Disturbances of the microcirculation in acute pancreatitis

BACKGROUND: Severe acute pancreatitis is characterized by pancreatic necrosis, resulting in local and systemic inflammation. Pancreatitis affects both the systemic and pancreatic vasculature. This review focuses on the underlying processes involved in the changes of microvascular anatomy following acute pancreatitis. METHODS: A Medline/PubMed search (January 1966 to December 2005) with manual cross-referencing was conducted. All relevant articles investigating the pancreatic microcirculatory anatomy and the effect of pancreatitis on the microcirculation were included. RESULTS: The pancreas is susceptible to ischaemic insult, which can exacerbate acute pancreatitis. There is also increasing evidence of pancreatic and systemic microvascular disturbances in the pathogenesis of pancreatitis, including vasoconstriction, shunting, inadequate perfusion, and increased blood viscosity and coagulation. These processes may be caused or exacerbated by ischaemia-reperfusion injury and the development of oxygen-derived free radicals. CONCLUSION: Acute pancreatitis impairs the pancreatic and systemic microcirculation, which is a key pathological process in the development of severe necrotizing disease.     

Inosine reduces microcirculatory disturbance and inflammatory organ damage in experimental acute pancreatitis in rats

BACKGROUND: Despite improvement in the management of severe necrotizing pancreatitis, mortality remains high. Today, no specific treatment exists. Inflammatory cascades and microcirculatory disturbances play a key role in the pathogenesis of acute pancreatitis. The aim of the present study was to evaluate the effects of inosine, an immunomodulatory substance, on the severity of experimental necrotizing pancreatitis. METHODS: Severe necrotizing pancreatitis was induced in rats. Treatment groups received inosine either prophylactically or therapeutically. Pancreatic injury was evaluated by microcirculatory assessment and histology. RESULTS: Prophylactic inosine significantly attenuated pancreatic microcirculatory disturbances and morphologic injury in necrotizing pancreatitis. However, inosine treatment did not have any beneficial effects when applied therapeutically several hours after onset of the disease. CONCLUSIONS: Prophylactic inosine reduces microcirculatory and pancreatic injury in acute necrotizing pancreatitis. These effects should be assessed in the clinical setting of ERCP and pancreas transplantation.     

Factors involved in the pathogenesis of acute pancreatitis

Pathophysiological and molecular research have marked the understanding of the primary events taking place in triggering acute pancreatitis, although the early diagnosis of pancreas diseases in general, continues to be a source of frustration in modem medicine. This presents the news about pathogenesis (co-localization theory, auto-activation theory of the tripsynogen), location of early events (acinar pancreatic cells which are the "key" involved: muscarinic receptors, acinar membrane, role of ionized calcium, the phenomenon of apoptosis), extracellular events in initiation of acute pancreatitis with the granting of a central place to enzyme activation and systemic inflammatory response. Aspects of early microvascular changes, disturbances of ischemia-reperfusion and systemic microvascular abnormalities are so important that justifies therapeutic concept of microcirculatory protection. Participation of monocyte/macrophage system, excessive activation of leukocytes that involving activation and release of lysosomal enzymes and oxygen free radicals associated with ischemia-reperfusion mechanism are defining for pathogenesis of acute pancreatitis.     

Mechanisms of action of recombinant human activated Protein C

Human activated protein C (APC) is a serineprotease and one of the most important physiological inhibitors of the coagulation system. Apart from anticoagulative effects, profibrinolytic and anti-inflammatory modes of action have been reported for APC. The administration of recombinant human activated protein C (rhAPC), drotrecogin alfa (activated), Xigris, to patients with severe sepsis and sepsis-induced multi-organ failure reduced mortality in large clinical trials. Anti-apoptotic and immunomodulatory effects of rhAPC have been examined in in vitro experiments and in experimental animal studies. Moreover, a reduction of endothelial cell permeability, enhanced endothelial cell survival as well as improvements of microcirculatory disorders have been proposed for rhAPC. The manifold mechanisms of action of APC may give reasons for its application in diseases other than sepsis, which are characterized by endothelial and microcirculatory dysfunction, e.g. acute pulmonary or renal failure, ischemic stroke, ischemia-reperfusion injury and acute pancreatitis. A better understanding of the anti-inflammatory, anti-apoptotic and immunomodulatory modes of action of APC could be relevant for dosing and mode of application and may lead to a broadening of the indication field for rhAPC.     

