Mechanism of liver regeneration after liver resection and portal vein embolization (ligation) is different?

Whether or not liver regeneration after portal branch embolization (PE) (ligation, PVL) in the non-embolized (ligated) lobe is by the same mechanism as regeneration in the remnant lobe after liver resection has been reviewed. Portal vein branch embolization and heat shock protein are then discussed. Tumor growth accelerated in the remnant liver after hepatectomy. In contrast, PE or PVL resulted in marked contralateral hepatic hypertrophy and significant reduction of tumor growth in the non-embolized (non-ligated) lobes. Follistatin administration significantly increased liver regeneration after hepatectomy in rats. In contrast, regeneration of non-ligated lobes after PVL was not accelerated by exogenous follistatin. Tumor growth also was not accelerated. The liver regeneration rate peaked at 48–72 h in the nonligated lobe after PVL, a delay of 24 h compared with the remnant liver after hepatectomy. In the postoperative early stage, the expression of activin βA, βC, and βE mRNAs was stronger in PVL than in hepatectomy. At 72 h the expression of activin receptor type IIA mRNA reached a peak in hepatectomy, but was significantly lower in PVL. Thus, regulation of activin signaling through receptors is one of the factors determining liver regeneration after hepatectomy and PVL. These serial experimental results imply that the mechanism of liver regeneration after portal branch ligation (embolization) is different from that after hepatectomy. Heat shock protein was induced in the liver experimentally by intermittent ischemic preconditioning and could play some beneficial role in the recovery of liver function after hepatectomy, even in cirrhotic patients. When heat shock protein following right portal vein embolization in both the embolized and non-embolized hepatic lobes was investigated in clinical cases, a two to fourfold increase in HSP70 was induced in the non-embolized lobe compared with the embolized lobe. Oral administration of geranylgeranylacetone (a non-toxic HSP inducer) suppressed inflammatory responses and improved survival after 95% hepatectomy by induction of HSP70 in rats.     

Liver regeneration after portal vein plus hepatic artery ligation performed heterochronously in rats

Abstract. Background/Purpose: Portal vein ligation (PVL) has been used clinically to decrease the amount of liver before surgical resection, consequently, minimizing postoperative dysfunction in the remaining hypertrophied liver lobes. To date, few reports in the literature have demonstrated the regenerative capacity of unaffected lobes following PVL plus hepatic artery ligation (HAL). This study was conducted in rats to determine a safe and efficacious method of PVL plus HAL, focusing on liver function, the MIB-5 labeling index, and the ratio of the weight of the nonligated lobes to the body weight. Methods: Group I rats were subjected to PVL of the left lateral and median branches alone (corresponding to approximately 70% total liver volume). In group II, we performed PVL and HAL of the same branches simultaneously, while in group III, HAL was performed 48 h after PVL. A laparotomy without ligature was performed in the control group. Rats from each group were killed at 24, 48, 72, 96, and 168 h after surgery. Standard serum liver functions were tested. Proliferative activity in the nonligated liver was expressed using the Ki-67 antigen (MIB-5) labeling index. Body and nonligated lobe weights were measured. Results: At 96 h post-surgery, the ratio of the weight of the nonligated lobe to body weight was significantly higher in group III than in group I and group II, and induction of the MIB-5 labeling index showed maximum levels in group III. However, quantitative determination of serum glutamic-oxaloacetate transaminase (GOT) showed peak levels in group II at 24 h after surgery. Conclusions: From these results, we conclude that the PVL plus HAL heterochronous procedure is safer and more efficacious than PVL only, or simultaneous PVL plus HAL. A better knowledge of the events following such heterochronous ligation should improve the clinical outcome of hepatic resection for liver diseases. Received: January 29, 2001 / Accepted: November 16, 2001     

Simultaneous hepatic and portal vein ligation induces rapid liver hypertrophy: A study in pigs

Background

Liver hypertrophy induced by partial portal vein occlusion (PVL) is accelerated by adding simultaneous parenchymal transection (“ALPPS procedure”). This preclinical experimental study in pigs tests the hypothesis that simultaneous ligation of portal and hepatic veins of the liver also accelerates regeneration by abrogation of porto-portal collaterals without need for operative transection.

