Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis

Background Neutrophil elastase (NE) is a major secretory product from activated neutrophils and a major contributor to tissue destruction. However, little is known about the pathogenic contribution of NE to ulcerative colitis (UC). This study was designed to investigate the contribution of NE by measuring NE activity in plasma and colonic mucosal tissue from UC patients and a murine acute colitis model, and to elucidate the therapeutic effect of the NE-specific inhibitor ONO-5046. Methods The NE enzyme activities in plasma and colonic mucosal tissue from UC patients were directly measured using an enzyme–substrate reaction. Acute colitis was induced in mice by administration of 1.5% dextran sulfate sodium (DSS) for 5 days. DSS-induced colitis mice were then treated with ONO-5046 (50 mg/kg body weight) intraperitoneally twice a day. Results In UC patients, the NE enzyme activity was significantly elevated in both the plasma and colonic mucosal tissue compared with healthy controls. In DSS-induced colitis mice, the NE enzyme activity increased in parallel with the disease development. ONO-5046 showed therapeutic effects in DSS-treated mice by significantly reducing weight loss and histological score. ONO-5046 suppressed the NE enzyme activities in both plasma and culture supernatant of colonic mucosa from DSS-induced colitis mice. Conclusions ONO-5046, a specific NE inhibitor, prevented the development of DSS-induced colitis in mice. NE therefore represents a promising target for the treatment of UC patients.     

Effect of a synthetic protease inhibitor (Fut-175) on coagulation abnormalities during experimental acute pancreatitis in dogs

The coagulation disturbance observed during severe acute pancreatitis before and after the infusion of a new synthetic low molecular weight protease inhibitor (Fut-175) was compared. The coagulofibrinolytic changes after acute pancreatitis was induced by the intraductal injection of an autologous bile and trypsin mixture showed decreased platelet counts, decreased plasma fibrinogen levels, prolonged partial prothrombin time and increased fibrinogen degradation products. In addition, markers of hypercoagulation showed increased fibrin-opeptide A and decreased antithrombin III. The two markers of fibrinolysis showed increased B_β15–42 immunoreactive peptide and decreased α₂ antiplasmin. After the infusisn of Fut-175, the coagulo-fibrinolytic abnormalities, which were bserved during severe acute pancreatitis without infusion of Fut-175, were improved. Furthermore, Fut-175 could suppress the rise in fibrino-peptide A and B_β15–42 immunoreactive peptide and decrease in antithrombin III and α₂ antiplasmin. Thus, Fut-175 seems to be an effective inhitor of protease-mediated hypercoagulation and fibrinolysis in severe acute pancreatitis. This work is supported by a part of grant-in aid of pancreatic disease of Japanese Ministry of Health and Welfare.     

Effect of a neutrophil elastase inhibitor on ventilator-induced lung injury in rats

Objective

We hypothesized that pretreatment with sivelestat therapy could attenuate ventilator-induced lung injury (VILI) and lung inflammation in a rat model.

Methods

The neutrophil elastase inhibitor was administered intraperitoneally 30 min before and at the initiation of ventilation. The rats were categorized as (I) sham group; (II) VILI group; (III) sivelestat group; (IV) early sivelestat group. Wet-to-dry weight ratio, bronchoalveolar lavage fluid (BALF) neutrophil and protein, tissue malondialdehyde (MDA) and histologic VILI scores were investigated.

Results

The ratio of wet-to-dry weight, BALF neutrophil and protein, tissue MDA and VILI scores were significantly increased in the VILI group compared to the sham group [3.85±0.32 vs. 9.05±1.02, P<0.001; (0.89±0.93)×10⁴ vs. (7.67±1.41)×10⁴ cells/mL, P<0.001; 2.34±0.47 vs. 23.01±3.96 mg/mL, P<0.001; 14.43±1.01 vs. 36.56±5.45 nmol/mg protein, P<0.001; 3.78±0.67 vs. 7.00±1.41, P<0.001]. This increase was attenuated in the early sivelestat group compared with the sivelestat group [wet-to-dry ratio: 6.76±2.01 vs. 7.39±0.32, P=0.032; BALF neutrophil: (5.56±1.13)×10⁴ vs. (3.89±1.05)×10⁴ cells/mL, P=0.021; BALF protein: 15.57±2.32 vs. 18.38±2.00 mg/mL, P=0.024; tissue MDA: 29.16±3.01 vs. 26.31±2.58, P=0.049; VILI scores: 6.33±1.41 vs. 5.00±0.50, P=0.024].

