Influence of Portosystemic Shunt on Liver Regeneration after Hepatic Resection in Pigs

Objective. The minimal amount of liver mass necessary for regeneration is still a matter of debate. The aim of the study was to analyze liver regeneration factors after extended resection with or without portosystemic shunt. Methods. An extended left hemihepatectomy was performed in 25 domestic pigs, in 15 cases after a portosystemic H-shunt. The expression of Ki-67, VEGF, TGF-, FGF, and CK-7 was analyzed in paraffin-embedded tissue sections. Results. The volume of the remnant liver increased about 2.5-fold at the end of the first week after resection. With 19 cells/10 Glisson fields versus 4/10, Ki-67-expression was significantly higher in the H-shunt group. VEGF- and CK-7-expressions were significantly higher in the control group. No significant change was found in FGF-expression. The expression of TGF- was higher, but not significantly, in the control group. Conclusions. The expression of Ki-67, and therefore hepatocyte regeneration, was increased in the shunt group. The expression of CK-7 on biliary epithelium and the expression of VEGF, however, were stronger in the control group.

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Cellular Liver Regeneration after Extended Hepatic Resection in Pigs

HPB Surgery ◽

10.1155/2009/306740 ◽

2009 ◽

Vol 2009 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Ruth Ladurner ◽

Frank Traub ◽

Martin Schenk ◽

Alfred Königsrainer ◽

Jörg Glatzle

Keyword(s):

Liver Regeneration ◽

De Novo ◽

Liver Volume ◽

Portosystemic Shunt ◽

Remnant Liver ◽

De Novo Synthesis ◽

Extended Resection ◽

Operation Procedure ◽

Left Hemihepatectomy

Background. The liver has an enormous capacity to regenerate itself. The aim of this study was to evaluate whether the regeneration is due to hypertrophy or hyperplasia of the remnant liver after extended resection and whether a portosystemic shunt is beneficial. Material and methods. An extended left hemihepatectomy was performed in 25 pigs, and in 14 after performing a portosystemic shunt. During follow up, liver regeneration was estimated by macroscopic markers such as liver volume and size of the portal fields as well as the amount of hepatocytes per portal field and the amount of hepatocytes per . Results. Regardless of the operation procedure, the volume of the remnant liver increased about 2.5 fold at the end of the first week after resection. The size of the portal fields increased significantly as well as the number of hepatocytes in the portal fields. Interestingly, the number of hepatocytes per remained the same. Conclusion. After extended resection, liver regeneration was achieved by an extensive and significant hyperplasia of hepatocytes within the preexisting portal fields and not by de novo synthesis of new portal fields. However, there was no difference in liver regeneration regarding the operation procedure performed with or without portosystemic shunt.

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Expression of Notch–Hif-1α signaling pathway in liver regeneration of rats

Journal of International Medical Research ◽

10.1177/0300060520943790 ◽

2020 ◽

Vol 48 (9) ◽

pp. 030006052094379

Author(s):

Yanshan Li ◽

Yunxiuxiu Xu ◽

Ruomei Wang ◽

Wenxin Li ◽

Wenguang He ◽

...

Keyword(s):

Cell Proliferation ◽

Body Weight ◽

Protein Expression ◽

Liver Regeneration ◽

Signaling Pathway ◽

Western Blotting ◽

Saline Control ◽

Control Group ◽

Mrna Levels ◽

Ki 67

Objective To investigate whether the Notch–Hif-1α signaling pathway is involved in liver regeneration. Methods Rats were divided into two groups and treated with daily intraperitoneal injections of saline (control) or the gamma-secretase inhibitor, Fli-06, for 2 days. Two-thirds of the rat livers were resected and rats were later euthanized at specific time points post-resection to analyze the remnant livers. Each group's liver/body weight ratio was calculated, and immunostaining and western blotting were used to determine the cell proliferation marker, PCNA and Ki-67 expression. Real-time PCR and western blotting were used to compare the mRNA expression of Notch homolog-1 ( Notch1), hairy and enhancer of split-1 ( Hes1), and vascular endothelial growth factor ( Vegf), and the protein expression of NICD and HIF-1α, respectively. Results The liver/body weight ratios and number of Ki-67- and PCNA-positive cells were significantly lower in the experimental group than the control group, indicating lower levels of liver regeneration following the disruption of Notch signaling by Fli-06. The Hes1 and Vegf mRNA levels and NICD and HIF-1α protein expression levels were all down-regulated by Fli-06 treatment. Conclusion Notch–Hif-α signaling pathway activation plays an important role in liver regeneration, where it may contribute toward liver cell proliferation.

