Gastroenterology in developing countries： Issues and advances

Developing countries shoulder a considerable burden of gastroenterological disease. Infectious diseases in particular cause enormous morbidity and mortality. Diseases which afflict both western and developing countries are often seen in more florid forms in poorer countries. Innovative techniques continuously improve and update gastroenterological practice. However, advances in diagnosis and treatment which are commonplace in the West, have yet to reach many developing countries. Clinical guidelines, based on these advances and collated in resource-rich environments, lose their relevance outside these settings. In this two-part review, we first highlight the global burden of gastroenterological disease in three major areas： diarrhoeal diseases, hepatitis B, and Helicobacter pylori. Recent progress in their management is explored, with consideration of future solutions. The second part of the review focuses on the delivery of clinical services in developing countries. Inadequate numbers of healthcare workers hamper efforts to combat gastroenterological disease. Reasons for this shortage are examined, along with possibilities for increased specialist training. Endoscopy services, the mainstay of gastroenterology in the West, are in their infancy in many developing countries. The challenges faced by those se~ing up a service are illustrated by the example of a Nigerian endoscopy unit. Finally, we highlight the limited scope of many clinical guidelines produced in western countries. Guidelines which take account of resource limitations in the form of ＂cascades＂ are advocated in order to make these guidelines truly global. Recognition of the different working conditions facing practitioners worldwide is an important step towards narrowing the gap between gastroenterology in rich and poor countries.     

Intestinal permeability and its association with the patient and disease characteristics in Crohn＇s disease

AIM：To assess the intestinal permeability （IP） in patients with Crohn＇s disease （CD） and study the association of IP with the patient and disease characteristics.
METHODS： One hundred and twenty five consecutive patients of CD （Males： 66） were diagnosed on the basis of a combination of standard clinical, endoscopic, imaging and histological features. CD activity index （CDAI） was used to calculate the activity of the disease while the behavior of the disease was assessed by the modified Montreal classification. IP was measured by the ratio of the percentage excretion of ingested doses of lactulose and mannitol in urine （LMR）. The upper limit of normality of LMR （0.037） was derived from 22 healthy controls.
RESULTS： Thirty six percent of patients with CD had increased IP. There was no significant difference in mannitol excretion （patients vs controls = 12.5% vs 14.2%, P = 0.4652）, but lactulose excretion was significantly higher in patients compared to healthy controls （patients vs controls = 0.326% vs 0.293%, P = 0.0391）. The mean LMR was also significantly higher in the patients as compared to healthy controls [0.027 （0.0029-0.278） vs 0.0164 （0.0018-0.0548）, P = 0.0044]. Male patients had a higher LMR compared to females [0.036 （95% CI 0.029, 0.046） vs 0.022 （95% CI 0.0178, 0.028） （P = 0.0024）, though there was no difference in the number of patients with abnormal IP in boththe sexes. Patients with an ileo-colonic disease had a higher LMR than those with only colonic disease [0.045 （95% CI 0.033, 0.06） vs 0.021 （95% CI 0.017, 0.025） （P 〈 0.001）]. Of patients with ileo-colonic disease, 57.8% had an abnormal IP, compared to 26.7% with colonic and 15.6% with small intestinal disease. Patients with a stricturing disease had significantly higher LMR compared to non-fistulising non-stricturing disease [0.043 （95% CI 0.032, 0.058） vs 0.024 （95% CI 0.019, 0.029） （P = 0.0062）]. There was no correlation of IP with age, disease activ     

New technologies in the gastrointestinal clinic and research： Impedance and high-resolution manometry

The last five years have been an exciting time in the study of esophageal motor disorders due to the recent advances in esophageal function testing. New technologies have emerged, such as intraluminal impedance, while conventional techniques, such as manometry, have enjoyed many improvements due to advances in transducer technology, computerization and graphic data presentation. While these techniques provide more detailed information regarding esophageal function, our understanding of whether they can improve our ability to diagnose and treat patients more effectively is evolving. These techniques are also excellent research tools and they have added substantially to our understanding of esophageal motor function in dysphagia. This review describes the potential benefits that these new technologies may have over conventional techniques for the evaluation of dysphagia.     