ALPPS一期术后肝内干/祖细胞的变化及其与肝再生的关系

目的:探讨肝内干/祖细胞在联合肝脏分割和门静脉结扎二步肝切除术(ALPPS)一期手术后肝再生中的作用。方法:将72只SD大鼠随机均分为ALPPS组、门静脉结扎(PVL)组和假手术组,分别行ALPPS一期手术、单纯PVL和假手术。分别在术后1、2、3、7 d检测各组血清转氨酶、炎症因子水平与肝右中叶肝再生率(HRR),并检测肝脏组织中细胞增殖指标Ki-67与肝内卵圆细胞(干/祖细胞)标志物OV-6表达水平。结果:与假手术组比较,ALPPS组与PVL组术后1~2 d的转氨酶与炎症因子水平均明显升高,且在ALPPS组的升高水平均大于PVL组(均P0.05);ALPPS组与PVL组术后肝右中叶HRR及肝组织Ki-67阳性率明显升高,但ALPPS组在术后3、7 d的HRR明显高于PVL组,术后2、3 d的Ki-67阳性率明显高于PVL组(均P0.05);ALPPS组与PVL组术后肝组织均有明显OV-6表达,但ALPPS组术后2、3 d的OV-6表达水平明显高于PVL组(均P0.05)。结论:ALPPS一期手术诱导的肝再生明显优于PVL,机制可能为ALPPS术后较高的炎症状态使激活肝内干/祖细胞的动员和活化,从而促进快速肝再生有关。     

Effect of partial portal vein ligation on hepatic regeneration

To evaluate the effect of portal hypertension and diminished portal venous blood flow to the liver on hepatic regeneration, male rats were subjected to partial portal vein ligation and subsequently to a two-thirds partial hepatectomy. The levels of ornithine decarboxylase activity at 6 h after partial hepatectomy were greater (p less than 0.001) in the rats with prior partial portal vein ligation than in those without portal hypertension. The rats with prior partial portal vein ligation also had greater (p less than 0.005) levels of thymidine kinase activity at 48 h after partial hepatectomy than did those without portal hypertension. Hepatic sex hormone receptor activity was not affected by prior partial portal vein ligation either before or after partial hepatectomy. The reductions in both estrogen and androgen receptor activity observed in the hepatic cytosol after partial hepatectomy were similar to those observed in control animals. These data indicate that animals with portal hypertension having a diminished hepatic portal blood flow have a normal capacity to regenerate hepatic mass following a hepatic resection.     

Hepatic Arterial Perfusion Is Essential for the Spontaneous Recovery From Focal Hepatic Venous Outflow Obstruction in Rats

We previously observed that focal hepatic venous outflow obstruction recovered spontaneously by the formation of sinusoidal canals in a rat model of portal hyperperfusion. We aimed to investigate whether the lack of hepatic arterial perfusion aggravates parenchymal damage, decelerates recovery and influences the formation of sinusoidal canals after focal hepatic venous outflow obstruction. Rats were subjected to arterialized versus nonarterialized syngeneic liver transplantation after ligating the right median hepatic vein in the donor. Hepatic damage, microcirculation, regeneration and vascular remodeling were evaluated. In arterialized‐recipients, confluent necrosis interspersed with viable periportal islands of hepatocytes, and vascularized sinusoidal canals with visible blood flow, surrounded by normal sinusoidal structure, were visible on postoperative day (POD) 2. Complete parenchymal recovery was consequently established by resorption of necrosis and hepatocyte proliferation, detected in viable portal islands and border zone. Lack of hepatic arterial perfusion caused complete necrosis in the obstruction zone without viable hepatocytes in the periportal area on POD2. Hepatocyte proliferation was only visible in the border zone. On POD28, perfused vascular structures, without neighboring normal sinusoidal structures, were observed in the scar‐like area. Hepatic arterial perfusion determined the extent of hepatic necrosis, the formation of vascularized sinusoidal canals and the parenchymal recovery, after focal hepatic venous outflow obstruction.     