Conclusions

Pretreatment with a neutrophil elastase inhibitor attenuates VILI in a rat model.     

The therapeutic effect of a new synthetic protease inhibitor (E-3123) on hemodynamic changes during experimental acute pancreatitis in dogs

The therapeutic effect of a new synthetic protease inhibitor on hemodynamic changes was studied in experimental acute pancreatitis. Pancreatitis was induced by the injection of autologous bile mixed with trypsin into the main pancreatic duct after ligating the accessory duct. Plasma beta-endorphin concentrations and cardiovascular function were measured. Seventeen dogs (control group) were given 10 ml/kg/hr of lactate Ringer’s solution intravenously 1 hr before the induction of pancreatitis and throughout the experiment. Seven dogs (the low protease inhibitor group) were given an intravenous bolus injection of 0.4mg/kg of a new synthetic protease inhibitor, E-3123 (4-(2-succiminido-ethylthio)4-geranidinobenzoate methanesulfate) 30 min after the induction of pancreatitis and then a continuous intravenous infusion at 3 Μg/kg/min throughout the experiment. Seven dogs (the high protease inhibitor group) received an intravenous bolus injection of 3 mg/kg and a continuous intravenous infusion at 50 Μg/kg/min of E-3123 according to the same method as in the low protease inhibitor group. The mortality rate during the experiment was 41% (7/17) in the control group, 28.5% (2/7) in the high protease inhibitor group and 0% in the low protease inhibitor group. The increase in the plasma beta-endorphin levels in the control group was statistically significant. When E-3123 was given 30 min after the induction of pancreatitis, the increase in the plasma beta-endorphin levels in the high protease inhibitor group was also found to be increased statistically significant, compared with preinduction levels, but the increase was statistically significantly lower than that in the control group. Plasma beta-endorphin levels in the low protease inhibitor group, however, did not increase. The protease inhibitor infusion as used in this experiment can bring about improvement in hypotension and myocardial depression to an extent by inhibiting the release of betaendorphin, suggesting that the inhibitory effect of the protease inhibitor on beta-endorphin release contributes to the improvement in hemodynamic changes during pancreatitis. There may also be an optimal therapeutic dose of this drug for the treatment of hypotension and myocardial depression secondary to betaendorphin release. This work was supported in part by a grant-in-aid from the Japanese Ministry of Health and Welfare (Pancreatic Disease) and Grant 03670638 from the Japanese Ministry of Education, Science and Culture.     

Effect of ONO-5046, a specific neutrophil elastase inhibitor, on the phorbol myristate acetate-induced injury in isolated dog lung

Phorbol myristate acetate (PMA) activates neutrophils and causes acute lung injury. We determined the effect of ONO-5046, a specific neutrophil elastase inhibitor, on the increase in microvascular permeability induced by PMA in isolated dog lung perfused with autologous blood at a constant perfusion flow. The vascular permeability was assessed by the capillary filtration coefficient (Kf, c) and the solvent-drag reflection coefficient (sigma f). PMA (13.3 micrograms) increased vascular permeability, as evidenced by an increase in Kf, c from 0.18 +/- 0.02 to 0.92 +/- 0.14 mL/min/cmH2O/100 g and a decrease in sigma f to 0.35 +/- 0.01 as compared to control values of 0.69 +/- 0.06. The PMA-induced changes in Kf, c and sigma f were dose-dependently attenuated by pretreatment with ONO-5046 (2-20 mg). We conclude that ONO-5046 can effectively attenuate the PMA-induced injury in the isolated blood-perfused dog lungs.     

