Pulmonary microcirculation in mild and severe experimental pancreatitis

BACKGROUND: Research aimed at elucidating the pathogenesis of pancreatitis-associated lung injury and evaluating novel strategies for preventing respiratory complications in acute pancreatitis (AP) has not yet involved intravital microscopic (IVM) studies of pulmonary microcirculation in animals with severe disease. OBJECTIVE: To characterize and compare pulmonary microcirculation in severe/necrotizing (NP) and mild/edematous pancreatitis (EP) in the rat. METHODS: EP was induced by intravenous cerulein infusion (n = 10) and NP by a standardized intraductal infusion of glycodeoxycholic acid followed by intravenous cerulein (n = 10). After 24 h a left-sided thoracotomy was performed for IVM examination of pulmonary capillary blood flow, permeability, leukocyte sticking and the thickness of alveolar septi. Further measurements included monitoring of arterial blood gases and histological evaluation of lung injury. RESULTS: In animals with NP, histology revealed severe pulmonary edema together with clustering of polymorphonuclear leukocytes in pulmonary microvessels and alveoli. IVM showed a greater number (n) of leukocytes sticking on the endothelium of pulmonary capillaries (9.4 +/- 0.7 vs. 1.8 +/- 0.2 in healthy control animals) and increased capillary permeability (260 +/- 14 vs. 136 +/- 6% relative fluorescein intensity) while capillary blood flow was decreased (0.41 +/- 0.05 vs. 0.57 +/- 0.03 mm/s). In comparison, changes in EP were significantly less pronounced (flow 0.5 +/- 0.04 mm/s, permeability 156 +/- 4%, leukocyte sticking n = 4.6 +/- 0.7). CONCLUSIONS: These findings suggest that deterioration of pulmonary microcirculation in AP correlates with disease severity and that a model featuring NP may therefore be more suitable to further study pancreatitis-associated pulmonary injury.     

Intravenous contrast medium aggravates the impairment of pancreatic microcirculation in necrotizing pancreatitis in the rat.

BACKGROUND: Previous reports demonstrated that radiographic contrast medium, as used in contrast-enhanced computed tomography, increases acinar necrosis and mortality in experimental pancreatitis. The authors studied the possibility that these changes may be related to an additional impairment of pancreatic microcirculation. METHODS: Fifty Wistar rats had acute pancreatitis induced by intraductal glycodeoxycholic acid (10 mmol/L for 10 min) and intravenous cerulein (5 micrograms/kg/hr for 6 hrs). After rehydration (16 mL/kg), pancreatic capillary perfusion was quantified by means of intravital microscopy at baseline before intravenous infusion of contrast medium (n = 25) or saline (n = 25), and 30 and 60 minutes thereafter. In addition to total capillary flow, capillaries were categorized as high- or low-flow (> or < 1.6 nL/min). RESULTS: Pancreatic capillary flow did not change in either high- or low-flow capillaries after saline infusion. However, contrast medium infusion induced a significant decrease of total capillary flow (p < 0.001). Analysis according to the relative flow rate revealed that this was primarily because of a significant additional reduction of perfusion in low-flow capillaries (p < 0.0001). Furthermore, complete capillary stasis was observed in 15.9 +/- 3.4% after contrast medium as compared with 3.2 +/- 1.2% after saline infusion (p < 0.006). CONCLUSION: Radiographic contrast medium aggravates the impairment of pancreatic microcirculation in experimental necrotizing pancreatitis.     

The relative safety of MRI contrast agent in acute necrotizing pancreatitis.