Cardiac and vascular changes in cirrhosis： Pathogenic mechanisms

Cardiovascular abnormalities accompany both portal hy-pertension and cirrhosis.These consist of hyperdynamiccirculation,defined as reduced mean arterial pressureand systemic vascular resistance,and increased cardiacoutput.Despite the baseline increased cardiac output,ventricular inotropic and chronotropic responses tostimuli are blunted,a condition known as cirrhotic car-diomyopathy.Both conditions may play an initiating oraggravating pathogenic role in many of the complicationsof liver failure or portal hypertension including ascites,variceal bleeding,hepatorenal syndrome and increasedpostoperative mortality after major surgery or livertransplantation.This review briefly examines the majormechanisms that may underlie these cardiovascular ab-normalities,concentrating on nitric oxide,endogenouscannabinoids,central neural activation and adrenergicreceptor changes.Future work should address the com-plex interrelationships between these systems.     

Interleukin-12 and Th1 immune response in Crohn＇s disease： Pathogenetic relevance and therapeutic inplication

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share clinical and pathological characteristics. The most accredited hypothesis is that both CD and UC result from a deregulated mucosal immune response to normal constituents of the gut microflora. Evidence, however, indicates that the main pathological processes in these two diseases are distinct. In CD, the tissue-damaging inflammatory reaction is driven by activated type 1 helper T-cell (Th1), whereas a humoral response predominates in UC. Consistently, a marked accumulation of macrophages making interleukin (IL)-12, the major Th1-inducing factor, is seen in CD but not in UC mucosa. Preliminary studies also indicate that administration of a monoclonal antibody blocking the IL-12/p40 subunit can be useful to induce and maintain clinical remission in CD patients. Notably, the recently described IL-23 shares the p40 subunit with IL-12, raising the possibility that the clinical benefit of the anti-IL-12/p40 antibody in CD may also be due to the neutralization of IL-23 activity. This review summarizes the current information on the expression and functional role of IL-12 and IL-12-associated signaling pathways both in patients with CD and experimental models of colitis, thus emphasizing major differences between IL-12 and IL-23 activity on the development of intestinal inflammation.     

Relation of Plasma Uric Acid Levels and the Lipid Parameters in Han and Uygur Ethnicity

INTRODUCTION Recent evidence supports a role for uric acid and lipid abnormal metabolism, especially hyperuricemia and hyperlipidaemia as a true cardiovascular risk factors, such as coronary heart disease and stroke. The aim of the present study was to es…     

Inflammatory bowel disease in rats： Bacterial and chemical interaction

AIM：To develop a novel model of colitis in rats, using a combination of iodoacetamide and enteropathogenic E. coli（EPEC）, and to elucidate the pathophysiologic processes implicated in the development of ulcerative colitis （UC）.
METHODS： Hale Sprague-Dawley rats （/7 = 158） were inoculated intrarectally on a weekly basis with 4 different combinations： （a） 1% methylcellulose （HC）, （b） 100 μL of 6% iodoacetamide （IA） in 1% HC, （c） 200 p.L containing 4×10^8 colony factor units （CFU） of EPEC, and （d） combined treatment of （IA） followed by bacteria （13） after 2 d. Thirty days post treatment, each of the four groups was divided into two subgroups; the inoculation was stopped for one subgroup and the other subgroup continued with biweekly inoculation until the end of the experiment. Colitis was evaluated by the clinical course of the disease, the macroscopic and microscopic alterations, activity of myeloperoxidase （HPO）, and by TNF-α gene expression. RESULTS： Findings indicative of UC were seen in the combined treatment （IA ＋ B） as well as the IA continued treatment groups： the animals showed slow rate of increase in body weight, diarrhea, bloody stools, high colonic ulcer score, as well as histological alterations characteristic of UC, with an extensive inflammatory reaction. During the course of the experiment, the MPO activity was consistently elevated and the TNF-α gene expression was upregulated compared to the control animals.
CONCLUSION： The experimental ulcerative colitis model used in the present study resembles, to a great extent, the human disease. It is reproducible with characteristics indicative of chronicity.     

