF-beta(1) level in the study group was similar to that in the sham group, whereas TGF-beta(1) in the study group was significantly lower than that of the jaundiced control group at 48 or 72 h (P < 0.001). The relative liver weight, mitotic index, and PCNA labeling index were significantly higher in the study group than in the jaundiced control group at 48 and 72 h (P < 0.001). The AST, ALT, and TGF-beta(1) levels were significantly higher in the jaundiced control group compared to the study group after 48 and 72 h, whereas these values were significantly lower in the nonjaundiced control group (P < 0.001). CONCLUSIONS: In obstructive jaundiced rats, TGF-beta(1) blockage with anti-TGF-beta(1) monoclonal antibody after liver resection improved liver regeneration both morphologically and functionally.

Alanine Transaminase↗
PubMed2004

A bioartificial liver support system using primary hepatocytes: a preclinical study in a new porcine hepatectomy model.

BACKGROUND: Bioartificial liver support systems providing a bridge to transplantation or even a definitive treatment of acute hepatic failure are a current focus of research. Different devices are used, although an impact on patient survival is doubtful for the time being. After developing a new flat membrane bioreactor, further preclinical studies have become necessary. Existing animal models of fulminant hepatic failure show common difficulties in defining a reproducible loss of functional liver tissue while considering systemic side effects. We now present a reproducible model with total hepatectomy in pigs, suitable to test the safety and efficacy of liver support systems. METHODS: Twelve pigs underwent total hepatectomy by using silicone tubes and a Y-adapter as vascular prosthesis; intracranial pressure was measured via a subdural probe. Anhepatic pigs were monitored under general anesthesia until death occurred. All were treated with a new flat membrane bioreactor (FMB) that contained porcine hepatocytes in 6 of the 12 cases. RESULTS: Our hepatectomy technique proved to be successful without requiring venovenous bypass circulation. Mean vascular clamping time was 9 minutes. The mean survival time was longer in animals treated with hepatocyte-equipped bioreactors than in untreated animals (24.8 +/- 4.3 vs 16.4 +/- 4.7 hours), which already showed increased intracranial pressure after 10 to 12 hours. Serum albumin levels indicated stable cell-specific functions of the FMB. CONCLUSIONS: The described technique of total hepatectomy is a well-reproducible animal model. The presented FMB maintained stable cell-specific functions and is a safe and efficient device.

Animals↗
PubMed2006

Combination gene therapy of HGF and truncated type II TGF-beta receptor for rat liver cirrhosis after partial hepatectomy.

BACKGROUND: In a cirrhotic liver, the regenerative ability and specific functions are impaired; a hepatic resection increases the possibility of postoperative liver failure. Hepatocyte growth factor (HGF) stimulates liver regeneration, accelerates restoration of hepatic function, and improves fibrosis. A truncated type II transforming growth factor-beta receptor (TbetaTR), which specifically inhibits TGF-beta signaling as a dominant-negative receptor, appears to prevent the progression of liver fibrosis. We demonstrated the therapeutic efficacy of adenovirus-mediated HGF and TbetaTR gene transduction after partial hepatectomy for liver cirrhosis. METHODS: Rats were treated with dimethylnitrosamine for 3 weeks, and they all had severe cirrhosis. After partial hepatectomy (10%), we injected adenovirus expressing bacterial beta-galactosidase (AdLacZ), adenovirus expressing a truncated type II TGF-beta receptor (AdTbetaTR), adenovirus expressing hepatocyte growth factor (AdHGF), or AdTbetaTR + AdHGF into the portal vein, which was followed by an additional 2-week dimethylnitrosamine treatment. RESULTS: On histologic examination, fibrotic tissue had decreased in the livers of the AdTbetaTR + AdHGF-treated rats compared with rats that were treated by AdLacZ, AdTbetaTR alone, and AdHGF alone. Liver function, which included serum levels of alanine aminotransferase, improved significantly in AdTbetaTR + AdHGF-treated rats compared with all other groups. The number of hepatocytes that were positive for proliferating-cell nuclear antigen was greater (P < .05) in AdHGF alone and AdTbetaTR + AdHGF-treated rat livers than in AdLacZ- and AdTbetaTR-treated rats. All AdTbetaTR + AdHGF-treated rats survived >60 days, and AdTbetaTR + AdHGF treatment markedly improved the survival rate after a partial hepatectomy. CONCLUSION: Our results suggest that the combination of HGF and TbetaTR gene therapy may increase the possibility of hepatectomy in a cirrhotic liver by improving fibrosis, hepatic function, and hepatocyte regeneration.