OBJECTIVE: To validate the safety of gadolinium-diethylenetriamine pentaacetic acid (GD-DTPA) by measuring its effect on pancreatic capillary perfusion and acinar injury in acute pancreatitis. BACKGROUND: Contrast-enhanced computed tomography (CECT) is proposed as a gold standard for early evaluation of acute necrotizing pancreatitis. However, iodinated contrast media used for CECT have been shown in these circumstances to reduce pancreatic capillary flow and increase necrosis and mortality. Recent reports suggest that post-GD MRI provides images comparable to CECT in the assessment of severe acute pancreatitis. METHODS: Necrotizing pancreatitis was induced in 14 Wistar rats by intraductal glycodeoxycholic acid (10 mM/L) and intravenous caerulein (5 microg/kg/h) over 6 hours. Intravital microscopic quantitation of pancreatic capillary blood flow was performed using fluorescein isothiocyanate-labeled erythrocytes after induction of pancreatitis and 30 and 60 minutes after an intravenous bolus of either Ringer's solution or GD-DTPA (0.2 mL/kg). RESULTS: The two study groups were comparable with regard to mean arterial pressure, heart rate, arterial blood gases, hematocrit, amylase, lipase, and trypsinogen activation peptide production throughout the experiment. GD-DTPA did not reduce capillary flow (1.93 +/- 0.05 nL/capillary/min) compared to animals infused with Ringer's solution (1.90 +/- 0.06 nL/capillary/min). CONCLUSIONS: Intravenous injection of GD-DTPA does not further impair pancreatic microcirculation or increase acinar injury in acute necrotizing pancreatitis. Because of this advantage over CT contrast medium, further development of MRI as a staging tool in acute pancreatitis seems desirable.     

Caerulein-induced pancreatitis and islet blood flow in anesthetized rats

BACKGROUND: Microcirculatory mechanisms have been suggested to be involved in the development of acute pancreatitis. Islet blood flow has not previously been studied in this disease. The present study aimed to investigate the effects of caerulein-induced pancreatitis on pancreatic blood perfusion, especially islet blood flow. MATERIALS AND METHODS: Continuous 4 h caerulein-infusion was used to induce mild, edemateous pancreatitis in anesthetized Sprague-Dawley rats. Some animals were then given an additional 2 h infusion of saline. Thus, at 4 or 6 h after initiating caerulein infusion the blood flow to the pancreas, pancreatic islets, and intestines was measured with a microsphere technique. RESULTS: All infused animals demonstrated an edemateous pancreatitis, without hemorrhages. Both total pancreatic and islet blood flow was increased after the 4-h infusion. However, the increase was less pronounced in the islets. After an additional 2 h with only saline infused, the blood flow values in rats initially infused with caerulein were lower than at 4 h, but total pancreatic blood was still higher than in control rats. No effects on intestinal blood flow values were seen. CONCLUSIONS: Pancreatic islet blood flow in rats with mild edematous pancreatitis is increased, but not to the same extent as that in the whole pancreas.     

皮下注射蛙皮缩胆囊肽诱发急性胰腺炎的早期胰腺微循环损伤特征

目的探索急性胰腺炎（ＡＰ）实验动物模型的早期胰腺局部微循环损伤特征及其规律。方法用异硫氰酸荧光素（ＦＩＴＣ）标记红细胞（ＦＩＴＣＲＢＣ）活体微循环技术、微血管树脂和墨汁灌注光镜和扫描电镜技术,对蛙皮缩胆囊肽（ｃａｅｒｕｌｅｉｎ）诱发ＡＰ早期胰腺局部微循环改变进行动态观察。结果实验组血淀粉酶均增高;光镜及扫描电镜显示胰腺小叶内动脉括约肌早期出现损伤,细胞胞浆内大量空泡形成,表现为持续痉挛,所属微动脉支配区域毛细血管床构形紊乱;ＦＩＴＣＲＢＣ显示胰腺微循环的流速减慢、流量减少（Ｐ＜００１）;机能毛细血管密度减少、出现灌注不稳定和不规则间歇性灌流（Ｐ＜００５）。结论ＡＰ早期胰腺微循环紊乱的始动环节是胰腺小叶内动脉括约肌损伤及其痉挛,是导致胰腺缺血、微循环障碍的早期关键因素。     

Early microcirculatory derangement in mild and severe pancreatitis models in mice

An in vivo microscopic technique was used to clarify the increase in microvascular permeability and enhanced leukocyte–endothelium interaction of pancreatic microcirculation in experimental pancreatitis of differing severity. Using bovine albumin fluorescein isothiocyanate (FITC) and carboxyfluorescein diacetate succinimidyl ester (CFDASE) as tracers, the change in permeability and the behavior of leukocytes in the acinar microcirculation were quantified during the initial 1, 2, 6, and 12 h after the induction of caerulein pancreatitis in mice. Cold stress was added to produce the severe model. It was revealed that the early microcirculatory changes in the pancreas of caerulein pancreatitis included the increased permeability of endothelial lining and an accumulation of extravasated fluid in the perilobular space, which were more severe if cold stress was added. A decrease in flow velocity was also noted 2 h after the onset of severe pancreatitis. Leukocyte adherence to the endothelial cells was not observed during the first 12 h in either model of severity. In contrast, observation of the hepatic microcirculation revealed a significant number of adherent leukocytes 2 h after the induction of severe pancreatitis. These results suggest that during the early course of acute pancreatitis, leukocyte adherence in the pancreatic microcirculation is a secondary event following the increase in pancreatic vascular permeability. Received: February 21, 2000 / Accepted: March 6, 2001     

