急性胰腺炎中胰腺腺泡细胞信号转导通路

急性胰腺炎(acute pancreatitis,AP)是一种炎症反应所致的胰腺腺泡细胞损伤、间质水肿和出血,并可导致局部和全身并发症.各种因素如胆结石、酒精、局部缺血、遗传等似乎都首先影响胰腺腺泡细胞,引起胰腺腺泡细胞胰酶活化,诱发局部炎症反应[1].AP发病机制中胰腺腺泡细胞受到多种细胞因子调控,这些细胞因子通过结合细胞表面受体,激活细胞内不同的信号转导通路,使胰腺腺泡细胞的功能结构发生变化.     

急性胰腺炎的重要病因:Oddi括约肌功能障碍

50多年以前Lium等指出:"分泌活跃的胰腺如果发生胰管梗阻,就会产生急性胰腺炎"[1].50年来,人们一直在研究急性胰腺炎发生的原因.如今,胆结石、酒精等与急性胰腺炎的关系已经明确.但有些急性胰腺炎患者并无明显的酒精、胆结石、高钙血症、高脂血症等病因,提示在胰腺发生过程中尚有其他病因.     

急性胰腺炎的重要病因：Oddi括约肌功能障碍

50多年以前Lium等指出：“分泌活跃的胰腺如果发生胰管梗阻，就会产生急性胰腺炎”。50年来，人们一直在研究急性胰腺炎发生的原因。如今，胆结石、酒精等与急性胰腺炎的关系已经明确。但有些急性胰腺炎患者并无明显的酒精、胆结石、高钙血症、高脂血症等病因，提示在胰腺发生过程中尚有其他病因。     

酒精性急性胰腺炎发病机制及临床特征

动物实验及临床研究表明,酒精及其代谢产物、细菌内毒素、病毒感染、饮酒方式、吸烟、肥胖及宿主的基因突变及基因多态性在酒精性急性胰腺炎发生中具有重要作用.酒精性急性胰腺炎的发病率已明显增加,其以男性为主,病死率高,重症存活者生活质量低下.本文综述了酒精性急性胰腺炎的发病机制及临床特征.     

细胞焦亡在急性胰腺炎发病机制中的作用

急性胰腺炎是常见的消化系统疾病,可出现局部并发症甚至多器官功能衰竭,其发病机制涉及胰酶自身消化、炎症反应、微循环障碍等方面。介绍了细胞焦亡在急性胰腺炎发病机制中的作用,简述了细胞焦亡的激活途径、炎性小体、效应分子对胰腺及胰腺外器官损伤的机制,认为细胞焦亡的调控在急性胰腺炎发病机制中发挥了重要作用,为急性胰腺炎防治提供新的思路。     

奥曲肽和柴芍承气湯、丹参液治疗重症胰腺炎的作用机制

重症胰腺炎的发病机制十分复杂,包括胰酶和腺泡细胞溶酶体酶的释放;血管通透性的增加和胰腺微循环障碍;巨噬细胞和中性粒细胞的过度刺激释放很多细胞因子、炎症介质和自由基,这些因素相互作用造成胰腺腺泡损伤和肠上皮屏障功能失调,如不及时纠正可导致肠管屏障功能损害、肠菌及毒素移位,引起感染、内毒素血症的双重打击,导致多器官功能失调综合征（ｍｕｌｔｉｐｌｅｏｒｇａｎｄｙｓ－ｆｕｎｃｔｉｏｎｓｙｎｄｒｏｍｅ）,甚至发生多器官衰竭。重症胰腺炎常由胆结石、高脂高蛋白饮食、酒精、缺血等多个因素诱发,因此其是一多因素引…     

慢性胰腺炎的危险因素分析

慢性胰腺炎病因复杂。近年来针对慢性胰腺炎的流行病学研究发现,慢性胰腺炎发病率逐年升高且病因构成发生改变。酒精虽然仍是导致慢性胰腺炎最常见的危险因素,但其比例显著下降,酒精摄入量与慢性胰腺炎的患病风险密切相关。长期吸烟也被认为是慢性胰腺炎相关的独立危险因素。其他病因如遗传性、自身免疫性及特发性慢性胰腺炎等发病率较前增加。在我国,酒精已超越胆道疾病成为慢性胰腺炎的主要病因。     