Effect of a selective neutrophil elastase inhibitor on early recovery from body water imbalance after transthoracic esophagectomy

The objective of the study was to evaluate the efficacy of sivelestat, a selective neutrophil elastase inhibitor, on body fluid balance after transthoracic esophagectomy. Esophagectomy with elective lymphadenectomy may induce excessive release of neutrophil elastase, which then promotes vascular permeability and an excessive water shift from the intravascular space to the peripheral compartment. Body fluid imbalance after esophagectomy often leads to circular instability, a decrease of urine output, and a delay in the shift to a diuretic state. The study was designed as a case‐control study with a historical control group. A retrospective analysis was performed to examine our hypothesis that sivelestat improves abnormal body fluid retention and prevents subsequent pulmonary complications. To reveal the direct influence of sivelestat on the postoperative course, we avoided using steroids or other diuretic agents. Eighty‐eight patients who underwent thoracic esophagectomy with extended lymphadenectomy from 2000 to 2008 were divided into two groups: those treated from 2003 to 2008, who all received postoperative administration of sivelestat (n = 60); and those treated from 2000 to 2002, who did not receive sivelestat and were used as the control group (n = 28). Both groups received fluid management using the same protocol. The time to reach a diuretic state, time until extubation of the tracheal tube, and development of delayed respiratory dysfunction were compared between the groups using univariate and multivariate analysis. The time until a shift to a diuretic state was significantly shorter after treatment with sivelestat (p < 0.0001) and with a shorter operation time (p < 0.0001). The tracheal tube was extubated significantly earlier in the sivelestat group (p < 0.0001) and the incidence of delayed respiratory dysfunction was also significantly lower (p = 0.0028) in this group. Multivariate logistic regression analysis showed that a delay in a shift to a diuretic state was a strong independent risk factor for the time to tracheal extubation (odds ratio 2.539, p = 0.0056) and occurrence of delayed respiratory dysfunction (odds ratio 1.989, p = 0.0104). Sivelestat treatment was not independently associated with reduced pulmonary complications, but the diuretic state was strongly regulated by sivelestat treatment (odds ratio 0.044, p = 0.0003). Thus, administration of sivelestat has a beneficial influence on recovery from body water imbalance through a more rapid return to a diuretic state after esophagectomy, which contributes to prevention of subsequent pulmonary complications.     

Beneficial effects of the synthetic trypsin inhibitor camostate in cerulein-induced acute pancreatitis in rats

The therapeutic effect and the mechanism of action of the synthetic trypsin inhibitor camostate were studied in a rat model of acute interstitial pancreatitis induced by four subcutaneous injections of 20 g/kg body weight of cerulein at hourly intervals. Rats with acute pancreatitis were given either 100 mg/kg body weight camostate or volume- and pH-adjusted water via an orogastric tube 30 min after the last cerulein injection. The elevation of serum amylase activity was significantly reduced by camostate treatment and the peak value was seen 1 hr earlier than that observed in the rats that did not receive camostate. Camostate also inhibited the reduction in pancreatic content of lipase and amylase seen during experimental pancreatitis. These effects were accompanied by alleviation of the histologic signs of acute pancreatitis such as cellular infiltration and acinar cell vacuolization. After oral administration, camostate and its metabolite were absorbed from the intestine and were detectable in plasma for more than 6 hr in concentrations high enough to have antiprotease activity. In addition, camostate in the duodenum was able to increase pancreatic juice flow and protein output and to stimulate endogenous secretin release. These results suggest that oral administration of camostate reduces the severity of cerulein-induced acute pancreatitis by releasing endogenous secretin and by its antiprotease activity.This work was supported in part by a grant from the Japanese Ministry of Health and Welfare (Intractable Disease of the Pancreas).     

Novel strategies for the treatment of acute pancreatitis based on the determinants of severity

Acute pancreatitis (AP) is a common disease for which a specific treatment remains elusive. The key determinants of the outcome from AP are persistent organ failure and infected pancreatic necrosis. The prevention and treatment of these determinants provides a framework for the development of specific treatment strategies. The gut‐lymph concept provides a common mechanism for systemic inflammation and organ dysfunction. Acute and critical illness, including AP, is associated with intestinal ischemia and drastic changes in the composition of gut lymph, which bypasses the liver to drain into the systemic circulation immediately proximal to the major organ systems which fail. The external diversion of gut lymph and the targeting of treatments to counter the toxic elements in gut lymph offers novel approaches to the prevention and treatment of persistent organ failure. Infected pancreatic necrosis is increasingly treated with less invasive techniques, the mainstay of which is drainage, both endoscopic and percutaneous. Further improvements will occur with the strategies to accelerate liquefaction and through a fundamental re‐design of drains, both of which will increase drainage efficacy. The determinants of severity and outcome in patients admitted with AP provide the basis for innovative treatment strategies. The priorities are to translate the gut‐lymph concept to clinical practice and to improve the design and active use of drains for infected complications of AP.     