缺血-再灌注损伤对大鼠急性胰腺炎胰腺细胞凋亡的影响

目的探讨缺血一再灌注(I／R)损伤对大鼠急性胰腺炎(AP)胰腺细胞凋亡的影响。方法将SD大鼠54只按编号法随机分为对照组(n=6)、胰腺炎组(n=24)和I／R损伤组(n=24)。经胆胰管逆行加压注入3％牛磺胆酸钠建立大鼠AP模型，在此基础上，I／R损伤组通过暂时阻断脾下动脉造成局部胰腺I／R模型，对照组于术后lh，其余两组于术后1h、3h、6h和12h采取断颈方法分批处死动物，应用末端脱氧核苷酸转换酶(TdT)介导的原位末端标记(TUNEL)法检测缺血一再灌注区胰腺细胞凋亡。并观察其病理改变。结果胰腺炎组大鼠术后1h、3h胰腺组织仅为充血、水肿性改变，6h出现出血、坏死性改变；而1／R损伤组大鼠术后1h缺血一再灌注区胰腺呈现出血、坏死性改变，病变持续加重；AP后胰腺凋亡细胞明显增多，I／R损伤组和胰腺炎组的凋亡细胞高峰值分别在术后3h和6h；I／R损伤组术后1h、3h缺血一再灌注区胰腺凋亡细胞显著高于相应时相的胰腺炎组(P＜0．01，P＜0．05)．而6h、12h明显低于胰腺炎组(P＜O．05，P＜O．01)。结论I／R损伤在促发胰腺炎从水肿型向出血坏死型转化过程中，同时诱导胰腺细胞凋亡，细胞凋亡可能是阻止AP病变加重的一个有利反应。     

Thromboxane A2 receptor antagonist prevents pancreatic microvascular leakage in rats with caerulein-induced acute pancreatitis

This study was designed to evaluate the protective effect of thromboxane A2 (TXA2) receptor antagonist, seratrodast, against pancreatic injuries during acute pancreatitis. Acute pancreatitis was induced in rats by intravenous infusion of a supramaximal dose of caerulein (5 microg/kg x h for 4 h). In this model, marked hyperamylasemia, a significant increase in pancreatic water content, and a significant increase in pancreatic micro-vascular leakage of Evans blue dye were observed. Pancreatic subcellular redistribution of a lysosomal enzyme, cathepsin B from the lysosomal fraction to the zymogen fraction as well as a significant increase in pancreatic trypsin content were also observed. Pretreatment with seratrodast at a dose of 2 mg/kg (twice, 8 and 4 h before caerulein infusion) significantly inhibited these pancreatic injuries including hyperamylasemia, increased pancreatic microvascular leakage, redistribution of cathepsin B and increased pancreatic trypsin content. These results suggest that TXA2 may be involved in the pathogenesis of acute pancreatitis in the early stage of the disease and that TXA2 receptor antagonist might be of therapeutic value for treatment of acute pancreatitis.     

Pathogenesis and prevention of early pancreatic infection in experimental acute necrotizing pancreatitis.

