Thrombotic thrombocytopenic purpura causing rapid unexpected death: value of CD61 immunohistochemical staining in diagnosis.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) shares histologic features with disseminated intravascular coagulation (DIC) but is clinically distinct. TTP may result in myocardial hemorrhages and rapid death. We compared rapidly fatal TTP with heart involvement and DIC cases to determine if the differential diagnosis of TTP and DIC could be aided by immunohistochemical techniques. DESIGN: We examined 11 hearts from seven women and four men dying with TTP (aged 34+/-10 years) and 8 hearts from patients dying with DIC (five women, three men, aged 58+/-16 years). The diagnosis of TTP was established on histologic findings and identification of thrombocytopenia with schistocytes on premortem blood smear. Underlying conditions for TTP were recent diarrheal illness (3), autoimmune disease (3), sickle cell disease, HIV infection, cocaine abuse, and none known (2). Underlying conditions for DIC were disseminated carcinoma (4), multiorgan failure after open-heart surgery (2), pancreatitis (1), and placental abruption (1). Antibodies against platelet glycoprotein IIIa (CD61) and fibrin II were applied to formalin fixed tissue sections and detected by the avidin biotin techniques, and platelet and fibrin capillary thrombi were quantitated. RESULTS: Gross myocardial hemorrhages were present in 7/11 cases of TTP and 0 cases of DIC (P<.001). Capillary thrombi were present in all cases by routine histologic techniques but were often difficult to discern. Platelet thrombi were strongly highlighted by stains for CD61 and seen at a density of 8.0+/-3.1/mm(2) in TTP versus 0.5+/-0.4/mm(2) in DIC (P=.0001). In TTP, there were 12.1+/-5.9/mm(2) fibrin capillary thrombi and 4.8+/-5.8/mm(2) in DIC (P=.05). CONCLUSION: In the myocardium, rapidly fatal TTP is characterized by the diffuse presence of intracapillary platelet-rich thrombi, in contrast to DIC, which is characterized by predominantly fibrin thrombi. Immunohistochemical staining for CD61 and fibrin II is helpful in diagnosing TTP and distinguishing it from DIC.     

早期无创正压通气对重症急性胰腺炎合并肺损伤的保护作用机制

重症急性胰腺炎（SAP）所致急性肺损伤（ALI）/急性呼吸窘迫综合征（ARDS）是SAP早期死亡的主要原因,是肺外型 ARDS 的典型代表,已有研究证实早期无创正压通气对 SAP所致 ARDS是一种行之有效治疗方法。本文主要就早期无创正压通气对重症急性胰腺炎合并肺损伤的保护作用及其作用机制研究情况进行综述,为早期无创正压通气用于重症急性胰腺炎合并肺损伤治疗提供依据。     

Pancreatitis and cholecystitis in primary acute symptomatic Epstein-Barr virus infection – Systematic review of the literature

Acute pancreatitis and acalculous cholecystitis have been occasionally reported in primary acute symptomatic Epstein-Barr virus infection. We completed a review of the literature and retained 48 scientific reports published between 1966 and 2016 for the final analysis. Acute pancreatitis was recognized in 14 and acalculous cholecystitis in 37 patients with primary acute symptomatic Epstein-Barr virus infection. In all patients, the features of acute pancreatitis or acalculous cholecystitis concurrently developed with those of primary acute symptomatic Epstein-Barr virus infection. Acute pancreatitis and acalculous cholecystitis resolved following a hospital stay of 25 days or less. Acalculous cholecystitis was associated with Gilbert-Meulengracht syndrome in two cases. In conclusion, this thorough analysis indicates that acute pancreatitis and acalculous cholecystitis are unusual but plausible complications of primary acute symptomatic Epstein-Barr virus infection. Pancreatitis and cholecystitis deserve consideration in cases with severe abdominal pain. These complications are usually rather mild and resolve spontaneously without sequelae.     

Acute pancreatitis associated with pegylated interferon-alpha-2a therapy in chronic hepatitis C

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma. Combination therapy of pegylated interferon-alpha (PEG-IFN-α) and ribavirin (RBV) is a current standard treatment for chronic HCV infection in Korea, which has considerable adverse effects. Acute pancreatitis is a rare complication of PEG-IFN-α administration. We report a case of a 62-year-old female who experienced acute pancreatitis after 4 weeks of PEG-IFN-α-2a and RBV combination therapy for chronic HCV infection. The main cause of the acute pancreatitis in this case was probably PEG-IFN-α rather than RBV for several reasons. A few cases have been reported in which acute pancreatitis occurred during treatment with PEG-IFN-α-2b. This is the first report of acute pancreatitis associated with PEG-IFN-α-2a in Korea.     