联合肝脏分割和门静脉结扎二步肝切除术大鼠模型的建立

目的:建立联合肝脏分割和门静脉结扎(PVL)二步肝切除术(ALPPS)大鼠模型。方法:将健康60只SD雄性大鼠随机均分为PVL组、ALPPS组、假手术组。PVL组行肝左外叶、左中叶、右叶门静脉分支结扎及尾状叶切除,保留肝右中叶分支;ALPPS组在PVL组手术的基础上,将肝左中叶与右中叶在缺血带处离断;假手术组仅游离出门静脉各分支,不结扎。检测大鼠术后肝再生率(HRR)、肝功能情况,以及肝左中叶病理损伤程度与肝右中叶Ki-67的表达。结果:与假手术组比较,ALPPS组、PVL组术后各时间点肝右中叶HRR均明显升高(均P0.05),且第4、7天ALPPS组肝右中叶HRR明显高于PVL组(155.96%vs.118.15%;174.86%vs.133.55%,均P0.05)。PVL组术后早期肝功能指标好于ALPPS组(均P0.05),但后期无统计学差异(均P0.05)。组织病理学检查显示,ALPPS组术后第1天肝左中叶坏死明显多于PVL组;ALPPS组肝右中叶Ki-67表达第2、4天明显高于PVL组(85.36%vs.61.84%;43.40%vs.29.06%,均P0.05)。结论:ALPPS与PVL均能促进肝再生,并且ALPPS比PVL能更快的促进肝再生;成功建立大鼠ALPPS模型,为研究ALPPS肝再生机制及相关并发症奠定了基础。     

Length of laparotomy incision and surgical stress assessed by serum IL-6 level

BACKGROUND: Because surgical stress is thought to have an effect on morbidity, mortality, and remnant tumour progression after surgery, diminishing surgical stress is important. The purpose of this study was to assess in a murine model whether the length and type of laparotomy incision influence surgical stress. METHODS: Serum IL-6 concentrations were measured sequentionally in 220 male BALB/c mice who were assigned to different basic laparotomies, (1-cm versus 2-cm versus 3-cm laparotomy with or without caecal resection), other types of laparotomy (3-cm, 1-cm x 3, 3-cm transverse, 3-cm laparotomy with rapid closure), or 3-cm skin incision with or without laparotomy. The serum level of IL-6 was measured by ELISA. RESULTS: Serum IL-6 levels at 3 and 6h after surgery were significantly higher in the 3-cm laparotomy group (1,680+/-802pg/ml and 1,066+/-507pg/ml, respectively), than in the 1-cm laparotomy group (797+/-427pg/ml and 515+/-212pg/ml, respectively). When caecal resection was added, the serum IL-6 level at 6h was significantly higher in the 3-cm laparotomy group (2,844+/-134pg/ml) than in the 1-cm laparotomy group (2,200+/-379pg/ml). Although the type of laparotomy incision was not associated with the serum level of IL-6, the serum IL-6 level after midline skin incision without laparotomy (245+/-142pg/ml) was significantly lower than that after 3-cm laparotomy (1,680+/-802pg/ml). CONCLUSIONS: The length of laparotomy incision was correlated with the serum level of IL-6 in a murine model. The surgical stress related to abdominal procedures might be decreased when laparotomy wounds are kept as small as possible.     