OBJECTIVE: The authors test antibiotic strategies aimed at either mitigating bacterial translocation from the gut or delivering antibiotics specifically concentrated by the pancreas for prevention of early secondary infection after acute necrotizing pancreatitis. BACKGROUND: Infection currently is the principal cause of death after severe pancreatitis. The authors have shown that the risk of bacterial infection correlates directly with the degree of tissue injury in a rodent model of pancreatitis. Bacteria most likely arrive by translocation from the colon. METHODS: Severe acute necrotizing pancreatitis was induced in rats by a combination of low-dose controlled intraductal infusion of glycodeoxycholic acid superimposed on intravenous cerulein hyperstimulation. At 6 hours, animals were randomly allocated to five treatment groups: controls, selective gut decontamination (oral antibiotics and cefotaxime), oral antibiotics alone, cefotaxime alone, or imipenem. At 96 hours, surviving animals were killed for quantitative bacterial study of the cecum, pancreas, and kidney. RESULTS: The 96-hour mortality (35%) was unaffected by any treatment regimen. Cecal gram-negative bacteria were significantly reduced only by the oral antibiotics. Pancreatic infection was significantly reduced by full-gut decontamination and by imipenem, but not by oral antibiotics or by cefotaxime alone. Renal infection was reduced by both intravenous antibiotics. CONCLUSIONS: Early pancreatic infection after acute necrotizing pancreatitis can be reduced with a full-gut decontamination regimen or with an antibiotic concentrated by the pancreas (imipenem) but not by unconcentrated antibiotics of similar spectrum (cefotaxime) or by oral antibiotics alone. These findings suggest that 1) both direct bacterial translocation from the gut and hematogenous seeding interplay in pancreatic infection while hematogenous seeding is dominant at extrapancreatic sites and 2) imipenem may be useful in clinical pancreatitis.     

Endothelin receptor blockade improves fluid sequestration, pancreatic capillary blood flow, and survival in severe experimental pancreatitis.

OBJECTIVE: To evaluate the effect of a new endothelin receptor antagonist (ET-RA) on the course of severe experimental pancreatitis. BACKGROUND: Endothelin-1 has been shown to reduce regional blood flow in various organs, including the pancreas, and to aggravate cerulein-induced mild pancreatitis. METHODS: Acute necrotizing pancreatitis (ANP) was induced in rats by standardized intraductal bile acid infusion and cerulein hyperstimulation. Serum trypsinogen activation peptides (TAP) were measured to verify comparable disease severity. Starting 6 hours after the onset of ANP, animals randomly received either saline or the new ET-RA LU-135252. Monitoring included cardiorespiratory parameters, urine output, hematocrit, and TAP levels. After 24 hours, animals were relaparotomized to determine pancreatic capillary blood flow and to assess the amount of free intraabdominal fluid and acinar cell necrosis. Survival was determined in a second set of experiments on 24 animals observed for 48 hours after pancreatitis induction and treatment with either normal saline or ET-RA. RESULTS: Comparable TAP increases confirmed equally severe ANP in both groups before treatment. Treatment with ET-RA significantly reduced the mortality rate, from 50% in untreated animals to 8%. Improved survival was associated with significantly decreased hematocrit, improved urinary output, decreased ascites, and increased pancreatic capillary blood flow. There were no significant differences in plasma TAP and acinar cell injury in the surviving animals of the two treatment groups. CONCLUSION: Therapy with the new ET-RA reduces the early mortality rate in experimental ANP, probably by reducing fluid sequestration and improving microcirculation.     

Oleic acid induced pancreatitis in pigs

An experimental model of edematous pancreatitis in pigs was established and measurement of pancreatic macro- and microcirculatory parameters and determinations of pancreatic enzymes (lipase, phospholipase A) and vasoactive mediators (prostanoids, kallikrein, kininogen) were performed. During general anesthesia the pancreas was isolated in situ. Pancreatic microcirculatory parameters were measured using videofluorescence microscopy after iv administration of FITC-Dextran. In hourly collected samples lipase and phospholipase A activities were determined enzymatically, concentrations of kallikrein, kininogen, and selected prostanoids were measured by radioimmunoassay. Two experimental groups were studied: (1) control (n = 9); (2) edematous pancreatitis induced by injection of oleic acid into the pancreatic artery (free fatty acid, ffa; n = 10). The animals were followed up for 6 hr. Systemic hemodynamic parameters remained constant in both groups. In the pancreatitis group pancreatic blood flow and O2-consumption decreased significantly (-55 and -49%), while pancreatic vascular resistance increased significantly (+50%). During baseline conditions 41% of all capillaries were perfused. In the pancreatitis group there were both areas with persistent stasis as well as areas with continuous perfusion. However, in the latter areas the portion of perfused capillaries decreased significantly to 27%. In the control group the portion of perfused capillaries remained constant. Liberation of lipase and phospholipase A especially into lymph and ascites fluid was measured during pancreatitis. Furthermore, considerable releases of kallikrein into lymph (+50%) and ascites (+800%) and a marked consumption of kininogen in lymph (+90%) and in ascites fluid (+80%) were measured. Activation of the arachidonic acid cascade and a significant release of prostacyclin and thromboxane A2 into pancreatic venous blood and lymph was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intestinal microcirculation and gut permeability in acute pancreatitis: Early changes and therapeutic implications