Long Non-coding RNA FENDRR Modulates Autophagy Through Epigenetic Suppression of ATG7 via Binding PRC2 in Acute Pancreatitis

Inflammation - Acute pancreatitis (AP) is an inflammatory, complicated pancreatic disease, carrying significant morbidity and mortality. However, the molecular and cellular mechanisms involved in...     

Wip1 Aggravates the Cerulein-Induced Cell Autophagy and Inflammatory Injury by Targeting STING/TBK1/IRF3 in Acute Pancreatitis

Inflammation - Acute pancreatitis (AP) is an inflammatory reaction of pancreatic tissue self-digestion, edema, hemorrhage, and even necrosis after the activation of pancreatic enzymes in the...     

Acute pancreatitis

Acute pancreatitis is characterized by the occurrence of necroinflammatory changes in the pancreas. Three types of necrosis may be distinguished: (1) interstitial tissue necrosis, which subsequently may also involve acinar and ductal cells, (2) ductal necrosis, and (3) acinar necrosis. The first type of necrosis is autodigestive in nature and is typical of the most common forms of acute pancreatitis, which are associated with alcohol, bile duct disease, metabolic conditions, and other rare factors. Clinically, these types of pancreatitis may be either mild or severe (Atlanta classification). The mild form is also known as edematous pancreatitis, because there is edematous swelling of the pancreas combined with tiny foci of interstitial (fat) necrosis. Severe or necrotizing pancreatitis shows large areas of often hemorrhagic necrosis of the pancreatic and particularly the peripancreatic tissue. The ductal type of necrosis is rare and may be seen in pancreatitis associated with prolonged circulatory failure. The acinar type of necrosis is caused by infectious agents. Complications of acute pancreatitis, such as pseudocyst, bleeding, and infection, determine the course of the disease.     

Impact of hyperglycemia and acute pancreatitis on the receptor for advanced glycation endproducts

Since hyperglycemia aggravates acute pancreatitis and also activates the receptor for advanced glycation endproducts (RAGE) in other organs, we explored if RAGE is expressed in the pancreas and if its expression is regulated during acute pancreatitis and hyperglycemia. Acute pancreatitis was induced by cerulein in untreated and streptozotocin treated diabetic mice. Expression of RAGE was analyzed by Western blot and immunohistochemistry. To evaluate signal transduction the phosphorylation of ERK1/ERK2 was assessed by Western blot and the progression of acute pancreatitis was monitored by evaluation of lipase activity and the pancreas wet to dry weight ratio. RAGE is mainly expressed by acinar as well as interstitial cells in the pancreas. During acute pancreatitis infiltrating inflammatory cells also express RAGE. Using two distinct anti-RAGE antibodies six RAGE proteins with diverse molecular weight are detected in the pancreas, whereas just three distinct RAGE proteins are detected in the lung. Hyperglycemia, which aggravates acute pancreatitis, significantly reduces the production of two RAGE proteins in the inflamed pancreas.     

PKC δ mediates pro-inflammatory responses in a mouse model of caerulein-induced acute pancreatitis

Acute pancreatitis is an inflammatory disorder of the pancreas. Protein kinase C (PKC) δ plays an important role in mediating chemokine production in mouse pancreatic acinar cells. This study aims to investigate the role of PKC δ in the pathogenesis of acute pancreatitis and to explore the mechanisms through which PKC δ mediates pro-inflammatory signaling. Acute pancreatitis was induced in mice by ten hourly intraperitoneal injections of caerulein. PKC δ translocation inhibitor peptide (δV1-1) at a dose of 1.0 mg/kg or Tat (carrier peptide) at a dose of 1.0 mg/kg was administered to mice either 1 h before or 1 h after the first caerulein injection. One hour after the last caerulein injection, the mice were killed and pancreas, lungs, and blood were collected. Prophylactic and therapeutic treatment with δV1-1 attenuated caerulein-induced plasma amylase levels and pancreatic edema. Treatment with δV1-1 decreased myeloperoxidase activity and monocyte chemotactic protein-1 levels in both pancreas and plasma. PKC δ mediated acute pancreatitis by activating pancreatic nuclear factor κB, activator protein-1, and mitogen-activated protein kinases. Moreover, blockade of PKC δ attenuated lung myeloperoxidase activity and edema. Histological examination of pancreatic and lung sections confirmed protection against acute pancreatitis. Treatment with Tat had no protective effect on acute pancreatitis. Blockade of PKC δ represents a promising prophylactic and/or therapeutic tool for the treatment of acute pancreatitis.     