Impact of antithrombin Ⅲ on hepatic and intestinal microcirculation in experimental liver cirrhosis and bowel inflammation: An in vivo analysis

AIM: To analyze the hepatic and intestinal microcirculation in an animal model of liver cirrhosis and inflammatory bowel disease (IBD) and to characterize the anti-inflammatory action of antithrombin Ⅲ (ATⅢ) on leukocyte kinetics and liver damage.METHODS: Hepatic and intestinal microcirculation was investigated by intravital videomicroscopy. Standardized models of experimental chronic liver cirrhosis and bowel inflammation were employed. Animals were divided into four groups (n = 6/group): controls, animals with cirrhosis,animals with cirrhosis and IBD, animals with cirrhosis and IBD treated with ATⅢ.RESULTS: Cirrhosis facilitated leukocyte rolling and sticking in hepatic sinusoids (1.91±0.28 sticker/μm vs0.5±0.5 sticker/μm in controls, P＜0.05). The effect enhanced in animals with cirrhosis and IBD (5.4±1.65sticker/μm), but reversed agter ATⅢ application (3.97±1.04sticker/μm, P＜0.05). Mucosal blood flow showed no differences in cirrhotic animals and controls (5.3±0.31nL/min vs5.4±0.25 nL/min) and was attenuated in animals with cirrhosis and IBD significantly (3.49±0.6 nL/min). This effect was normalized in the treatment group (5.13±0.4nL/min, P＜0.05). Enzyme values rose during development of cirrhosis and bowel inflammation, and reduced after ATⅢ application (P＜0.05).CONCLUSION: Liver cirrhosis in the presence of IBD leads to a significant reduction in mucosal blood flow and an increase in hepatic leukocyte adherence with consecutive liver injury, which can be prevented by administration of ATⅢ.     

Functional hepatic flow in patients with liver cirrhosis

AIM: To evaluate hepatic reserve function by investigating the change of functional hepatic flow and total hepatic flow in cirrhotic patients with portal hypertension. METHODS: HPLC method was employed for the determination of concentration of D-sorbitol in human plasma and urine. The functional hepatic flow (FHF) and total hepatic flow (THF) were determined by means of modified hepatic clearance of D-sorbitol combined with duplex doppler color sonography in 20 patients with cirrhosis and 10 healthy volunteers. RESULTS: FHF, evaluated by means of the D-sorbitol clearance, was significantly reduced in patients with cirrhosis in comparison to controls (764.74+/-167.91 vs 1195.04+/-242.97 mL/min, P<0.01). While THF was significantly increased in patients with cirrhosis in comparison to controls (1605.23+/-279.99 vs 1256.12+/-198.34 mL/min, P<0.01). Portal blood flow and hepatic artery flow all were increased in cirrhosis compared to controls (P<0.05 and P<0.01). D-sorbitol total clearance was significantly reduced in cirrhosis compared to control (P<0.01), while D-sorbitol renal clearance was significantly increased in cirrhosis (P<0.05). In controls FHF was similar to THF (1195.05+/-242.97 vs 1256.12+/-198.34 mL/min, P=0.636), while FHF was significantly reduced compared with THF in cirrhosis (764.74+/-167.91 vs 1605.23+/-279.99 mL/min, P<0.01). CONCLUSION: Our method that combined modified hepatic clearance of D-sorbitol with duplex doppler color sonography is effective in the measurement of FHF and THF. FHF can be used to estimate hepatic reserve function.     