Translocation of bacteria from the intestine causes local and systemic infection in severe acute pancreatitis. Increased intestinal permeability is considered a promoter of bacterial translocation. The mechanism leading to increased gut permeability may involve impaired intestinal capillary blood flow. The aim of this study was to evaluate and correlate early changes in capillary blood flow and permeability of the colon in acute rodent pancreatitis of graded severity. Edematous pancreatitis was induced by intravenous cerulein; necrotizing pancreatitis by intravenous cerulein and intraductal glycodeoxycholic acid. Six hours after induction of pancreatitis, the permeability of the ascending colon was assessed by the Ussing chamber technique; capillary perfusion of the pancreas and colon (mucosal and subserosal) was determined by intravital microscopy. In mild pancreatitis, pancreatic capillary perfusion remained unchanged (2.13 ± 0.06 vs. 1.98 ± 0.04 nl-min^−l.cap ⁻¹ [control]; P = NS), whereas mucosal (1.59 _± 0.03 vs. 2.28 ± 0.03 nl.min^−l.cap ⁻¹ [control]; P <0.01) and subserosal (2.47 ± 0.04 vs. 3.74 ± 0.05 nl-min^−l.cap ^-1 [control]; P <0.01) colonic capillary blood flow was significantly reduced. Severe pancreatitis was associated with a marked reduction in both pancreatic (1.06 = 0.03 vs. 1.98 ± 0.04 nl’min^-1.cap ^-1 [control]; P <0.01) and colonic (mucosal: 0.59 = 0.01 vs. 2.28 ± 0.03 nl.min^−l.cap ^-1 [control], P < 0.01; subserosal: 1.96 ± 0.05 vs. 3.74 ± 0.05 nl.min^−l.cap ^-1 [control], P <0.01) capillary perfusion. Colon permeability tended to increase with the severity of the disease (control: 147 ±19 nmol.hr^−l.cm {−2}2; mild pancreatitis: 158±23 nmol-hr^−l.cm^-2; severe pancreatitis: 181 ±33 nmol.hr^−l.cm^-2; P = NS). Impairment of colonic capillary perfusion correlates with the severity of pancreatitis. A decrease in capillary blood flow in the colon, even in mild pancreatitis not associated with significant protease activation and acinar cell necrosis or impairment of pancreatic capillary perfusion, suggests that colonic microcirculation is especially susceptible to inflammatory injury. There was no significant change in intestinal permeability in the early stage of pancreatitis, suggesting a window of opportunity for therapeutic interventions to prevent the later-observed increase in gut permeability, which could result in improved intestinal microcirculation. Presented at the Thirty-Seventh Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, Calif., May 19–22, 1996. Supported in part by Deutsche Forschungsgemeinschaft (DFG Fo 197/3).     

Enterokinase induces severe necrosis and rapid mortality in cerulein pancreatitis: characterization of a novel noninvasive rat model of necro-hemorrhagic pancreatitis

BACKGROUND: Unlike edematous pancreatitis, induction of severe necrotizing pancreatitis in rats generally requires an invasive laparotomy with infusion and/or ligation of the pancreatic duct or duodenal or arterial occlusion. The aim of this study was to establish and characterize a noninvasive model of severe acute pancreatitis in rats. METHODS: Wistar rats were infused intravenously with cerulein or a combination of cerulein and enterokinase. Saline (154-mmol/L NaCl) or enterokinase only was infused in controls. In a first set of experiments, intrapancreatic protease activation and the release of cytokines were correlated with the severity of organ injury. Pancreatic and pulmonary injuries were determined at 6 h. In a second set of experiments, we assessed 24-h survival, serum parameters possibly reflecting the course of the disease, and morphologic changes later in the course of the disease. RESULTS: The severity of pancreatic injury and survival were correlated strongly with the amount of enterokinase infused simultaneously with cerulein. Trypsin as well as elastase and cathepsin B activity in pancreatic tissue samples were increased markedly in these animals. Marked pancreatic hemorrhage, necrosis, and leukocyte infiltration were present in animals with the greatest amounts of enterokinase infused. IL-6 and LDH, but not IL-1beta, CRP, and amylase, in serum correlated with the severity of pancreatitis. CONCLUSIONS: This noninvasive rat model of acute pancreatitis is characterized by major pancreatic necrosis, hemorrhage, and fatality. The simple and noninvasive induction technique may have advantages for future studies on inflammatory changes and sepsis in necrotizing pancreatitis compared with other currently available invasive models.     