Recovery of hepatic function determined by cytochrome P450-dependent drug metabolism lags after compensatory hepatic volume changes after portal vein ligation in rats

BACKGROUND: Clinically, portal vein embolization has been proven to be useful as a preoperative treatment for major hepatic surgeries with impaired liver function. However, its effects on the metabolism and elimination of various drugs after portal vein embolization or ligation remain to be elucidated. MATERIALS AND METHODS: A portal vein branch that perfuses the central and left lobes of the liver of male Wistar rat was ligated, and changes in the weights of ligated and nonligated lobules as well as hepatic levels and activities of cytochrome P450 (CYP) isoforms, such as CYP3A2 and CYP2C11, were determined. To evaluate in vivo the effect of PVL on hepatic drug metabolism, the narcotic activity (sleep time) of midazolam, a specific substrate for CYP3A2, was measured. RESULTS: Although plasma levels of alanine aminotransferase and hepatic weight returned to basal levels at day 7 after the portal vein ligation, hepatic activities of CYP3A2 and CYP2C11 still remained low (53% and 54% of control levels, respectively), and returned to their initial levels after about day 14. The metabolism of midazolam was prolonged by approximately three times at day 7 after ligation and returned to basal levels at day 14. CONCLUSIONS: Because hepatic CYP-dependent drug metabolism by CYP isoforms recovered more slowly than the apparent recovery of hepatic volume and plasma alanine aminotransferase levels, the therapeutics of drugs metabolized by the CYP isoforms should be used carefully in patients who receive major hepatectomy with portal vein branch embolization.     

Direct visualization of nitric oxide release by liver cells after the arrest of metastatic tumor cells in the hepatic microvasculature

BACKGROUND: Our previous studies have shown that the injection of B16F1 melanoma cells into the mesenteric vein can induce the rapid local release of nitric oxide (NO) in the liver, causing apoptosis of the melanoma cells in the liver sinusoids and inhibiting the subsequent formation of hepatic metastases. In this study, we have investigated the distribution and cellular source of NO in this model. MATERIALS AND METHODS: In situ liver perfusion was established in both wild-type (wt) and endothelial nitric oxide synthase knockout (eNOS KO) C57BL/6 mice. A specific fluorescent NO probe, 4,5-diaminofluorescein diacetate (DAF-2 DA) (5 micromol/L), was perfused into the portal venous system to label the liver tissue. Then, a MitoTracker Orange labeled B16F1 melanoma cell suspension (2 x 10(6) cells/ml) was injected through a portal vein catheter by a peristaltic pump. Images of the liver tissue were taken by confocal microscopy from a selected area to determine the cellular source of NO. For quantification, the fluorescence intensity of this area was measured over time by Fluoview software. RESULTS: Diaminotriazolofluorescein (DAF-2T) fluorescence (indicating NO generation) was detected in hepatic parenchymal cells located in the periportal region in both wt C57BL/6 and eNOS KO C57BL/6 mice and was intensified by increased flow rate in the portal venous system. The B16F1 cells arrested in the periportal sinusoids, corresponding to zone 1 of the hepatic acinus. DAF-2T fluorescence was expressed by both sinusoidal lining cells and hepatocytes at the site of tumor cell arrest. The fluorescence intensity of these cells increased approximately 2-fold over a time of 500 s. In contrast, there was no increase in the fluorescence intensity of the sinusoidal lining cells and hepatocytes in mice perfused with buffer or in eNOS KO mice perfused with B16F1 cells. CONCLUSION: This study demonstrates that NO is produced by hepatic parenchymal cells mainly located in the periportal zones and that the arrest of the B16F1 melanoma cells causes an eNOS-dependent local burst of NO by the sinusoidal lining cells and hepatocytes in the periportal areas.     

Hepatic arterial buffer response after pediatric living donor liver transplantation: report of a case

Background

Excessive portal pressure at an early stage after living-donor liver transplantation (LDLT) can damage sinusoidal endothelial cells and hepatocytes through shear stress leading to graft failure, or hepatic arterial complications due to low hepatic artery flow from a hepatic arterial buffer response. We encountered a case in which excessive portal vein flow was observed from an early stage after pediatric LDLT. The hepatic artery flow decreased due to a hepatic arterial buffer response.