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Preoperative Chemotherapy on Functional Liver Regeneration for Colorectal Liver Metastases Assessed With 99mTc-GSA SPECT/CT Imaging

International Surgery ◽

10.9738/intsurg-d-16-00209.1 ◽

2018 ◽

Vol 102 (9-10) ◽

pp. 431-439 ◽

Cited By ~ 1

Author(s):

Toru Beppu ◽

Hiromitsu Hayashi ◽

Morikatsu Yoshida ◽

Hidetoshi Nitta ◽

Katsunori Imai ◽

...

Keyword(s):

Liver Resection ◽

Liver Metastases ◽

Liver Regeneration ◽

Preoperative Chemotherapy ◽

Colorectal Liver Metastases ◽

Major Hepatectomy ◽

Liver Volume ◽

Control Group ◽

Remnant Liver ◽

Resection Rate

Objective: To investigate the functional liver regeneration after chemotherapy and liver resection for colorectal liver metastases (CRLM). Background/Purpose: Preoperative chemotherapy followed by liver resection for CRLM has been increasing; however, its negative impact on liver regeneration remains unknown. Methods: From January 2009 to December 2013, we enrolled 40 selected patients who underwent major hepatectomy without viral hepatitis and severe liver fibrosis. CRLM patients with preoperative chemotherapy (CT-CRLM group, n = 12) and patients without preoperative chemotherapy (control group, n = 28) were evaluated. Liver volume (LV) and functional liver volume (FLV) was assessed using Tc-99m–labeled galactosyl human serum albumin (99mTc-GSA) scintigraphy, single-photon emission computed tomography (SPECT), CT-fused images. Preoperative, future remnant liver, and post 1-month values were compared. Results: Median course of preoperative chemotherapy was 8 (range: 6–16). Preoperative background factors were almost identical including resection rate and functional resection rate. In the CT-CRLM group and in the control group, the percentage increases in LV were 39.3% ± 29.0% and 23.2% ± 23.5% (P = 0.037), and FLV were 79.4% ± 43.1% and 57.0% ± 33.4% (P = 0.417), respectively; absolute differences in LV were 216.2 ± 155.7 cm3 and 148.7 ± 134.7 cm3 (P = 0.086) and FLV were 19.4% ± 8.5%/m2 and 17.4% ± 7.9%/m2 (P = 0.235), respectively. We found no obvious tendency for negative influence on liver functional regeneration by the preoperative regimens for CRLM. Conclusions: Several courses of preoperative chemotherapy may not affect functional liver regeneration for CRLM patients after major hepatectomy.

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Sirolimus influence on hepatectomy-induced liver regeneration in rats

Revista do Colégio Brasileiro de Cirurgiões ◽

10.1590/s0100-69912014000300012 ◽

2014 ◽

Vol 41 (3) ◽

pp. 203-207 ◽

Cited By ~ 4

Author(s):

Edimar Leandro Toderke ◽

Giorgio Alfredo Pedroso Baretta ◽

Ozimo Pereira Gama Filho ◽

Jorge Eduardo Fouto Matias

Keyword(s):

Liver Regeneration ◽

Negative Influence ◽

Control Group ◽

Cell Multiplication ◽

Study Group ◽

Adult Rats ◽

Ki 67 ◽

Immunohistochemical Markers ◽

Significant Difference ◽

And Control

OBJECTIVE: To evaluate the influence of sirolimus on liver regeneration triggered by resection of 70% of the liver of adult rats. METHODS: we used 40 Wistar rats randomly divided into two groups (study and control), each group was divided into two equal subgroups according to the day of death (24 hours and seven days). Sirolimus was administered at a dose of 1mg/kg in the study group and the control group was given 1 ml of saline. The solutions were administered daily since three days before hepatectomy till the rats death to removal of the regenerated liver, conducted in 24 hours or 7 days after hepatectomy. Liver regeneration was measured by the KWON formula, by thenumber of mitotic figures (hematoxylin-eosin staining) and by the immunohistochemical markers PCNA and Ki-67. RESULTS: there was a statistically significant difference between the 24h and the 7d groups. When comparing the study and control groups in the same period, there was a statistically significant variation only for Ki-67, in which there were increased numbers of hepatocytes in cell multiplication in the 7d study group compared with the 7d control group (p = 0.04). CONCLUSION: there was no negative influence of sirolimus in liver regeneration and there was a positive partial effect at immunohistochemistry with Ki-67.