中性粒细胞趋化因子在重症急性胰腺炎中的表达及临床意义

目的:探讨中性粒细胞趋化因子(CINC)在重症急性胰腺炎 (SAP)发病机制中的作用．方法:采用向胆胰管逆行注射50 g／L牛磺胆酸钠建立大鼠 SAP模型,48只♂SD大鼠随机分为手术对照组和SAP组,分别检测各组不同时间点血清淀粉酶和胰腺组织病理学改变, 用免疫组织化学法和半定量逆转录聚合酶链反应(RT-PCR) 法检测胰腺组织中CINC蛋白和CINCmRNA表达的变化情况．结果:牛磺胆酸钠组与手术对照组相比,大鼠的血清淀粉酶明显增高、胰腺组织学改变明显;术后1 h胰腺腺泡细胞 CINC蛋白和胰腺组织中CINC mRNA的表达高于手术对照组,随着时间的延长表达逐渐增强,牛磺胆酸钠组术后1 h胰腺腺泡细胞CINC mRNA表达较手术对照组明显增高分别为 (0.37±0．10 vs 0．29±0．10,P<0．05),并且随着时间的延长差别更加明显;免疫组化显示CINC蛋白表达也高于手术对照组．结论:CINC可能在SAP发病过程中起了重要的作用.     

Prospective randomized controlled study on the effects of perioperative administration of a neutrophil elastase inhibitor to patients undergoing video‐assisted thoracoscopic surgery for thoracic esophageal cancer

Sivelestat sodium hydrate (Ono Pharmaceutical Co., Osaka, Japan) is a selective inhibitor of neutrophil elastase (NE) and is effective in reducing acute lung injury associated with systemic inflammatory response syndrome (SIRS). We conducted a prospective randomized controlled study to investigate the efficacy of perioperative administration of sivelestat sodium hydrate to prevent postoperative acute lung injury in patients undergoing thoracoscopic esophagectomy and radical lymphadenectomy. Twenty‐two patients with thoracic esophageal cancer underwent video‐assisted thoracoscopic esophagectomy with extended lymph node dissection in our institution between April 2007 and November 2008. Using a double‐blinded method, these patients were randomly assigned to one of two groups preoperatively. The active treatment group received sivelestat sodium hydrate intravenously for 72 hours starting at the beginning of surgery (sivelestat‐treated group; n= 11), while the other group received saline (control group; n= 11). All patients were given methylprednisolone immediately before surgery. Postoperative clinical course was compared between the two groups. Two patients (one in each group) were discontinued from the study during the postoperative period because of surgery‐related complications. Of the remaining 20 patients, 2 patients who developed pneumonia within a week after surgery were excluded from some laboratory analyses, so data from 18 patients (9 patients in each group) were analyzed based on the arterial oxygen pressure/fraction of inspired oxygen ratio, white blood cell count, serum C‐reactive protein level, plasma cytokine levels, plasma NE level, and markers of alveolar type II epithelial cells. In the current study, the incidence of postoperative morbidity did not differ between the two groups. The median duration of SIRS in the sivelestat‐treated group was significantly shorter than that in the control group: 17 (range 9–36) hours versus 49 (15–60) hours, respectively (P= 0.009). Concerning the parameters used for the diagnosis of SIRS, the median heart rates on postoperative day (POD) 2 were significantly lower in the sivelestat‐treated group than in the control group (P= 0.007). The median arterial oxygen pressure/fraction of inspired oxygen ratio of the sivelestat‐treated group were significantly higher than those of the control group on POD 1 and POD 7 (POD 1: 372.0 [range 284.0–475.0] vs 322.5 [243.5–380.0], respectively, P= 0.040; POD 7: 377.2 [339.5–430.0] vs 357.6 [240.0–392.8], P= 0.031). Postoperative white blood cell counts, serum C‐reactive protein levels, plasma interleukin‐1β, tumor necrosis factor‐α levels, and plasma NE levels did not differ significantly between the two groups at any point during the postoperative course, nor did serum Krebs von den Lungen 6, surfactant protein‐A, or surfactant protein‐D levels, which were used as markers of alveolar type II epithelial cells to evaluate the severity of lung injury. Plasma interleukin‐8 levels were significantly lower in the sivelestat‐treated group than in the control group on POD 3 (P= 0.040). In conclusion, perioperative administration of sivelestat sodium hydrate (starting at the beginning of surgery) mitigated postoperative hypoxia, partially suppressed postoperative hypercytokinemia, shortened the duration of SIRS, and stabilized postoperative circulatory status after thoracoscopic esophagectomy.     