表观遗传调节因子SIRT6通过减少小鼠氧化应激来保护肝脏免受酒精诱导的组织损伤

正【据《J Hepatol》2019年6月报道】题:表观遗传调节因子SIRT6通过减少小鼠氧化应激来保护肝脏免受酒精诱导的组织损伤(作者Kim HG等)sirtuin 6(SIRT6)作为一种NAD+依赖性去乙酰化酶及一种关键的表观遗传调节因子,其参与调节代谢、DNA修复和炎症反应。然而,SIRT6在酒精性肝病(ALD)中的作用仍不清楚。该研究旨在探讨SIRT6在ALD发病机制中的作用和机制。来自美国印第安纳大学医学院的Kim等开发并表征了Sirt6敲除(KO)和转基因(Tg)小鼠模型,分别用对     

激活蛋白与急性胰腺炎的研究进展

急性胰腺炎(AP)发病机制极为复杂，已知胰酶自身消化、胰腺微循环障碍、细菌移位、炎症介质、细胞因子、氧化应激、一氧化氮、细胞凋亡等参与了作用。随着全身性炎症反应综合征(SIRS)概念的提出，进一步发现AP的发生与白细胞过度激活导致大量细胞因子级联反应引起的SIRS密切相关。激活蛋白(AP-1)是近年来发现的重要转录因子，可以调控炎性蛋白的合成，在AP中有高表达并与其他因子如核因子-κB(NF-κB)共同对AP的发生及转归发挥重要作用。     

急性胰腺炎肝损伤的分子机制

急性胰腺炎进展十分迅速,如不及时控制,可能引发多脏器损伤,更有甚者会因器官功能衰竭而死亡。目前因肝衰竭而死亡的急性胰腺炎患者比例仍较大。肝脏与胰腺在生理上相互联系,在病理上相互影响。本文通过胰腺与肝脏的生理联系、细胞因子、炎症反应、氧化应激、微循环障碍及肠道菌群移位等6个方面对急性胰腺炎肝损伤的分子机制进行阐述。     

Genetics and Alcohol: A Lethal Combination in Pancreatic Disease?

An association between alcohol consumption and pancreatic diseases has been recognized for decades, but the absolute risk for pancreatic disease for individuals who drink alcohol is low. Other than smoking, few additional environmental factors have been identified, which suggests that genetic risk factors may be important. Studies in our laboratory using the Lieber-DeCarli feeding technique demonstrate that alcohol causes oxidative stress and mitochondrial damage and alters neruohormonal regulation of the pancreas after a threshold dose is exceeded, which makes the pancreas susceptible to withdrawal hypersensitivity and acute pancreatitis. Alcohol also shifts cell death from apoptosis to necrosis and promotes fibrosis through anti-inflammatory immune mechanisms. Others have demonstrated that alcohol lowers the threshold for trypsin activation in acinar cells, which increases sensitivity to triggering pancreatitis. In addition, we used the Lieber-DeCarli diet plus recurrent acute pancreatitis insults to develop the first animal model of chronic pancreatitis that mimics human disease. Finally, our North American Pancreatitis Study 2 (NAPS2), which was built on insights from animal studies, confirmed the threshold effect predicted by Charles Lieber (>5 drinks per day and >35 drinks/week). These studies and others also defined distinctive roles of alcohol and genetics in the etiology and progression of chronic pancreatitis.     