Serum chromogranin-A in hepatocellular carcinoma： Diagnostic utility and limits

AIM: The utility of serum alpha-fetoprotein (α-FP) for the detection of hepatocellular carcinoma (HCC) is questionable. High serum levels of chromogranin-A (CgA) have recently been reported in HCC. Impaired hepatic, renal, and heart functions influence circulating CgA. The aim of this study was to assess sensitivity and specificity of serum CgA as a marker of HCC in patients with liver cirrhosis (LC). METHODS: Serum CgA levels were measured by RIA in 339 patients of which 54 HCC, 132 LC, 45 chronic hepatitis (CH), 27 chronic heart failure (CHF), 36 chronic renal failure (CRF), 45 chronic inflammatory bowel disease (IBD) as disease controls and in 75 healthy controls. Patients with liver disease or IBD and concomitant renal and/or heart failure were excluded. Pearson correlation, non-parametric combination test and confidence interval analysis were used for statistical analysis. RESULTS: Serum CgA above normal values (100 ng/mL) were found in 83% of HCC patients, in 48% of LC patients, in 20% of CH patients, in 33% of IBD patients, in 92% of CRF patients, in 100% of CHF patients, and in none of the healthy controls. The mean CgA values in HCC (769±1046), in LC (249±369), in CH (87±94), in CRF (1390±1401), in CHF (577±539), in IBD (146±287) were significantly higher than those in healthy controls (48±18). HCC patients had higher CgA values (P<0.01) than LC, CH, and IBD patients but did not differ from those with CRF or CHF. The 95% CI for the mean (250-1289 ng/mL) in HCC patients was selected as a CgA range and the lower value of such range was assumed as cut-off. Sensitivity and specificity of CgA, calculated in relation to the cut-off in patients with cirrhosis and HCC, were respectively 61% (CI 48-73%) and 82% (CI 75-88%). Serum a-FP values were >200 ng/mL in 21% of the HCC patients and in none of the LC patients. No significant correlation was found between a-FP and CgA in patients with HCC and in patients with cirrhosis. CONCLUSION: When HCC is suspected and a-FP is normal or <200 ng/mL, CgA serum values represent a complementary diagnostic tool, unless kidney or heart failure is present.     

Persistence of impaired hepatic microcirculation after nonarterialized liver transplantation in the rat

OBJECTIVES: The nonarterialized orthotopic rat liver transplant (NOLT) is a frequently used model in transplantation research that was recently used to investigate microcirculatory alterations during acute rejection, which occurs within 7 days. The present study sought to establish whether NOLT represents a reasonable model for the study of the hepatic microcirculation beyond the immediate reperfusion phase. METHODS: Three groups of animals were studied: sham-operated control (n = 8), NOLT (n = 7) and arterialized orthotopic liver transplant (AOLT; n = 8). The hepatic microcirculation was investigated by intravital fluorescence microscopy and laser Doppler flowmetry (LDF) on day 7 postoperatively. Liver histology and plasma levels of liver enzymes were also assessed. RESULTS: Plasma levels of aspartate aminotransferase, alanine aminotransferase, and bilirubin were significantly higher in NOLT than in AOLT and control animals. The low LDF signal recorded from the surface of the NOLT liver (92 +/- 25 vs. 210 +/- 25 and 172 +/- 14 PU in AOLT and control liver, respectively; p < 0.05) was associated with heterogeneous perfusion at both the lobular and sinusoidal levels (density of perfused sinusoids (n/40,000 microm(2)): 5.8 +/- 0.8, 8.1 +/- 0.3, 8.0 +/- 0.3, respectively; p < 0.05). The percentage of hyperfluorescent Ho342-stained hepatocytes (apoptotic) ranged between 2 and 5% and was not significantly different between groups. The lack of post-transplant arterial supply was associated with an increased hepatic cord width-to-sinusoid diameter ratio (3.77 +/- 0.3, 2.02 +/- 0.04, and 1.72 +/- 0.06 in NOLT, AOLT, and control animals, respectively; p < 0.001 vs. control and AOLT) and increased temporary leukocyte adherence to the walls of the terminal hepatic venules. Intense vitamin A autofluorescence around shunt- and large-diameter, slow-velocity vessels was occasionally encountered in the NOLT liver, which coincided with mild fibrosis and bile ductular proliferation. In the well-perfused areas, both AOLT and NOLT were associated with a significant rise in sinusoidal RBC(vel), which was more marked in the NOLT group. CONCLUSIONS: Our data indicate that NOLT represents an inappropriate model for the long-term study of the hepatic microcirculation. Lack of a post-transplant arterial supply may lead to persistent microvascular perfusion failure, hepatocellular/endothelial cell swelling, and microvascular anomalies related to bile duct injury. Recovery from microcirculatory alterations induced by cold preservation/reperfusion injury appears to depend on an intact hepatic arterial blood supply.     