大黄对大鼠急性出血性胰腺炎的影响

目的 观察中药大黄对大鼠急性出血性胰腺炎的作用以及对胰腺外分泌功能的影响。方法 采用铃蟾肽加水浸束缚应激的方法诱导大鼠急性出血性胰腺炎，经口灌服大黄醇抽提物75～150mg／kg2次。观察血清淀粉酶、胰腺湿重、胰腺血流量及胰腺组织病理改变；并观察大黄与奥曲肽对胰液外分泌功能的影响。结果 大黄治疗组的胰腺坏死和中性粒细胞浸润明显减轻；胰腺湿重、血清淀粉酶活性和胰腺血流量均有剂量依赖性改善。胰腺炎组大鼠胰液流量、胰液蛋白含量均明显下降，胰液碳酸氢根含量没有明显改变，大黄治疗组胰液淀粉酶活性明显降低，与奥曲肽治疗组比较无统计学差异，其胰液碳酸氢根含量明显升高，奥曲肽则无此作用。结论 大黄可有效改善大鼠急性出血性胰腺炎的严重程度，与抑制胰腺炎性反应、改善胰腺血流量和抑制胰酶分泌、促进胰液引流等多靶位作用有关。     

重症急性胰腺炎患者器官功能衰竭的临床特点与治疗

器官功能衰竭是导致重症急性胰腺炎(SAP)患者死亡的重要因素。近年得益于对SAP病理生理研究的进一步深入和经验技术的不断积累,在SAP患者器官功能衰竭诊断治疗方面取得了长足的进步。介绍了SAP并发器官功能衰竭的临床特点和SAP应注意重点加强的治疗措施。目前认为SAP一旦发生容易造成器官功能衰竭,及时规范的治疗能缩短病程,显著降低病死率。     

Neutrophil elastase inhibitor (ONO-5046) prevents lung hemorrhage induced by lipopolysaccharide in rat model of cerulein pancreatitis

The protective effects of a neutrophil elastase inhibitor (ONO-5046) on cerulein-induced pancreatitis followed by a septic challenge with intraperitoneal lipopolysaccharide (LPS) were studied in a rat model. Pancreatitis was induced by four intramuscular injections of cerulein (50 μg/kg at 1-hr intervals). ONO-5046 was administered by continuous intravenous infusion via the right jugular vein (50 mg/kg/hr, 30 min prior to the first cerulein injection to 20 hr following the last cerulein injection). Significant differences in serum amylase and pancreatic wet weight ratio were not observed between the animals with pancreatitis treated with or without ONO-5046. There was no significant difference in thein vitro tumor necrosis factor-alpha (TNF-α) production by peritoneal macrophages from rats with pancreatitis treated with or without ONO-5046. In a second experiment, LPS (10 mg/kg) was administered intraperitoneally as the septic challenge 6 hr following the first cerulein injection. Lung hemorrhage was seen in the animals with pancreatitis untreated with ONO-5046 24 hr following the first cerulein injection. No significant lung hemorrhage was observed in the animals with pancreatitis treated with ONO-5046 administering 30 min prior to the first cerulein injection. These results suggest that lung hemorrhage in cerulein-induced pancreatitis that follows a septic challenge with LPS can be prevented by the intravenous administration of ONO-5046. Thus there is a significant role for neutrophil elastase in pancreatitisassociated lung injury.     