Theories, mechanisms, and models of alcoholic chronic pancreatitis

Alcoholic chronic pancreatitis is a severe, disabling, chronic inflammatory condition of the pancreas that is seen in fewer than 5% of alcoholics. The severity and unpredictability of this condition has lead to several theories on the mechanism causing chronic pancreatitis based on careful clinical observation. Hypothetical mechanisms were applied to various animal models. Finally, following multiple lines of evidence, there is a convergence of thought and development of some new models that are quite instructive. Taken together, chronic alcohol consumption by rats results in multiple effects on the pancreas that increase the risk of acute pancreatitis, including ongoing acinar cell injury that lowers the threshold for hyperstimulation-induced acute pancreatitis, neurohormonal injury, and adaptation that results in acinar cell hyperstimulation, increased susceptibility to viral mediated acute pancreatitis, and possibly other factors. After acute pancreatitis initiates the inflammatory process, the chronic inflammation and fibrosis of alcoholic chronic pancreatitis are driven by diet, the acinar cell stress response to continued alcohol that may be potentiated by toxic alcohol metabolites, hypoxia, hyperstimulation, and partial duct obstruction; plus the effects of proinflammatory immunocytes and cytokines; and by stellate cell-mediated fibrosis driven by anti-inflammatory cytokines, alcohol, and alcohol metabolites. The factors determining which alcoholic will develop alcoholic chronic pancreatitis likely involve genetic factors, dietary factors, and susceptibility to pancreatic injury through several mechanisms ranging from trauma to gallstones to viruses.     

A Prospective Cohort Study of Smoking in Acute Pancreatitis

Background/Aims: Little is known about risk factors for acute pancreatitis other than gallstones and alcohol consumption. The aim of this study was to investigate if smoking or body mass index (BMI) are associated with acute pancreatitis and to determine relative risks (RR) for acute pancreatitis related to smoking, BMI, and alcohol consumption. Methods: From 1974 to 1992, selected birth-year cohorts of residents in Malmö, Sweden (born 1921–1949) were invited to a health-screening investigation including physical examination, blood sampling and a questionnaire. In total, 33,346 individuals participated. Cases of acute pancreatitis were identified from diagnosis registries (n = 179). Incidence rates were calculated in different risk factor categories. A Cox's analysis revealed RR. Results: Current versus never smoking at baseline was associated with acute pancreatitis (RR 2.14, 95% confidence interval (CI) 1.48–3.09) after adjustment for age, sex, BMI and alcohol consumption. This association was stronger in heavy smokers (20–30 cigarettes/day) (RR 3.19, 95% CI 2.03–5.00). Smoking was associated with a RR of 3.57 (95% CI 0.98–13.0) for acute pancreatitis in subjects who reported no alcohol consumption. An increased risk for acute pancreatitis was also found for high versus low risk, self-reported alcohol consumption (RR 2.55,95% CI 1.59–4.08) and for γ-GT levels in the highest versus the lowest quartile (RR 2.14,95%CI 1.32–3.49). There was alsoa weakcorrelation between BMI and acute pancreatitis. Conclusions: Smoking is associated with the incidence of acute pancreatitis in a dose-response manner.     

JPN Guidelines for the management of acute pancreatitis: epidemiology,etiology, natural history,and outcome predictors in acute pancreatitis

Acute pancreatitis is a common disease with an annual incidence of between 5 and 80 people per 100 000 of the population. The two major etiological factors responsible for acute pancreatitis are alcohol and cholelithiasis (gallstones). The proportion of patients with pancreatitis caused by alcohol or gallstones varies markedly in different countries and regions. The incidence of acute alcoholic pancreatitis is considered to be associated with high alcohol consumption. Although the incidence of alcoholic pancreatitis is much higher in men than in women, there is no difference in sexes in the risk involved after adjusting for alcohol intake. Other risk factors include endoscopic retrograde cholangiopancreatography, surgery, therapeutic drugs, HIV infection, hyperlipidemia, and biliary tract anomalies. Idiopathic acute pancreatitis is defined as acute pancreatitis in which the etiological factor cannot be specified. However, several studies have suggested that this entity includes cases caused by other specific disorders such as microlithiasis. Acute pancreatitis is a potentially fatal disease with an overall mortality of 2.1%–7.8%. The outcome of acute pancreatitis is determined by two factors that reflect the severity of the illness: organ failure and pancreatic necrosis. About half of the deaths in patients with acute pancreatitis occur within the first 1–2 weeks and are mainly attributable to multiple organ dysfunction syndrome (MODS). Depending on patient selection, necrotizing pancreatitis develops in approximately 10%–20% of patients and the mortality is high, ranging from 14% to 25% of these patients. Infected pancreatic necrosis develops in 30%–40% of patients with necrotizing pancreatitis and the incidence of MODS in such patients is high. The recurrence rate of acute pancreatitis is relatively high: almost half the patients with acute alcoholic pancreatitis experience a recurrence. When the gallstones are not treated, the risk of recurrence in gallstone pancreatitis ranges from 32% to 61%. After recovering from acute pancreatitis, about one-third to one-half of acute pancreatitis patients develop functional disorders, such as diabetes mellitus and fatty stool; the incidence of chronic pancreatitis after acute pancreatitis ranges from 3% to 13%. Nevertheless, many reports have shown that most patients who recover from acute pancreatitis regain good general health and return to their usual daily routine. Some authors have emphasized that endocrine function disorders are a common complication after severe acute pancreatitis has been treated by pancreatic resection.     