Case report

A 6-month-old boy with biliary atresia showed excessive portal vein flow early after LDLT with a decreasing hepatic artery flow without anastomotic stenosis from postoperative day 3. The PV flow gradually exhibited a decrease at approximately postoperative day 8 and, similtaneously, hepatic artery flow exhibited improvement.

Conclusion

Because excessive portal pressure after LDLT is reversible, it has been suggested that it may be possible to prevent the progress of hepatic arterial complications if temporary portal pressure modulation can be performed for cases among the high-risk group for hepatic arterial complications.     

Changes of protein synthesis in liver tissue following ligation of hepatic artery or portal vein in rats

The effects of short-term (1 h) complete liver ischemia, hepatic artery ligation (HAL) and portal vein ligation (PVL) on protein synthesis and ATP in liver tissue were studied in rats. Protein synthesis was measured by determining rate of amino acid incorporation into protein in incubated liver slices and was reduced to 34% of the control value after 1 h of complete liver ischemia. ATP was reduced from 3.2 to 0.28 mumol X g-1 wet weight. Following HAL for 1 h, protein synthesis was reduced to 63% of control value and ATP to 2.4 mumol X g-1 wet weight. No significant changes of protein synthesis or ATP were noticed 1 h after PVL. The results indicate that deprivation of hepatic arterial blood plays a greater role than exclusion of portal blood for impairment of protein synthesis in short-lasting liver ischemia. The effect of complete ischemia was more pronounced than the sum effect of HAL and PVL, suggesting that accumulation of metabolites and tissue acidosis might contribute to the consequences of abolished blood supply in liver ischemia. In another series of experiments the effects of HAL and PVL on protein synthesis and ATP in liver tissue were studied after 1, 3 and 7 days. Protein synthesis was reduced 1 day after HAL but normalized after 3 days, probably reflecting development of collaterals. Following PVL, protein synthesis was reduced after 1 day and remained depressed up to 7 days at which time it was 55% of the control value.(ABSTRACT TRUNCATED AT 250 WORDS)     

右美托咪定经门静脉预处理对肝部分切除术患者术中炎症反应和氧化应激的影响

目的探讨右美托咪定经门静脉预处理对肝部分切除术患者术中肝脏缺血-再灌注损伤中炎症反应和氧化应激的影响。方法拟在全麻下行肝部分切除术患者60例,男34例,女26例,年龄25~64岁,体重55~70 kg,ASAⅡ级,肝功能Child-Pugh A级。采用随机数字表法将患者分为三组,每组20例。DP组在游离出门静脉后经门静脉输注右美托咪定1.0μg/kg,DJ组在游离出门静脉后经颈内静脉输注右美托咪定1.0μg/kg,C组给予等容量生理盐水。分别于肝门阻断前10 min、肝门开放后1、6、12、24 h经颈内静脉采血检测血清ALT、AST、TNF-α、IL-33、高迁移率族蛋白1(HMGB1)、血红素氧合酶-1(HO-1)浓度和超氧化物歧化酶(SOD)活性。结果与肝门阻断前10 min比较,肝门开放后1、6、12、24 h三组血清ALT、AST、TNF-α、IL-33、HMGB1和HO-1浓度明显升高,SOD活性明显降低(P<0.05)。与C组比较,肝门开放后1、6、12、24 h DP组和DJ组血清ALT、AST、TNF-α、IL-33、HMGB1浓度明显降低,HO-1浓度和SOD活性明显升高(P<0.05)。与DJ组比较,肝门开放后1、6、12、24 h DP组血清ALT、AST、TNF-α、IL-33、HMGB1浓度明显降低,HO-1浓度和SOD活性明显升高(P<0.05)。结论经门静脉输注右美托咪定能更有效抑制炎症反应和氧化应激,增强机体抗炎抗氧化能力,减轻肝部分切除术患者肝缺血-再灌注损伤。     