Wirkungsweise von rekombinantem humanem aktiviertem Protein C

Human activated protein C (APC) is a serineprotease and one of the most important physiological inhibitors of the coagulation system. Apart from anticoagulative effects, profibrinolytic and anti-inflammatory modes of action have been reported for APC. The administration of recombinant human activated protein C (rhAPC), drotrecogin alfa (activated), Xigris^®, to patients with severe sepsis and sepsis-induced multi-organ failure reduced mortality in large clinical trials. Anti-apoptotic and immunomodulatory effects of rhAPC have been examined in in vitro experiments and in experimental animal studies. Moreover, a reduction of endothelial cell permeability, enhanced endothelial cell survival as well as improvements of microcirculatory disorders have been proposed for rhAPC. The manifold mechanisms of action of APC may give reasons for its application in diseases other than sepsis, which are characterized by endothelial and microcirculatory dysfunction, e.g. acute pulmonary or renal failure, ischemic stroke, ischemia-reperfusion injury and acute pancreatitis. A better understanding of the anti-inflammatory, anti-apoptotic and immunomodulatory modes of action of APC could be relevant for dosing and mode of application and may lead to a broadening of the indication field for rhAPC.     

The Microcirculation of the Septic Kidney

The renal microcirculation plays a major role in the delivery of blood and oxygen to the kidney. In sepsis, alterations in renal microvascular perfusion, in conjunction with increased oxygen requirements, may contribute to renal failure even when renal macrovascular perfusion is preserved. In this review, we discuss the pathophysiology of the renal microcirculation during sepsis and how it contributes to acute kidney injury. Endothelial dysfunction largely is owing to inflammatory, oxidative, and nitrosative factors. Coagulative disorders and glycocalyx disruption also may contribute to the microcirculatory dysfunction. New technologies in experimental models and human beings are being developed to explore renal microcirculation in vivo. These technologies will allow a better understanding of the pathophysiopathology of the renal microcirculation and will help guide specific therapeutic strategies in sepsis-induced acute kidney injury.     

In vivo microscopy of microcirculatory injury in skeletal muscle following ischemia/reperfusion

While the sequence of biochemical and cellular events in the pathogenesis of ischemia/reperfusion injury is increasingly well understood, the way that these processes interact at the level of microcirculation to promote a distinctive reperfusion injury is less well defined. It is becoming clear, however, that these processes are initiated at the level of microcirculation, and that microcirculatory damage may precede actual tissue injury. Such damage causes microvascular no-reflow, which in turn effectively prolongs the time of tissue ischemia and extends tissue injury. Recently, microcirculatory models have been adapted for study of the microvascular effects of ischemia/reperfusion. We have used a new in vivo mouse cremaster muscle model to study, by direct and quantitative measurement, the acute microvascular changes involved in ischemia/reperfusion. Previously described changes in capillary perfusion and venular leukocyte adhesion were observed in this model following reperfusion after prolonged ischemia (4–6 hours). We have further characterized an intense reactive vasoconstriction or vasospasm that occurs after prolonged ischemia; this vessel reaction may represent an important overlooked cause of no-reflow following ischemia/reperfusion. This article summarizes our work in the context of other available methods that have been used to define the microvascular changes of ischemia/reperfusion. © 1994 Wiley-Liss, Inc.     

Treatment with Met-RANTES reduces lung injury in caerulein-induced pancreatitis

BACKGROUND: Severe acute pancreatitis leads to a systemic inflammatory response characterized by widespread leucocyte activation and, as a consequence, distant lung injury. In CC chemokines the first two cysteine residues are adjacent to each other. The aim of this study was to evaluate the effect of Met-RANTES, a CC chemokine receptor antagonist, on pancreatic inflammation and lung injury in caerulein-induced acute pancreatitis in mice. METHODS: Acute pancreatitis was induced in mice by hourly intraperitoneal injection of caerulein. Met-RANTES was administered either 30 min before or 1 h after starting caerulein injections, and pancreatic inflammation and lung injury were assessed. There were five groups of eight mice each including controls. RESULTS: Treatment with Met-RANTES had little effect on caerulein-induced pancreatic damage. Met-RANTES, however, reduced lung injury when given either before administration of caerulein (mean(s.e.m.) lung myeloperoxidase (MPO) 1.47(0.19) versus 3.70(0.86)-fold increase over control, P = 0.024; mean(s.e.m.) microvascular permeability 1.15(0.05) versus 3.57(0.63) lavage to plasma fluorescein isothiocyanate-labelled albumin fluorescence ratio (L/P) per cent, P = 0.002) or after caerulein administration (lung MPO 1.96(0.27) versus 3.65(0.63)-fold increase over control, P = 0.029; microvascular permeability 0.94(0.04) versus 2.85(0.34) L/P per cent, P < 0.001). CONCLUSION: Treatment with Met-RANTES reduces lung damage associated with caerulein-induced pancreatitis in mice. Chemokine receptor antagonists may be of use for the treatment of the systemic complications of acute pancreatitis.     

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