Actualités sur la prise en charge de la pancréatite aiguë

Over the past decades, the incidence and the number of hospital admissions for acute pancreatitis have increased in the Western countries. The two most common etiological factors of acute pancreatitis are gallstones (including small gallstones or microlithiasis) and alcohol abuse. Acute pancreatitis is associated with a significant mortality (4–10%) and 25% in case of pancreatic necrosis, especially. Edematous pancreatitis is benign and oral feeding can be restarted once abdominal pain is decreasing and inflammatory markers are improving. Enteral tube feeding should be the primary therapy in patients with predicted severe acute pancreatitis who require nutritional support. Enteral nutrition in acute pancreatitis can be administered via either the nasojejunal or nasogastric route. In case of necrosis, preventive antibiotics are not recommended. The single indication is infected necrosis confirmed by fine needle aspiration. The incidence trends of acute pancreatitis possibly reflect a change in the prevalence of main etiological factors (e.g. gallstones and alcohol consumption) and cofactors such as tobacco, obesity and genetic susceptibility. Priority is to search for associated causes, especially in cases with atypical symptoms. In case of first acute pancreatitis in patients older than 50 years, the presence of a tumor (benign or malignant) has to be specifically ruled out, using CT-scan, MRI and endoscopic ultrasound.     

Alcohol consumption in patients with acute or chronic pancreatitis.

Understanding of the relation between the alcoholic consumption and the development of pancreatitis should help in defining the alcoholic etiology of pancreatitis. Although the association between alcohol consumption and pancreatitis has been recognized for over 100 years, it remains still unclear why some alcoholics develop pancreatitis and some do not. Surprisingly little data are available about alcohol amounts, drinking patterns, type of alcohol consumed and other habits such as dietary habits or smoking in respect to pancreatitis preceding the attack of acute pancreatitis or the time of the diagnosis of chronic pancreatitis. This review summarizes the current knowledge. Epidemiological studies clearly show connection between the alcohol consumption in population and the development of acute and chronic pancreatitis. In the individual level the risk to develop either acute or chronic pancreatitis increases along with the alcohol consumption. Moreover, the risk for recurrent acute pancreatitis after the first acute pancreatitis episode seems also to be highly dependent on the level of alcohol consumption. Abstaining from alcohol may prohibit recurrent acute pancreatitis and reduce pain in chronic pancreatitis. Therefore, all the attempts to decrease alcohol consumption after acute pancreatitis and even after the diagnosis of chronic pancreatitis should be encouraged. Smoking seems to be a remarkable co-factor together with alcohol in the development of chronic pancreatitis, whereas no hard data are available for this association in acute pancreatitis. Setting the limits for accepting the alcohol as the etiology cannot currently be based on published data, but rather on the 'political' agreement.     

Susceptibility Factors and Cellular Mechanisms Underlying Alcoholic Pancreatitis

Alcohol is a major cause of acute and chronic pancreatitis. There have been some recent advances in the understanding of the mechanisms underlying alcoholic pancreatitis, which include perturbation in mitochondrial function and autophagy and ectopic exocytosis, with some of these cellular events involving membrane fusion soluble N-ethylmaleimide–sensitive factor receptor protein receptor proteins. Although new insights have been unraveled recently, the precise mechanisms remain complex, and their finer details have yet to be established. The overall pathophysiology of pancreatitis involves not only the pancreatic acinar cells but also the stellate cells and duct cells. Why only some are more susceptible to pancreatitis and with increased severity, while others are not, would suggest that there may be undefined protective factors or mechanisms that enhance recovery and regeneration after injury. Furthermore, there are confounding influences of lifestyle factors such as smoking and diet, and genetic background. Whereas alcohol and smoking cessation and a generally healthy lifestyle are intuitively the advice given to these patients afflicted with alcoholic pancreatitis in order to reduce disease recurrence and progression, there is as yet no specific treatment. A more complete understanding of the pathogenesis of pancreatitis from which novel therapeutic targets could be identified will have a great impact, particularly with the stubbornly high fatality (>30%) of severe pancreatitis. This review focuses on the susceptibility factors and underlying cellular mechanisms of alcohol injury on the exocrine pancreas.     