急性胰腺炎外周循环和胰腺微循环血小板内皮细胞粘附分子-1的表达

目的　探讨急性胰腺炎 (AP)外周循环和胰腺微循环中血小板内皮细胞粘附分子 1(PECAM 1)表达的变化规律。方法　Wistar大鼠 48只 ,诱发AP动物模型 ,用流式细胞仪分析脾静脉和下腔静脉血中多形核白细胞 (PMN )PECAM 1的表达。结果　 ( 1)在急性水肿性胰腺炎(AEP)动物模型中 ,外周循环和胰腺微循环PMNPECAM 1的表达水平在AEP 2、4h组相近 ,自 4h开始 ,外周循环PMNPECAM 1的表达上调直至 8h ;胰腺微循环PMNPECAM 1的表达下调直至 8h ,在AEP 8h组 ,差异有显著性 ( P <0 .0 5 )。 ( 2 )在急性坏死性胰腺炎 (ANP)模型中 ,胰腺微循环PMNPECAM 1的表达下调 ;外周循环组PMNPECAM 1的表达未见明显变化 ,在ANP 4、6h组 ,差异有显著性 (P <0 .0 5 )。结论　AEP胰腺微循环和外周循环PMNPECAM 1的表达呈逆向性 ,在胰腺微循环呈下调趋势 ,在外周循环呈上调趋势 ;ANP胰腺微循环PMNPECAM 1的表达呈加速性下调 ,该结果显示 ,在ANP早期 ,抑制PMNPECAM 1的过度表达可能有助于改善AP病理改变。     

A better model of acute pancreatitis for evaluating therapy.

Existing models of acute pancreatitis have limitations to studying novel therapy. Whereas some produce mild self-limited pancreatitis, others result in sudden necrotizing injury. The authors developed an improved model providing homogeneous moderately severe injury by superimposing secretory hyperstimulation on minimal intraductal bile acid exposure. Sprague-Dawley rats (n = 231) received low-pressure intraductal glycodeoxycholic acid (GDOC) at very low (5 or 10 mmol/L) concentrations followed by intravenous cerulein. Cerulein or GDOC alone caused only very mild inflammation. However, GDOC combined with cerulein was uniformly associated with more edema (p less than 0.0005), acinar necrosis (p less than 0.01), inflammation (p less than 0.006), and hemorrhage (p less than 0.01). Pancreatic injury was further increased and death was potentiated by increasing volume and duration of intraductal low-dose GDOC infusion. There was significant morphologic progression between 6 and 24 hours. The authors conclude that (1) combining minimal intraductal bile acid exposure with intravenous hyperstimulation produces homogeneous pancreatitis of intermediate severity that can be modulated at will; (2) the injury is progressive over at least 24 hours with finite mortality rate; (3) the model provides superior opportunity to study innovative therapy.     

Systemic intravenous infusion of bovine hemoglobin significantly reduces microcirculatory dysfunction in experimentally induced pancreatitis in the rat

OBJECTIVE: To evaluate the effectiveness of bovine hemoglobin on pancreatic microcirculation and outcome in experimental acute rodent pancreatitis. SUMMARY BACKGROUND DATA: Stasis of the pancreatic microcirculation initiates and aggravates acute pancreatitis. Hydroxyethyl-starch (HES) has been shown to improve pancreatic microcirculation. Similarly, bovine hemoglobin might improve rheology due to its colloid effect, but additionally supplies oxygen to oxygen depleted pancreatic tissue. METHODS: In Wistar rats, severe acute pancreatitis was induced by administration of glucodeoxycholic acid i.d. and cerulein i.v. Pancreatic microcirculation was continuously monitored by fluorescence microscopy. Fifteen minutes after the initiation of acute pancreatitis, animals received either 0.8 mL bovine hemoglobin (Oxyglobin), HES, or 2.4 mL 0.9% NaCl i.v. at random. After 6 hours, animals were killed and histopathological damage of the pancreas was assessed using a validated histology score (0-16). RESULTS: In comparison to controls, pancreatic microcirculation improved significantly in the HBOC group (mean difference of capillary density 31.4%; standard error 5.6%; P < 0.001; 95% confidence interval for difference 17.5-45.3). HES was not as effective as HBOC substitution. The histology score revealed less tissue damage in the HBOC group [6.25 vs. 9.25 (3-8.5 vs. 8-10.75, P < 0.001)] in comparison to controls and also in comparison to the HES group [6.25 vs. 8 (3-8.5 vs. 6.5-10.25, P < 0.006)]. CONCLUSIONS: In severe acute pancreatitis, single i.v. injection of bovine hemoglobin improves pancreatic microcirculation and reduces tissue damage.     