Diabetes increases pancreatitis induced systemic inflammation but has little effect on inflammation and cell death in the lung

Acute pancreatitis (AP) can lead to a systemic inflammatory response that often results in acute lung injury and single or multiple organ failure. In a previous study we demonstrated that diabetes aggravates the local pathophysiological process during AP. In this study we explore, if diabetes also increases pancreatitis induced systemic inflammation and causes lung injury. Acute pancreatitis was induced in untreated and streptozotocin‐treated diabetic mice by injection of cerulein. Systemic inflammation was studied by IL‐6 ELISA in blood plasma and white blood cell count. Lung inflammation and lung injury were quantified by chloroacetate esterase staining, evaluation of the alveolar cellularity index and cleaved caspase‐3 immunohistochemistry. In normoglycaemic mice AP increased the IL‐6 concentration in plasma and caused lymphocytopenia. Diabetes significantly increased the IL‐6 concentration in plasma and further reduced the number of lymphocytes during AP, whereas diabetes had little effect on these parameters in the absence of pancreatitis. However, diabetes only marginally increased lung inflammation and did not lead to cell death of the lung epithelium during AP. We conclude that diabetes increases parameters of systemic inflammation during AP, but that this increase is insufficient to cause lung injury.     

兔急性胰腺炎并发十二指肠粘膜损伤与一氧化氮合酶改变的关系

目的:探讨急性胰腺炎并发十二指肠粘膜损伤与一氧化氮合酶(nitric oxide synthase,NOS)改变的关系。方法:用胰管结扎及加压注射法建立大白兔急性胰腺炎模型,采用黄递酶组织化学染色法观察与比较两组动物胰腺及十二指肠组中NOS的变化。结果:经Winslow法测定血清淀粉酶分析及组织学检查,急性胰腺炎模型建立;经NADPH-d染色表明:实验组NOS染色强度明显高于对照组。结论:一氧化氮(nitric cxide,NO)在急性胰腺炎并发十二指肠粘膜损伤的病变过程中起重要的介导作用。     

胰腺组织的P物质与急性胰腺炎轻重的关系

目的 研究急性胰腺炎时胰腺组织P物质的变化规律。水肿性和出血/坏死性胰腺炎时P物质水平，观察中药复方MCP-1对P物质水平的影响。方法 皮下注射蛙皮缩胆囊肽（caerulein)诱发大鼠急性水肿性胰腺炎，胆总管插管注射牛磺胆酸钠诱发急性出血/坏死性胰腺炎，以免疫组化方法检测P物质。结果 水肿性和出血性/坏死性胰腺炎，2h时SP免疫反应性明显增强，轻型和重型胰腺炎的SP免疫反应性无明显差别；MCP-1使SP免疫反应性明显减弱。结论 P物质在轻型和重型胰腺炎中所起作用相同。MCP-1可能通过降低P物质含量。发挥其抗局部微循环损伤作用。     

Metastasis-induced acute pancreatitis in a patient with small cell carcinoma of the lung

Acute pancreatitis in cancer patients can be secondary to the malignant process itself or a complication of antineoplastic agent administration. However, acute pancreatitis caused by metastatic carcinoma of the pancreas is an uncommon condition with a poor prognosis. We report a case of a 63-year-old man with small cell carcinoma of the lung, who developed acute pancreatitis lately. Thirteen months earlier, he developed small cell carcinoma of the lung and received 6 cycles of chemotherapy. Abdominal CT scan showed swelling of the pancreas with multiple masses. The patient was managed conservatively and pancreatitis subsided. This case indicates that metastasis induced acute pancreatitis can be a manifestation of lung cancer, especially in small cell carcinoma.     

Hepatitis A and acute pancreatitis

Acute pancreatitis in association with acute viral hepatitis A in uncommon. We present the case of a young girl with acute pancreatitis complicating acute viral hepatitis A. The finding of IgM anti-HAV and exclusion of a vast array of other etiologies implicates hepatitis A the cause.     