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A Protective Effect of Sivelestat From Ischemia/Reperfusion Injury in a Porcine Hepatectomy Model

International Surgery ◽

10.9738/intsurg-d-17-00033.1 ◽

2018 ◽

Vol 103 (3-4) ◽

pp. 191-198 ◽

Cited By ~ 2

Author(s):

Mitsugi Shimoda ◽

Yoshimi Iwasaki ◽

Shuji Suzuki

Keyword(s):

Liver Regeneration ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Liver Volume ◽

Therapeutic Drug ◽

Control Group ◽

Tunel Staining ◽

Remnant Liver ◽

Elastase Inhibitor ◽

Sivelestat Sodium Hydrate

Summary of background data: Sivelestat sodium hydrate (Sive), a neutrophil elastase inhibitor, has been approved as a worldwide therapeutic drug for acute lung injury associated with systemic inflammatory response syndrome. Yet how Sive influences hepatic ischemic reperfusion (I/R) injury and liver regeneration has not been clarified. Objective: We investigated the effect of Sive against hepatic I/R injury and liver regeneration using porcine hepatectomy model, and found that Sive contributes significantly in increasing the liver volume. Methods: We induced 1-hour ischemia by occluding the vessels and the bile duct of the right and median lobes. About 40% left hepatectomy was performed after reperfusion. A total of 6 animals received Sive (10 mg/kg/h) intravenously and 6 control animals received physiologic saline (10 mg/kg/h) from commencement of laparotomy. Remnant liver volume, hemodynamics, and liver function test were compared between the groups. Expressions of TRL4 mRNA in hepatic tissues were examined using RT-PCR. Apoptosis and cell proliferation were demonstrated by TUNEL staining. Results: AST, LDH, and LA levels at 5 minutes after reperfusion were significantly lower in Sive group than in the control group. Sive significantly increased the liver volume, yet did not have any effect for liver regeneration. Conclusion: Sive is considered to reduce hepatic injury in the early phase of I/R injury.

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Portal Modulation Effects of Terlipressin on Liver Regeneration and Survival in a Porcine Model Subjected to 90% Hepatectomy

10.21203/rs.3.rs-154345/v1 ◽

2021 ◽

Author(s):

Hye-sung Jo ◽

Hyun-Jin Park ◽

Yoon Young Choi ◽

Jin-I Seok ◽

Jae-Hyun Han ◽

...

Keyword(s):

Liver Regeneration ◽

Porcine Model ◽

Portal Pressure ◽

Total Bilirubin Level ◽

Antigen Expression ◽

Nuclear Antigen ◽

Control Group ◽

Ki 67 ◽

Partial Liver Transplantation ◽

Extensive Hepatectomy

Abstract BackgroundExcessive postoperative portal pressure is associated with post-hepatectomy liver failure and small-for-size syndrome after partial liver transplantation. This study aimed to identify the portal modulation effects of terlipressin on liver regeneration and survival in a porcine model subjected to 90% hepatectomy.MethodsTwenty pigs undergoing 90% hepatectomy were divided into control (n=10) and terlipressin (n=10) groups. Terlipressin 0.5 mg was injected subcutaneously three times a day, from immediately before hepatectomy to 7 days after surgery, for surviving pigs in the terlipressin group. Portal pressure measurement, biochemical analysis, assessment of molecular markers for liver regeneration, and immunohistochemistry were performed in both groups. ResultsThe 7-day survival rate was significantly higher in the terlipressin group than in the control group. Portal pressure in the terlipressin group was lower than that in the control group at 30 min and 1 h after hepatectomy. Total bilirubin level was lower in the terlipressin group than in the control group at 1 h and 6 h after hepatectomy. Proliferating cell nuclear antigen expression was higher in the control group than in the terlipressin group at 6 h after hepatectomy, while the proportion of Ki-67-positive cells was higher in the terlipressin group than in the control group at 7 days after hepatectomy. Endothelin-1 levels reflecting liver injury were lower in the terlipressin group than in the control group at 1 h and 6 h after hepatectomy.ConclusionTerlipressin could optimize liver regeneration and improve survival through rapid and effective portal modulation after extensive hepatectomy.