Surgical procedures for decompression of excessive shear stress in small-for-size living donor liver transplantation--new hepatic vein reconstruction

We have reported that acute elevation of portal pressure, reflecting wall shear stress of sinusoidal endothelial cells, triggers liver regeneration after partial hepatectomy and that excessive portal hypertension induces liver failure. For prevention of excessive shear stress in small-for-size living donor liver transplantation (LDLT), we developed a new hepatic vein reconstruction to expand the anastomotic site. Fourteen adult patients, who underwent LDLT, were divided into two groups: previous end-to-end hepatic vein reconstruction in nine patients (group P) and the new method in five patients (group N). The outside middle and left hepatic veins of the graft were incised and enlarged to 40 mm. The vena cava was cut 40 mm longitudinally. The graft was positioned a quarter turn counterclockwise with the hepatic vein of the graft anastomosed end-to-side to the vena cava longitudinally. Postoperative portal pressures and serum total bilirubin levels of these two groups showed portal pressure in group N to rapidly decrease below 25 cm H2O following LDLT. No cases showed posttransplanted hyperbilirubinemia above 10 mg/dL in group N; however, all cases were small-for-size grafts. Moreover, serum total bilirubin levels in group N were significantly lower than those in group P. This procedure is simple despite not using a venous patch. If the hepatic vein is narrow or obstructed, such as in Budd-Chiari syndrome, the procedure is applicable. Even in small-for-size grafts, excessive tension did not occurred at the portal vein or hepatic artery anastomoses. Moreover, it is possible to avoid outflow block and posttransplanted hyperbilirubinemia.     

Hyperbaric oxygenation after portal vein emobilization for regeneration of the predicted remnant liver

BACKGROUND: Liver failure often develops after extensive liver resection. Preoperative portal vein embolization to induce compensatory hypertrophy in the predicted remnant liver decreases clinical complications after hepatectomy. The aim of this study was to examine whether hyperbaric oxygenation (HBO) after portal vein embolization increases compensatory hypertrophy of the predicted liver remnant. We performed portal vein ligation and HBO in rats to investigate whether HBO after portal vein embolization increases compensatory hypertrophy of the predicted remnant liver. METHODS: Rats were divided into four groups that underwent (1) laparotomy only (control group); (2) right portal vein ligation (RPL group); (3) RPL followed by HBO at 2 atm (HBO-2 atm group; 1 h/day, 5 days/week for 2 weeks); or (4) RPL followed by HBO at 3 atm (HBO-3 atm group). Laparotomy was repeated after 2 weeks in each group; serum levels of albumin and hepatocyte growth factor (HGF) were measured, and the ratio of the weights of nonligated to ligated hepatic segments and the percentage of hepatocytes expressing proliferating cell nuclear antigen (PCNA) in ligated hepatic segments were determined. RESULTS: In rats that had received HBO after RPL, serum levels of HGF, weight ratios of nonligated to ligated hepatic segments, and the percentage of PCNA-positive hepatocytes in nonligated liver were significantly higher than those in the control group. Furthermore, rats that had undergone 3-atm HBO after RPL had significantly higher serum levels of HGF and percentages of PCNA-positive hepatocytes in nonligated hepatic segments. CONCLUSIONS: Preoperative HBO after portal vein embolization may be useful for inducing compensatory hypertrophy of the predicted remnant liver.     