多层螺旋计算机X线体层扫描肝脏灌注成像的临床应用初步研究

目的 探讨多层螺旋CT肝脏灌注成像技术在肝脏疾病诊断中的应用价值。方法 48例接受多层螺旋CT肝脏灌注成像检查,其中20例为无明显肝脏疾病的志愿者,17例肝硬化患者,11例肝癌患者。计算各组受检者的各项灌注指标并进行比较。结果 (1)肝硬化组与正常组相比,门静脉灌流量(HPP,ml·min~(-1)·ml~(-1))与门静脉灌流指数(PPI)明显减低(HPP:0.49±0.19与0.60±0.16,P=0.038;PPI:0.58±0.14与0.67±0.06,P=0.015),门静脉与肝动脉灌流比率(HPP/HAP)亦明显减低(1.63±0.87与2.12±0.65,P=0.04),肝动脉灌流指数升高(0.42±0.14与0.33±0.06,P=0.015),提示肝硬化时门静脉的灌流量减少,门静脉血流在肝脏血供中的比例减少,而动脉的灌流比重增加。(2)肝癌组的肝动脉灌流量明显高于正常组与肝硬化组(F=11.71,P<0.0001),而HPP明显下降(F=22.84,P<0.0001),HPP/HAP也明显减小(F=20.67,P<0.0001),说明肝癌主要由动脉供血,动脉、门静脉两部分对其供血的比例与正常肝和肝硬化相反。结论 多层螺旋CT肝脏灌注可分别评价肝脏动脉、门静脉的灌注情况,以灌注特点及测得的灌注指标反映肝脏病变的血流动力学改变,且此方法具有无创性和可重复性,在肝脏疾病的诊断、鉴别诊断等方面具有重要的临床实用价值。     

Effect of ischemic preconditioning on P-selectin expression in hepatocytes of rats with cirrhotic ischemia-reperfusion injury

AIM: To investigate the effects and mechanisms of ischemic preconditioning (IPC) on the ischemia/reperfusion (I/R) injury of liver cirrhosis in rats and the effect of IPC on P-selectin expression in hepatocytes.METHODS: Forty male SD rats with liver cirrhosis were randomly divided into sham operation group (SO group),ischemia/reperfusion group (I/R group), ischemic preconditioning group (IPC group), L-Arginine preconditioning group (APC group), L-NAME preconditioning group (NPC group), eight rats in each group. Hepatocellular viability was assessed by hepatic adenine nucleotide level and energy charge (EC) determined by HPLC, ALT, AST and LDH in serum measured by auto- biochemical analyzer and bile output.The expression of P-selectin in the liver tissue was analyzed by immunohistochemical technique. Leukocyte count in ischemic hepatic lobe was calculated.RESULTS: At 120 min after reperfusion, the level of ATP and EC in IPC and APC groups was higher than that in I/R group significantly. The increases in AST, ALT and LDH were prevented in IPC and APC groups. The livers produced more bile in IPC group than in I/R group during 120 min after reperfusion (0.101±0.027 versus 0.066±0.027 ml/g liver,P=0.002). There was a significant difference between APC and I/R groups, (P=0.001). The leukocyte count in liver tissues significantly increased in I/R group as compared with SO group (P＜0.05). The increase in the leukocyte count was prevented in IPC group. Administration of L-arginine resulted in the same effects as in IPC group. However,inhibition of NO synthesis (NPC group) held back the beneficial effects of preconditioning. Significant promotion of P-selectin expression in hepatocytes in the I/R group was observed compared with the SO group (P＜0.01). IPC or L-arginine attenuated P-selectin expression remarkably (P＜0.01). However, inhibition of NO synthesis enhanced Pselectin expression (P＜0.01). The degree of P-selectin expression was positively correlated with the leukocyte counts infiltrating in liver (r=0.602, P=0.000).CONCLUSION: IPC can attenuate the damage induced by I/R in cirrhotic liver and increase the ischemic tolerance of the rats with liver cirrhosis. IPC can abolish I/R induced leukocyte adhesion and infiltration by preventing postischemic P-selectin expression in the rats with liver cirrhosis via a NO-initiated pathway.     