GC-MS based metabolomics strategy to distinguish three types of acute pancreatitis

Acute pancreatitis (AP) is a progressive systemic inflammatory response with high morbidity and high mortality, which is mainly caused by alcohol, bulimia, gallstones and hyperlipidemia. The early diagnosis of different types of AP and further explore potential pathophysiological mechanism of each type of AP is beneficial for optimized treatment strategies and better patient's care. In this study, a metabolomics approach based on gas chromatography-mass spectrometry (GC-MS), and random forests algorithm was established to distinguish biliary acute pancreatitis (BAP), Hyperlipidemia acute pancreatitis (HLAP), and alcoholic acute pancreatitis (AAP), from healthy controls. The classification accuracies for BAP, HLAP, and AAP patients compared with healthy control, were 0.886, 0.906 and 0.857, respectively, by using 5-fold cross-validation method. And some special metabolites for each type of AP were discovered, such as l-Lactic acid, (R)-3-Hydroxybutyric acid, Phosphoric acid, Glycine, Erythronic acid, l-Phenylalanine, d-Galactose, l-Tyrosine, Arachidonic acid, Glycerol 1-hexadecanoate. Furthermore, associations between these metabolites with the metabolism of amino acids, fatty acids were identified. Our studies have illuminated the biomarkers and physiological mechanism of disease in a clinical setting, which suggested that metabolomics is a valuable tool for identifying the molecular mechanisms that are involved in the etiology of BAP, AAP, HLAP and thus novel therapeutic targets.     

Molecular mechanisms of pancreatitis: current opinion

Pancreatitis (necroinflammation of the pancreas) has both acute and chronic manifestations. Gallstones are the major cause of acute pancreatitis, whereas alcohol is associated with acute as well as chronic forms of the disease. Cases of true idiopathic pancreatitis are steadily diminishing as more genetic causes of the disease are discovered. The pathogenesis of acute pancreatitis has been extensively investigated over the past four decades; the general current consensus is that the injury is initiated within pancreatic acinar cells subsequent to premature intracellular activation of digestive enzymes. Repeated attacks of acute pancreatitis have the potential to evolve into chronic disease characterized by fibrosis and loss of pancreatic function. Our knowledge of the process of scarring has advanced considerably with the isolation and study of pancreatic stellate cells, now established as the key cells in pancreatic fibrogenesis. The present review summarizes recent developments in the field particularly with respect to the progress made in unraveling the molecular mechanisms of acute and chronic pancreatic injury secondary to gallstones, alcohol and genetic factors. It is anticipated that continued research in the area will lead to the identification and characterization of molecular pathways that may be therapeutically targeted to prevent/inhibit the initiation and progression of the disease.     

New approaches to acute pancreatitis: role of inflammatory mediators

Regardless of whether the initiating event is alcohol, gallstones or some other less common cause, acute pancreatitis progresses in a predictable manner eventually leading to failure of multiple unrelated organs. Very quickly following the inciting event, a local inflammatory process is initiated which results in the local production of inflammatory mediators. Virtually all patients with acute pancreatitis will experience some symptoms related to this local inflammation, with some resolving completely at this point. Most patients will go on to develop a systemic hyperinflammatory state expressed as the development of fever, tachycardia, tachypnea, and mild acid-base disturbances. Although this systemic hyperinflammatory state is usually mild, occasionally it may be very severe resulting in overt distant organ failure. With a more thorough understanding of the inflammatory mediators responsible for this hyperinflammatory state, many new therapeutic approaches are on the horizon.