Significance of apoptotic cell death in systemic complications with severe acute pancreatitis

In severe acute pancreatitis, multiple organ failure in the early stage after onset, and sepsis in the late stage, due to infection of pancreatic or peripancreatic devitalized tissue, contribute to its high mortality. In analogy with sepsis, evidence has accumulated of the significance of apoptotic cell death in the systemic manifestations associated with acute pancreatitis. Since we identified apoptosis-inducing activity in pancreatitis-associated ascitic fluid in 1995, a number of investigators, including our group, have reported, through animal experiments, that apoptosis occurred in the parenchymal cells constituting organs, such as alveolar epithelial cells in the lung, renal tubular cells in the kidney, and hepatocytes in the liver, and this apoptosis was involved in organ dysfunction with severe acute pancreatitis. Moreover, through clinical and experimental investigations, apoptosis has been revealed to be involved in the mechanism of infectious complications in acute pancreatitis. Namely, apoptosis in lymphatic tissues and peripherally circulating lymphocytes is involved in the impairment of cellular immunity, and apoptosis in gut epithelial cells is implicated in bacterial translocation. These results suggest that apoptotic cell death may play a considerable role in affecting mortality and morbidity in severe acute pancreatitis. Control of apoptosis could be a potent strategy for improvement of the clinical outcome in severe acute pancreatitis.     

中性粒细胞弹性蛋白酶抑制剂对小鼠实验性结肠炎的作用研究

目的 观察中性粒细胞弹性蛋白酶(NE)抑制剂西维来司他对葡聚糖硫酸钠(DSS)诱导的小鼠实验性结肠炎的作用.方法 26只健康雄性BALB/C小鼠分为正常对照组(6只)、实验对照组(6只,腹腔注射磷酸盐缓冲液,9 d)、低剂量组(7只,腹腔注射西维来司他50 mg/kg,9 d)、高剂量组(7只,腹腔注射西维来司他100 mg/kg,9 d).除正常对照组外,其余小鼠均予5%DSS溶液自由饮用以制备实验性结肠炎模型.实验第10天时处死全部小鼠并取结肠组织,行组织学损伤评分.酶联免疫吸附法检测小鼠血浆及结肠组织培养上清中NE含量.Western印迹法检测远端结肠组织中NE表达水平.结果 实验对照组小鼠结肠组织学损伤评分(12.00±2.45)显著高于正常对照组(1.88±0.83,P＜0.01).低剂量组和高剂量组的结肠组织学损伤评分差异有统计学意义(分别为10.17±1.17和5.00±1.15,P＜0.05),均显著低于实验对照组(P值均＜0.05),但均显著高于正常对照组(P值均＜0.05).实验对照组血浆NE浓度、结肠组织培养上清NE含量、结肠组织中NE表达水平均较正常对照组明显升高(P值均＜0.05);与实验对照组相比,低剂量组稍有降低(P值均＞0.05),但仍高于正常对照组(P值均＜0.05);高剂量组则显著降低(P值均＜0.05),与正常对照组无差异(P值均＞0.05);高剂量组较实验组和低剂量组显著降低(P值均＜0.05).结论 NE抑制剂西维来司他可改善DSS诱导的小鼠实验性结肠炎病理损伤,高剂量应用效果优于低剂量.NE可能参与溃疡性结肠炎的发病.     