Significance of hepatic arterial responsiveness for adequate tissue oxygenation upon portal vein occlusion in cirrhotic livers

We investigated sinusoidal blood flow and hepatic tissue oxygenation during portal vein occlusion in cirrhotic rat livers to examine the effect of cirrhosis on the properties of hepatic microvascular blood flow regulation. After 8 weeks of CCl4/phenobarbital sodium treatment to induce cirrhosis Sprague-Dawley rats were prepared surgically to allow assessment of portal venous and hepatic arterial inflow using miniaturized flow probes with simultaneous analysis of hepatic microcirculation and tissue oxygenation by fluorescence microscopy and polarographic oxymetry. Age-matched noncirrhotic animals served as controls. Upon portal vein occlusion in cirrhotic livers (flow reduction to < 20%), hepatic arterial blood flow increased 1.5-fold (61 +/- 8 ml/min per 100 g liver) of baseline (40 +/- 7 ml/min per 100 g liver), reflecting an appropriate hepatic arterial buffer response (HABR), similarly as seen in control livers. The net result was a reduction in total liver inflow from 90 +/- 12 to 72 +/- 11 ml/min per 100 g liver, which was associated with a significant decrease in both sinusoidal red blood cell velocity and volumetric blood flow to approx. 71% and 76% of baseline values. However, portal vein occlusion did not cause a deterioration in hepatic tissue pO2 (11 +/- 3 vs. 10 +/- 3 mmHg at baseline). Sinusoidal diameters were found unchanged, disproving a major role of the sinusoidal tone in the regulation of HABR. Microvascular response of cirrhotic livers did not generally differ from that in noncirrhotic livers upon portal inflow restriction. We conclude that HABR in cirrhotic livers operates sufficiently to meet the liver tissue oxygen demand, most probably by an increased relative contribution of arterial perfusion of hepatic sinusoids.     

The role of nitric oxide in the modulation of hepatic microcirculation and tissue oxygenation in an experimental model of hepatic steatosis

BACKGROUND: Impairment of hepatic microcirculation in fatty liver has been assumed to reduce tolerance of the liver against ischemia-reperfusion injury. The present study was aimed to investigate the role of nitric oxide (NO) in the regulation of hepatic microcirculation and tissue oxygenation in hepatic steatosis. METHODS: Sprague-Dawley rats (200-250 g) were fed a 2% cholesterol diet (n = 12) to induce hepatic steatosis or normal diet (n = 12) served as controls for 12 weeks. Hepatic blood flow, microcirculation, tissue oxyhemoglobin (HbO2) and cytochrome c oxidase radox status (Cyt Ox) in response to intravenous bolus administrations of l-arginine (300 mg/kg) or l-NAME (20 mg/kg) were assessed. RESULTS: Animals which developed moderate hepatic steatosis showed significant increase in tissue level of total lipids. Portal blood flow and hepatic microcirculation were significantly reduced as compared to controls (5.7 +/- 0.9 vs. 9.7 +/- 0.9 ml/min, P = 0.003 and 114.5 +/- 9.5 vs. 167.3 +/- 10.0 flux unit, P = 0.003). l-Arginine improved hepatic arterial and portal blood flows as well as microcirculation in fatty livers (P < 0.05), while l-NAME significantly worsened these parameters (P < 0.05). Hepatic tissue HbO2 and Cyt Ox were improved both in fatty and control livers following l-arginine, while l-NAME resulted in decreased HbO2 and Cyt Ox although a transit increase in tissue oxygenation was observed in fatty livers. CONCLUSIONS: NO is involved in the modulation of hepatic microcirculatory perfusion and oxygenation in cholesterol-induced hepatic steatosis. NO metabolisms may be regulated as a potential therapeutic strategy for impaired microcirculation in hepatic steatosis.     