Oxidative stress is enhanced by hypothermia imposed on cerulein-induced pancreatitis in rats

BACKGROUND: Hypothermia is a frequent event in severe acute pancreatitis (AP) and its real effects on the normal pancreas have not been well demonstrated. Moreover, neither have its effects on the outcome of acute pancreatitis been fully investigated. One hypothesis is that oxidative stress may be implicated in lesions caused or treated by hypothermia. AIM OF THE STUDY: To investigate the effect of hypothermia in cerulein-induced acute pancreatitis (CIAP) in rats and the role played by oxidative stress in this process. METHODS: Male Wistar rats were divided into hypothermic and normothermic groups. Hypothermia was induced with a cold mattress and rectal temperature was kept at 30 masculineC for one hour. Acute pancreatitis was induced with 2 doses of cerulein (20 ìg/kg) administered at a one-hour interval. Serum amylase, pancreas vascular permeability by Evan's blue method, pancreas wet-to-dry weight ratio and histopathology were analyzed in each group. RESULTS: When compared with normothermic rats, hypothermic animals, with cerulein-induced acute pancreatitis, showed higher levels of pancreatic vascular permeability (p < 0.05), pancreas wet-to-dry weight ratio (p = 0.03), and histologically verified edema (p < 0.05), but similar serum amylase levels. The hypothermic group showed a higher oxidized-reduced glutathione ratio than the normothermic group. CONCLUSION: Moderate hypothermia produced a greater inflammatory response in established acute pancreatitis induced by cerulein in rats. Moreover, this study suggests that oxidative stress may be one of the mechanisms responsible for the worse outcome in hypothermic rats with cerulein-induced acute pancreatitis.     

Alcoholic pancreatitis: mechanisms of viral infections as cofactors in the development of acute and chronic pancreatitis and fibrosis

Acute and chronic pancreatitis is associated with alcohol abuse, but symptomatic pancreatitis develops in only a small proportion of persons (10-20%) who abuse alcohol. This apparent paradox has led to the notion that additional cofactors are involved in the development of alcoholic pancreatitis. Potential cofactors, such as diet and smoking, have been suggested, but there are no compelling epidemiologic data to support this idea. A number of viruses and some bacteria have been shown to infect the pancreas and produce pancreatitis. One important mediator of pancreatitis in persons with a compromised immune system is a viral infection. The increased susceptibility of immunocompromised persons to viral pancreatitis led to the hypothesis, described in this paper, that the well-known immunosuppression associated with alcohol abuse would result in a more severe viral pancreatitis in mice, which are provided ethanol, than in control animals. To test this hypothesis, C57BL/6 mice were infected with a virulent strain of coxsackievirus B3, which preferentially induces pancreatitis, or with a strain that is naturally avirulent. The study findings presented in this paper show that ethanol consumption alone does not produce pancreas damage but results in a more severe and prolonged pancreatitis after infection with a virulent virus and interestingly, after infection with the avirulent strain of virus. This was associated with an increased number of viruses in the pancreas and spleen, which correlated with decreased humoral immune responses to the virus.     

Role of platelet-activating factor in pancreatitis-associated acute lung injury in the rat.

Acute necrotizing pancreatitis induced by infusion of bile salt into the pancreatic duct in rats is consistently associated with acute lung injury similar to the adult respiratory distress syndrome. The role of platelet-activating factor (PAF) in this pancreatitis-associated remote organ failure (lung injury) was investigated. Pulmonary tissue levels of PAF were increased gradually and reached a level of 1345 +/- 455 pg/g (6 times the control level) at 12 hours after induction of pancreatitis, whereas pancreatic PAF levels were undetectable and blood PAF remained unchanged. This local pulmonary PAF accumulation occurred at approximately the same time as the progression of lung injury. Pulmonary responses detected (i.e., eicosanoid production, leukocytic infiltration, Evan's blue extravasation, beta-glucuronidase release) were attenuated to varying degrees by treatment of rats in which pancreatitis was initiated with the PAF receptor antagonists (WEB2170 and BN52021). Rat lung lavages were examined after a 12-hour course of pancreatitis and no changes in PAF concentration, surfactant content, and phospholipase A2 (PLA2) activity were noted. Intravenous administration of PLA2 promoted pulmonary PAF production in experimental rats with pancreatitis but not in normal rats. This observation indicates that PLA2, which was determined to be elevated in plasma during pancreatitis, may be responsible for the accumulation of PAF in the lung. In conclusion, pancreatitis-associated lung injury appears to result from an endogenous inflammatory response in which PAF may play an important role.     