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Inhaled Argon Impedes Hepatic Regeneration after Ischemia/Reperfusion Injury in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms21155457 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5457

Author(s):

Sophia M. Schmitz ◽

Henriette Dohmeier ◽

Christian Stoppe ◽

Patrick H. Alizai ◽

Sandra Schipper ◽

...

Keyword(s):

Liver Regeneration ◽

Reperfusion Injury ◽

Noble Gases ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Hepatic Regeneration ◽

Control Group ◽

Sprague Dawley ◽

Regenerative Capacity ◽

Ki 67

Organoprotective effects of noble gases are subject of current research. One important field of interest is the effect of noble gases on hepatic regenerative capacity. For the noble gas argon, promising studies demonstrated remarkable experimental effects in neuronal and renal cells. The aim of this study was to investigate the effects of argon on the regenerative capacity of the liver after ischemia/reperfusion injury (IRI). Male, Sprague-Dawley rats underwent hepatic IRI by clamping of the hepatic artery. Expression of hepatoproliferative genes (HGF, IL-1β, IL-6, TNF), cell cycle markers (BrdU, TUNEL, Ki-67), and liver enzymes (ALT, AST, Bilirubin, LDH) were assessed 3, 36, and 96 h after IRI. Expression of IL-1β and IL-6 was significantly higher after argon inhalation after 36 h (IL-1β 5.0 vs. 8.7 fold, p = 0.001; IL-6 9.6 vs. 19.1 fold, p = 0.05). Ki-67 was higher in the control group compared to the argon group after 36 h (214.0 vs. 38.7 positive cells/1000 hepatocytes, p = 0.045). Serum levels of AST and ALT did not differ significantly between groups. Our data indicate that argon inhalation has detrimental effects on liver regeneration after IRI as measured by elevated levels of the proinflammatory cytokines IL-1β and IL-6 after 36 h. In line with these results, Ki-67 is decreased in the argon group, indicating a negative effect on liver regeneration in argon inhalation.

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ENHANCERS OF LIVER REGENERATION IN ONCOLOGICAL SURGERY

British Journal of Surgery ◽

10.1093/bjs/znab160.010 ◽

2021 ◽

Vol 108 (Supplement_3) ◽

Author(s):

M Osorio Capitan ◽

S Rose ◽

I Novo Sukia ◽

B Herrero de la Parte ◽

I Ruiz Montesinos ◽

...

Keyword(s):

Folic Acid ◽

Liver Function ◽

Liver Regeneration ◽

Control Group ◽

Depressant Effect ◽

Oncological Surgery ◽

Portal Branch ◽

Treatment Control ◽

Early Application ◽

Mean Size

Abstract INTRODUCTION Chemotherapy hinders liver function and probably its regenerating capacity, forcing to delay it after surgery. Our objective has been to verify this effect in an experimental model and to see if a hepatotrophic agent can prevent it. MATERIAL AND METHODS Four groups of 6 WAG/RijHsd rats (males, 3-4 months) were submitted to ligation of the portal branch to the left lateral and left paramedian lobes. They were sacrificed 36 h later to quantify the percentage of liver corresponding to the ligated lobes (weight), the number of hepatocyte’s nuclei (nº/100 µm2) and their mean size (µm2). One group received no treatment (control); another folic acid (2.5 mg/kg ip, during surgery); other 5-Fluorouracil (5-FU 50 mg/kg ip 48 h before); and the fourth received folic&5-FU. RESULTS The animals treated with folic acid showed a greater number of hepatocyte’s nuclei (24.4 ± 2.77 vs 15.2 ± 1.51) and their mean size was also greater (121 ± 2.34 vs 111 ± 1.8). However, the reduction in weight of the ligated parenchyma was less than in control group (33.4 ± 1.08 vs 29.5 ± 1.08). 5-FU did not modify the number of nuclei (15.6 ± 18.4), although they were smaller in size (104 ± 1.7). The addition of folic acid to 5-FU increased the number of nuclei (21.7 ± 2.8) and normalized their size (111 ± 3.2). CONCLUSIONS 5-FU exerts a depressant effect on livers regeneration, and folic acid overcomes it. Thus, folic acid could allow early application of chemotherapy without affecting liver regeneration.