Adenoviridae↗
PubMed2004

Fibronectin protects endotoxin-induced liver injury after partial hepatectomy in rats.

Endotoxemia following extended hepatectomy may be a cause of postoperative death. Multiple organ failure related to septemia is a common cause of early mortality after liver transplantation. Fibronectins (Fns) are involved in cellular adhesion, motility, differentiation, apoptosis, hemostasis, wound healing, and ischemic injury. Studies were performed to determine whether Fn influences the survival rate of rats subjected to endotoxin-induced liver injury after partial hepatectomy. Male Sprague-Dawley rats were intravenously administered lipopolysaccharide (LPS) 48 hours after 70% hepatectomy. Prior to LPS administration, plasma Fn or bovine serum albumin was given intravenously. The survival rate of the Fn-treated group was higher than that of the controls. Fn prevented increases in serum enzyme activity and total bilirubin related to liver injury. The levels of inflammatory cytokines including tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 interferon-gamma were also significantly lower in the Fn-treated than the control group. Furthermore, the number of apoptotic cells and the degree of necrosis in the remnant liver were significantly decreased in the Fn-treated rats compared with controls. These results indicate that Fn prevents endotoxin-induced liver injury after partial hepatectomy, at least in part through inhibiting the production of inflammatory cytokines, and the necrosis apoptosis in the remaining liver.

Animals↗
PubMed2003

Mitogenic properties of endogenous and pharmacological doses of macrophage inflammatory protein-2 after 70% hepatectomy in the mouse.

Recent studies show CXC chemokine elevations after hepatic resection; blockade of epithelial neutrophil-activating protein (ENA-78), a CXC chemokine, retards hepatic regeneration after resection. Additional studies demonstrate that exogenous macrophage inflammatory protein (MIP)-2, another CXC chemokine, is therapeutic in a murine acetaminophen toxicity model when other therapies fail. The current investigations study MIP-2's effects on the cellular mechanisms involved in liver regeneration in mice after 70% hepatectomy. Administration of exogenous MIP-2 after 70% hepatectomy dramatically increased hepatocyte proliferation as measured by 5-bromo-2'-deoxyuridine staining. Signal transducer and activator of transcription-3 (stat-3) was also detected in greater abundance and persisted in hepatic nuclear extracts from MIP-2-treated mice compared with control mice after hepatic resection. Further, inhibition of the MIP-2 receptor, CXCR2, decreased baseline hepatocyte proliferation and stat-3 expression in the setting of partial hepatectomy. These data show that MIP-2 is important for hepatocyte proliferation after partial hepatectomy and that pharmacological MIP-2 doses after hepatic injury accelerate hepatic regeneration.

Animals↗
PubMed1993

Hepatectomy impairs hepatic processing of somatostatin-14.

Somatostatin-14 (SS-14) inhibits the hepatotrophic effect of a variety of growth factors in cultured hepatocytes. We hypothesized that hepatic somatostatin processing might be altered during regeneration. Male Sprague-Dawley rats underwent the intraportal injection of radiolabeled SS-14 after sham or 70% hepatectomy. To study the mechanisms of hepatic SS-14 transport in the rat, the lysosomal enzyme inhibitors, chloroquine and leupeptin, and the microtubule inhibitors, vinblastine and colchicine, were administered 1 to 2 hours prior to the intraportal injection of SS-14. Bile was collected, organs were weighed, and radioactivity was quantitated. The analysis of serial timed collections of bile revealed that, for saline, chloroquine, and leupeptin, peak biliary radioactivity appeared at 20 minutes. Pretreatment with vinblastine and colchicine abolished the 20-minute peak of radioactivity. The appearance of biliary and hepatic iodine 125-SS-14 (125I-[tyr11]-SS-14) at various times after 70% hepatectomy showed a significant decrease starting at 2 hours, which persisted for up to 24 hours. In regenerating liver, both vinblastine and chloroquine decreased 125I-[tyr11]-SS-14 in bile and the liver. In summary, after sham or 70% hepatectomy, vinblastine and colchicine inhibit biliary and increase hepatic 125I-[tyr11]-SS-14 accumulation. After 70% hepatectomy was performed, chloroquine also inhibited 125I-[tyr11]-SS-14 accumulation. We concluded that an important mechanism for hepatic regeneration is decreased responsiveness to SS-14, by decreased SS-14 uptake and increased SS-14 degradation.

Animals↗