Macrophage inflammatory protein-2 contributes to liver resection-induced acceleration of hepatic metastatic tumor growth

AIM:To study the role of macrophage inflammatoryprotein(MIP)-2 in liver resection-induced acceleration oftumor growth in a mouse model of hepatic metastasis.METHODS:After a 50% hepatectomy,1×10~5 CT26.WTcells were implanted into the left liver lobe of syngeneicbalb/c mice(PHx).Additional animals were treated witha monoclonal antibody(MAB452)neutralizing MIP-2(PHx mAB).Non-resected and non-mAB-treated mice(Con)served as controls.After 7 d,tumor angiogenesisand microcirculation as well as cell proliferation,tumorgrowth,and CXCR-2 expression were analyzed using in-travital fluorescence microscopy,histology,immunohisto-chemistry,and flow cytometry.RESULTS:Partial hepatectomy increased(P<0.05)theexpression of the MIP-2 receptor CXCR-2 on tumor cellswhen compared with non-resected controls,and mark-edly accelerated(P<0.05)angiogenesis and metastatictumor growth.Neutralization of MIP-2 by MAB452 treat-ment significantly(P<0.05)depressed CXCR-2 expres-sion.Further,the blockade of MIP-2 reduced the angio-genic response(P<0.05)and inhibited tumor growth(P<0.05).Of interest,liver resection-induced hepatocyteproliferation was not effected by anti-MIP-2 treatment.CONCLUSION:MIP-2 significantly contributes to liverresection-induced acceleration of colorectal CT26.WT he-patic metastasis growth.     

Gender differences in hepatic ischemic reperfusion injury in rats are associated with endothelial cell nitric oxide synthase-derived nitric oxide

AIM: This study was designed to examine the hypothesis that gender differences in I/R injury are associated with endothelial cell nitric oxide synthase (eNOS)-derived nitric oxide (NO). METHODS: Wistar rats were randomized into seven experimental groups (12 animals per group). Except for the sham operated groups, all rats were subjected to total liver ischemia for 40 min followed by reperfusion. All experimental groups received different treatments 45 min before the laparotomy. For each group, half of the animals (six) were used to investigate the survival; blood samples and liver tissues were obtained in the remaining six animals after 3 h of reperfusion to assess serum NO, alanine aminotransferase (ALT) and TNF-α levels, liver tissue malondialdehyde (MDA) content, and severity of hepatic I/R injury. RESULTS: Basal serum NO levels in female sham operated (FS) group were nearly 1.5-fold of male sham operated (MS) group (66.7±11.0 μmol/L vs45.3μ10.1 μmol/L, P<0.01). Although serum NO levels decreased significantly after hepatic I/R (P<0.01, vs sham operated groups), they were still significantly higher in female rat (F) group than in male rat (M) group (47.8±8.6 μmol/L vs 23.8±4.7 μmol/L, P<0.01). Serum ALT and TNF-α levels, and liver tissue MDA content were significantly lower in F group than in M group (370.5±46.4 U/L, 0.99±0.11 μg/L and 0.57±0.10 μmol/g vs668.7±78.7 U/L, 1.71±0.18μg/L and 0.86±0.11 μmol/g, respectively, P<0.01). I/R induced significant injury to the liver both in M and F groups (P<0.01 vs sham operated groups). But the degree of hepatocyte injury was significantly milder in F group than in M group (P<0.05 and P<0.01). The median survival time was six days in F group and one day in M group. The overall survival rate was significantly higher in F group than in M group (P<0.05). When compared with male rats pretreated with saline (M group), pretreatment of male rats with 17-β-estradiol (E2) (M+E2 group) significantly increased serum NO levels and significantly decreased serum ALT and TNF-α levels, and liver tissue MDA content after I/R (P<0.01). The degree of hepatocyte injury was significantly decreased and the overall survival rate was significantly improved in M+E2 group than in M group (P<0.01 and P<0.05). The NOS inhibitor Nw-nitro-L-arginine methyl ester (L-NAME) treatment could completely abolish the protective effects of estrogen in both male and female rats. CONCLUSION: The protective effects afforded to female rats subjected to hepatic I/R are associated with eNOS-derived NO.