Pancreatic microcirculation in acute pancreatitis

We present a review of the microvascular morphology of the pancreas and microstructure of the pancreatic lobule, and report our experimental results of the investigation of pancreatic microcirculation following acute pancreatitis. Impairment of pancreatic microcirculation in the early phase of acute pancreatitis may play a key role in the progression of this disease. Possible contributory mechanisms include increased vascular permeability, reduced blood flow, leukocyte-endothelial cell interaction and intravascular thrombus formation. Using an in-vivo microscope system and off-line computer analysis, we achieved direct visualization and quantification of changes in microvascular permeability and leukocyte behavior in pancreas with acute pancreatitis. Bradykinin and oxygen radicals have been demonstrated to be involved in the increase of vascular permeability in the early stage of caerulein pancreatitis. Leukocyte adherence to the vessels in the pancreatic microcirculation is a secondary event following permeability changes in acute pancreatitis. Leukocyte infiltration during exacerbation of acute pancreatitis is mediated by leukocyte-endothelial cell interaction via leukocyte integrin CD11b/18. Received for publication on Jan. 29, 1997; accepted on April 24, 1997     

质子泵抑制剂对犬胰腺外分泌功能影响的研究

目的 探索质子泵抑制剂（proton pump inhibitor,PPI）对犬胰腺外分泌功能的影响。方法健康成年犬24只平均随机分成4组：对照组（A组）、对照给药组（B组）、胰腺炎组（C组）、胰腺炎给药组（D组）。A组和B组制备犬胰液外引流模型,C组和D组制备犬急性水肿型胰腺炎胰液外引流模型。采用5%牛磺胆酸钠（0.5 mL/kg）以1 mL/min胰管逆行注射制备急性水肿型胰腺炎模型。B组和D组建模成功后立即给予泮托拉唑（0.7 mg/kg+生理盐水50 mL,q12 h）,A组和C组给予等量的生理盐水。各组每12 h收集胰液一次,并测量胰液的分泌量,胰液中的淀粉酶、脂肪酶、总蛋白含量和pH值。胰腺组织送病理学和电镜检查。结果 B组与A组比较,胰液的分泌量,胰液中淀粉酶、脂肪酶的浓度和pH值在第1天和第2天均降低（P ＜0.05）。胰液中总蛋白的含量第1天B组和A组无明显统计学差异（P ＞0.05）,第2天B组低于A组（P ＜0.05）。D组与C组比较,胰液的分泌量,胰液中淀粉酶、脂肪酶、总蛋白的浓度和pH值无明显变化（P ＞0.05）。D组和C组在不同时间段的血淀粉酶、脂肪酶浓度无明显差别（P ＞0.05）。病理学检查未见明显的差别。电镜下可见PPI作用后胰腺腺泡细胞内酶原颗粒增多。结论 质子泵抑制剂能够明显抑制正常犬的胰腺外分泌,但对急性水肿型胰腺炎犬的胰腺外分泌功能影响不大。     

Does edematous pancreatitis exist in biliary-related pancreatitis? A hemodynamic and histologic study of the progression of bile-induced pancreatitis

The progression of pancreatitis induced in dogs by either single or hourly injections of two different bile solutions was monitored to determine whether acute necrotizing pancreatitis developed through an earlier mild interstitial form. In this model of biliary-related pancreatitis, acute interstitial pancreatitis could not be produced. The earliest lesion produced, although having the macroscopic appearance of edematous pancreatitis, was histologically a mild necrotizing form of the disease. If the bile solution was of sufficient concentration, then further injections resulted in progression of the pancreatitis from this mild form of scattered areas of focal acinar necrosis through coalescence of these areas to areas of parenchymal hemorrhage. Pancreatic blood flow, measured through its arterial inflow, increased during the earliest phase of the disease, but then decreased as the disease progressed.