切应力对大鼠肝窦内皮细胞分泌功能的影响

目的了解不同切应力下肝窦内皮细胞分泌肝细胞生长因子（HGF）、白细胞介素-6（IL-6）、-氧化氮（N0）及-氧化氮合成酶（NOS）的分泌量，探讨切应力对原代培养的大鼠肝窦内皮细胞分泌功能的影响。方法构建血流动力学模型。实验分为对照组（切应力为0 dyn／cm^2）和实验组2组。实验组又按切应力不同分为12、24和48dyn／cm^2 3个亚组。每组分别在4、8、12及24h抽取1ml培养基，利用试剂盒检测培养基中HGF、IL-6、NO和NOS浓度。结果在不同切应力下，肝窦内皮细胞分泌HGF、IL-6、NO和NOS各不相同，在同一时相随着切应力的升高。HGF、IL-6、NO和NOS的分泌量也升高，实验组明显高于对照组（P〈0．01），且48dyn／cm^2组明显高于另两个亚组（P〈0．01）；实验组作用8、12、24h时，HGF、IL-6、No及NOS分泌量明显高于作用4h时。结论体外实验证实，切应力升高时肝窦内皮细胞分泌HGF、IL-6、NO和NOS的量明显增加，提示部分肝切除术后门静脉压力急剧升高能促使肝窦内皮细胞活化。分泌大量促肝细胞再生的细胞因子和介质。     

门静脉分支结扎后门静脉压力变化与肝再生的关系

目的 探讨90%门静脉分支结扎后大鼠门静脉压力变化与肝再生的关系.方法 45只雄性SD大鼠行90%门静脉分支结扎术,其中5只进行假手术作为对照.观察不同时相点门静脉压力和非结扎侧肝脏质量变化,光学显微镜下观察非结扎侧肝细胞的形态学变化,免疫组织化学方法检测未结扎侧肝细胞的增殖细胞核抗原(PCNA),TUNEL法检测未结扎侧肝细胞的凋亡情况,并进行定最分析.采用Pearson相关分析和t检验分析数据.结果 95%(38/40)的大鼠存活.结扎侧肝叶进行性萎缩,非结扎侧肝叶占全肝质量的比例随时问推移而增加,12 h内增加较缓慢,仅为10.75%;而1～5 d则增加速度明显加快,达到27.57%;7～28 d达到平台期,缓慢增加到32.37%.术前门静脉压力为(9.1±1.8)cm H_2O(1 cm H_2O=0.098 kPa);结扎后立即升高,12 h达到高峰(15.8±2.7)cm H_2O,与术前比较差异有统计学意义(t=6.847,P<0.05);1～28 d由(13.6±2.3)cm H_2O逐渐下降为(9.3±2.0)cm H_2O.术前大鼠PCNA阳性细胞计数为7%±3%,术后12 h至3 d由14%±5%上升至21%±6%,第5天达到高峰为26%±7%,与术前比较差异有统计学意义(t=9.129,P<0.05),随后逐渐恢复正常.TUNEL法检测结果显示,术前大鼠肝脏和术后各时相点大鼠未结扎侧肝脏仅见极少量凋亡细胞.大鼠门静脉压力与非结扎侧肝叶肝细胞PCNA的表达在术后1、3、5 d呈正相关(r=0.913,0.896,0.908,P<0.05),在术后14 d时相点呈负相关(r=-0.926,P<0.05).结论 大鼠90%门静脉分支结扎术后,引起未结扎侧肝细胞的活跃再生,再生后的肝脏可恢复原来的质量;肝再生以肝细胞增殖加速为主,而非肝细胞凋亡减少;门静脉压力变化在肝再生过程中可能发挥重要作用.     

The 21-aminosteroid U74389G enhances hepatic blood flow and preserves sinusoidal endothelial cell function and structure in endotoxin-shocked dogs.