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Characterization of Cytokines and Proliferation Marker Ki67 in Chronic Rhinosinusitis with Nasal Polyps: A Pilot Study

Medicina ◽

10.3390/medicina57060607 ◽

2021 ◽

Vol 57 (6) ◽

pp. 607

Author(s):

Rudolfs Janis Viksne ◽

Gunta Sumeraga ◽

Mara Pilmane

Keyword(s):

Connective Tissue ◽

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Cellular Proliferation ◽

Rank Correlation ◽

Control Group ◽

Relative Distribution ◽

Proliferation Marker ◽

Ki 67 ◽

Stimulation Of

Background and Objectives: Chronic rhinosinusitis (CRS) is a condition that affects as much as 10.9% of the population and, along with presence of nasal polyps, is associated with significant morbidity and decreased quality of life. Studies on molecular pathways that have been activated in nasal polyp tissue are mainly based on cytokine concentration detection. Therefore, our aim is to investigate the complex appearance, relative distribution and interlinks of IL-1, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 and Ki 67 in chronic rhinosinusitis with nasal polyps (CRSwNP) affected human nasal mucosa. Materials and Methods: Samples of nasal polyps were obtained from 12 patients with previously diagnosed CRSwNP and no prior surgery. Control group consisted of samples from 17 otherwise healthy individuals with isolated nasal septum deviation. Tissues were stained for IL-1, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 and Ki67 immunohistochemically. Non-parametric statistic, Mann–Whitney U test and Spearman’s rank correlation coefficient were used. Results: All factors, except connective tissue cytokine IL-10 and proliferation marker Ki-67, had increased presence in connective tissue and decreased presence in epithelium of nasal polyps when compared to controls. Very strong and strong positive correlations between factors were observed. Conclusions: Decreased appearance of IL-1α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 positive structures in the nasal epithelium with selective increase of IL-1α and IL-12 in nasal subepithelial connective tissue characterize the cytokine endotype with dysfunctional epithelial barrier and local stimulation of immune response in the connective tissue in case of chronic rhinosinusitis with polyps. Decrease of IL-6 in both—epithelium and connective tissue with strong correlation between it and IL-7 and IL-10 in connective tissue suggests significant stimulation of this regulatory cytokine and, possibly, the important role in pathogenesis of the development in nasal polyps. Correlations between Ki67 and cytokines indicate possible involvement of IL-4, IL-7 and IL-12 in regulation of cellular proliferation.

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LINC00265 maintains hepatocyte proliferation during liver regeneration by targeting miRNA-28-5p

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbaa049 ◽

2021 ◽

Vol 85 (3) ◽

pp. 528-536

Author(s):

Sheng Yu ◽

Zhonglin Cui ◽

Jie Zhou ◽

Kai Wang ◽

Qingping Li ◽

...

Keyword(s):

Liver Resection ◽

Liver Regeneration ◽

Therapeutic Option ◽

Weight Ratio ◽

Hepatocyte Proliferation ◽

Phase Cell ◽

Luciferase Reporter ◽

Hepatocyte Regeneration ◽

M Phase ◽

Reporter Assays

ABSTRACT Long noncoding RNAs have been implicated in many biological processes, but their roles in liver regeneration still need to be illustrated. Therefore, we aimed to investigate the role of LINC00265 as a pivotal regulator of hepatocyte proliferation during liver regeneration. It was found that LINC00265 is significantly upregulated in rat liver tissues at various time points after 2/3 liver resection. LINC00265 knockdown inhibited hepatocyte proliferation, induced cell apoptosis and led to G2/M phase cell cycle arrestment. In rats subjected to surgery, LINC00265 knockdown decreased liver/body weight ratio, attenuated improvement from liver damage and reduced Ki67 and PCNA expression. Luciferase reporter assays confirmed that miR-28-5p was a direct target of LINC00265, and inhibition of miR-28-5p abolished the effect of LINC00265 knockdown. In summary, LINC00265 might maintain hepatocyte proliferation by targeting miR-28-5p during liver regeneration and should be considered as a promising therapeutic option for hepatocyte regeneration after liver resection.

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