连续性血液净化治疗重症急性胰腺炎合并多器官功能障碍综合征的效果观察

目的观察连续性血液净化(CBP)对重症急性胰腺炎(SAP)合并多器官功能障碍综合征(MODS)患者血清炎症介质的影响。方法选取2008年4月-2013年12月成都军区总医院收治的SAP合并MODS患者65例,采用非随机同期对照试验方法按治疗方式不同分为两组,其中对照组(n=33)接受内科综合治疗,治疗组(n=32)在内科综合治疗基础上给予CBP治疗。监测患者CBP治疗前后APACHEⅡ评分、MODS评分以及血清肿瘤坏死因子(TNF)α、C-反应蛋白(CRP)、血小板衍化生长因子(PAF)、白细胞介素(IL)6、IL-18、一氧化氮(NO)水平变化。计量资料组间比较采用成组t检验,同组治疗前后比较采用配对t检验;计数资料组间比较采用χ2检验。结果两组患者治疗后,APACHEⅡ、MODS评分及血清TNFα、CRP、IL-6、IL-18、PAF、NO水平均较治疗前明显降低,差异均有统计学意义(P值均0.05),且治疗组较对照组降低更为明显(P值均0.001);治疗组患者存活率为90.6%(29/32),对照组患者存活率为78.8%(26/33),两组存活率比较差异无统计学意义(χ2=1.749,P=0.186)。结论 CBP能够有效清除SAP合并MODS患者血清中的炎症介质,从而阻断炎症反应,改善脏器功能,是治疗SAP的有效方法之一。     

Timing of mortality in severe acute pancreatitis： Experience from 643 patients

AIM： To determine the timing of mortality after onset of severe acute pancreatitis （SAP） and the course of the disease in a large series of patients. METHODS： From July 1996 to June 2005, all patients diagnosed with acute pancreatitis at Chang Gung Memorial Hospital, Taipei, Taiwan were retrospectively studied. Three thousand two hundred and fifty episodes of acute pancreatitis were recorded in 2248 patients （1431 males and 817 females; median age, 55.6 years; range, 18-97 years）. Mortality was divided into two groups： early death （≤ 14 d after admission）, and late death （〉 14 d after admission）. The clinical features of patients in these two groups were compared. RESULTS： Although the overall mortality rate of acute pancreatitis was 3.8% （123/3250）, mortality rate of SAP was as high as 16.3% （105/643）. Of those 105 SAP mortalities, 44 （41.9%） deaths occurred within the first 14 d after admission and 61 （58.1%） occurred after14 d. Incidence of early death did not significantly differ from that of late death. The co-morbidities did not contribute to the timing of death. Early deaths mainly resulted from multiple organ failure. Late deaths were mainly caused by secondary complication of infected necrosis. Intraabdominal bleeding significantly caused higher mortality in late death. CONCLUSION： Approximately half （42%） of SAP deaths occur within 14 d and most were due to multiple organ failure. The late deaths of SAP were mostly due to infected necrosis.     

Effect of naloxone on the haemodynamics and the outcome of experimental acute pancreatitis in dogs

Endogenous opioid peptides may play a role in the genesis of pancreatic damage in acute pancreatitis. The effects of naloxone on the haemodynamic changes in acute pancreatitis were investigated by inducing it in dogs with pancreatic ductal injection of fresh trypsin-bile mixture. In the control group (n = 8), acute pancreatitis was characterized haemodynamically by falls in the maximum positive and negative dP/dt (+/- dP/dt), cardiac output (CO) and cardiac index (CI), and increases in the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) as well as an early reduction of pancreatic blood flow (PBF). In another set of eight dogs (naloxone group), naloxone was given intravenously 10 min after the induction of acute pancreatitis (80 micrograms/kg as a bolus + 80 micrograms/kg/h for 3 h). Compared with untreated dogs, naloxone significantly increased PBF and the +/- dP/dtmax; prevented the significant decreases in CO and CI and increases in PVR and SVR, and reduced significantly the severity of pancreatitis, as assessed by both the histological staging and the mortality rate. These results suggest that naloxone limits the progression of acute pancreatitis from oedematous to haemorrhagic form. It is proposed that endogenous opioid peptides may play a role in the pathophysiology of acute pancreatitis.     

实验室指标对急性胰腺炎发生器官衰竭的预测价值

急性胰腺炎(acute pancreatitis,AP)是由多种病因(包括胆源性、酒精性、高脂血症等)引起的腺泡细胞损伤及胰酶释放继以发生胰腺自身消化,从而导致胰腺炎症、出血、坏死、全身性炎症反应综合征和多器官功能衰竭等严重后果的疾病。在大多数患者中,AP患者一般病情较轻,病程及住院时间较短。轻度AP与器官衰竭无关,因此死亡率不到1%。