BACKGROUND: 21-Aminosteroids are potent anti-inflammatory and antioxidant drugs that provide remarkable endothelial protection in different models of tissue ischemia-reperfusion and inflammation. The effects of 21-aminosteroids in sepsis, a highly inflammatory condition leading to panendothelial activation and injury, are largely uninvestigated. We therefore explored the effects of the 21-aminosteroid U74386G on hepatic blood flow, endothelial cell function, and sinusoidal structure in a canine model of fluid-resuscitated, hyperdynamic endotoxic shock. MATERIALS AND METHODS: Following invasive hemodynamic monitoring and placement of ultrasonic flow probes around the common hepatic artery and the portal vein, 12 anesthetized dogs received 2 mg/kg iv of Escherichia coli endotoxin, followed by generous saline infusion, before randomization into two groups. One group (N = 6) received U74389G as an iv bolus of 80 microg/kg, followed by a continuous infusion of 10 microg/kg. min. The other group (N = 6) received an equivalent volume of vehicle. Hyaluronic acid was measured in plasma for in vivo evaluation of endothelial cell function. Liver biopsies were taken after 4 h of endotoxic shock and prepared for light and electron microscopic examination. RESULTS: Compared with the vehicle-treated controls, U74389G maintained a higher blood flow in the hepatic artery and in the portal vein, without markedly influencing the systemic hemodynamic response. The endotoxin-induced increase in plasma hyaluronic acid levels was significantly attenuated following U74389G treatment (70 +/- 14 vs 188 +/- 24 ng/mL after 3 h of endotoxic shock; P < 0.05). Morphological studies showed that the U74389G-treated group had less sinusoidal endothelial cell damage together with a dramatic reduction of neutrophil infiltration into the liver tissue. CONCLUSION: U74389G can preserve the functional and structural integrity of endothelial cells in the hepatic sinusoid during hyperdynamic endotoxic shock. This endothelial-protective effect was associated with a better maintained hepatic blood flow and a significant attenuation of inflammatory liver injury.     

Preventive effect of preoperative portal vein ligation on endotoxin-induced hepatic failure in hepatectomized rats is associated with reduced tumour necrosis factor alpha production

BACKGROUND: Preoperative portal vein embolization successfully reduces the incidence of postoperative hepatic failure in which endotoxin is postulated to be involved. To identify the mechanism of this preventive effect, the relationship of endotoxin-induced liver injury with tumour necrosis factor (TNF) alpha and nitric oxide production in the peripheral blood, liver and spleen of rats subjected to preoperative portal vein branch ligation (PVL) was compared with that in rats undergoing sham operation. METHODS: Rats with PVL and those that underwent sham operation were subjected to resection of ligated liver lobes (PVL-Hx rats) and two-thirds hepatectomy (noPVL-Hx rats) respectively at day 5, followed by intravenous administration of endotoxin 200 microgram/kg body-weight at day 7. At various time intervals after endotoxin injection, the peripheral blood, liver and spleen tissues were harvested and analysed for TNF-alpha and nitric oxide production. RESULTS: The survival rates of noPVL-Hx and PVL-Hx rats at 48 h after endotoxin administration were 40 and 100 per cent respectively. The former rats showed more extensive liver injury as represented by higher serum aminotransferase and hyaluronate levels than the latter. Plasma concentrations of TNF-alpha at 1.5 h after endotoxin treatment were significantly higher in noPVL-Hx rats (mean(s.e.m.) 22 125(2175) pg/ml; n = 6) than PVL-Hx rats (8344(4076) pg/ml; n = 6) (P < 0.01). Consistent with this, expression of TNF-alpha messenger RNA in the liver and spleen was suppressed in PVL-Hx rats. In two-thirds hepatectomized rats, plasma TNF-alpha concentrations after endotoxin administration at 1, 2 and 3 days (14 350(2186), 26 375(2478) and 23 000(3745) pg/ml respectively; n = 6 each) were significantly higher than that before operation (9067(1559) pg/ml; n = 6) (P < 0.05), whereas those at 5 and 7 days (10 102(3616) and 8580(1427) pg/ml respectively; n = 6 each) showed no significant increase. Furthermore, nitric oxide production in peripheral blood and liver was suppressed by preoperative PVL. CONCLUSION: Prevention of endotoxin-induced liver failure by preoperative PVL is associated with reduced production of TNF-alpha in the later phase of liver regeneration.