The fusion of autophagosome with lysosome is impaired in L-arginine-induced acute pancreatitis

Background & aims: Acute pancreatitis is an inflammatory pancreatic disease that carries considerable morbidity and mortality. The pathogenesis of this disease remains poorly understood. We investigated the incidence of autophagy in mice following induction of acute pancreatitis. Methods: Mice were received intraperitoneal injections of L-arginine (200 mg × 2/100 g BW), while controls were administered with saline. Pancreatic tissues were assessed by histology, electron microscopy and western blotting. Results: Injection of L-arginine resulted in the accumulation of autophagosomes and a relative paucity of autolysosomes. Moreover, the autophagy marker p62 is significantly increased. However, the lysosomal-associated membrane protein-2 (Lamp-2), a protein that is required for the proper fusion of autophagosomes with lysosomes, is decreased in acute pancreatitis. These results suggest that a crucial role for autophagy and Lamp-2 in the pathogenesis of acute pancreatitis. Conclusions: Our data suggest that the autophagic flux is impaired in acute pancreatitis. The depletion of Lamp-2 may play a role in the pathogenesis of acute pancreatitis.     

The effect of CP96,345 on the expression of tachykinins and neurokinin receptors in acute pancreatitis

Acute pancreatitis (AP) is a life-threatening condition that involves an acute inflammatory process in the pancreas. The involvement of tachykinins and neurokinin receptors in acute pancreatitis has been described only recently, despite their long-established role in inflammatory conditions. Among these, substance P (SP) is believed to play a central role in exacerbating the inflammatory process by acting through neurokinin-1 receptor (NK1R). Treatment with the NK1R antagonist, CP96,345, results in protection against caerulein-induced acute pancreatitis in mice. However, the mechanism by which NK1R and SP worsen the condition is still unclear. In the present study, we have investigated the effect of NK1R blockage on the expression of preprotachykinin genes and neurokinin receptors in acute pancreatitis. In the pancreas, CP96,345 treatment resulted in suppression of the elevation of SP concentration, preprotachykinin-A gene (PPT-A) mRNA expression, and NK1R mRNA and protein expression. In the lungs, the antagonist was found to suppress the increase in SP concentration, PPT-A mRNA expression and preprotachykinin-C gene (PPT-C) mRNA expression. However, the antagonist treatment further promoted the accumulation of pulmonary NK1R mRNA and protein expression. Neurokinin-2 receptor (NK2R) mRNA expression was not detected in normal pancreas. However, up-regulated expression of the mRNA for this receptor was observed during acute pancreatitis and treatment with CP96,345 further increased this expression. Pulmonary NK2R mRNA expression was found to be reduced during acute pancreatitis and CP96,345 treatment normalized this reduction. Neurokinin-3 receptor (NK3R) mRNA expression was absent in both pancreas and lung. These data have provided valuable information regarding the regulation of tachykinins and neurokinin receptors during acute pancreatitis.     

Organellar dysfunction in the pathogenesis of pancreatitis

SIGNIFICANCE: Acute pancreatitis is an inflammatory disease of exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. During the past decade, new insights have been gained into signaling pathways and molecules that mediate the inflammatory response of pancreatitis and death of acinar cells (the main exocrine pancreas cell type). By contrast, much less is known about the acinar cell organellar damage in pancreatitis and how it contributes to the disease pathogenesis. RECENT ADVANCES: This review summarizes recent findings from our group, obtained on experimental in vivo and ex vivo models, which reveal disordering of key cellular organelles, namely, mitochondria, autophagosomes, and lysosomes, in pancreatitis. Our results indicate a critical role for mitochondrial permeabilization in determining the balance between apoptosis and necrosis in pancreatitis, and thus the disease severity. We further investigate how the mitochondrial dysfunction (and hence acinar cell death) is regulated by Ca(2+), reactive oxygen species, and Bcl-xL, in relation to specific properties of pancreatic mitochondria. Our results also reveal that autophagy, the principal cellular degradative, lysosome-driven pathway, is impaired in pancreatitis due to inefficient lysosomal function, and that impaired autophagy mediates two key pathological responses of pancreatitis-accumulation of vacuoles in acinar cells and the abnormal, intra-acinar activation of digestive enzymes such as trypsinogen. CRITICAL ISSUES AND FUTURE DIRECTIONS: The findings discussed in this review indicate critical roles for mitochondrial and autophagic/lysosomal dysfunctions in the pathogenesis of pancreatitis and delineate directions for detailed investigations into the molecular events that underlie acinar cell organellar damage.