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Acute pancreatitis promotes the generation of two different exosome populations.

ABSTRACT: Exosomes are small extracellular vesicles that act as intercellular messengers. Previous studies revealed that, during acute pancreatitis, circulating exosomes could reach the alveolar compartment and activate macrophages. However, proteomic analysis suggested that the most likely origin of these exosomes could be the liver instead of the pancreas. The present study aimed to characterize the exosomes released by pancreas to pancreatitis-associated ascitic fluid (PAAF) as well as those circulating in plasma in an experimental model of taurocholate-induced acute pancreatitis in rats. We provide evidence that during acute pancreatitis two different populations of exosomes are generated with relevant differences in cell distribution, protein and microRNA content as well as different implications in their physiological effects. During pancreatitis plasma exosomes, but not PAAF exosomes, are enriched in the inflammatory miR-155 and show low levels of miR-21 and miR-122. Mass spectrometry-based proteomic analysis showed that PAAF exosomes contains 10-30 fold higher loading of histones and ribosomal proteins compared to plasma exosomes. Finally, plasma exosomes have higher pro-inflammatory activity on macrophages than PAAF exosomes. These results confirm the generation of two different populations of exosomes during acute pancreatitis. Deep understanding of their specific functions will be necessary to use them as therapeutic targets at different stages of the disease.

SUBMITTER: Jimenez-Alesanco A

PROVIDER: S-EPMC6934470 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Acute pancreatitis promotes the generation of two different exosome populations.

Jiménez-Alesanco A A Marcuello M M Pastor-Jiménez M M López-Puerto L L Bonjoch L L Gironella M M Carrascal M M Abian J J de-Madaria E E Closa D D

Scientific reports 20191227 1

Exosomes are small extracellular vesicles that act as intercellular messengers. Previous studies revealed that, during acute pancreatitis, circulating exosomes could reach the alveolar compartment and activate macrophages. However, proteomic analysis suggested that the most likely origin of these exosomes could be the liver instead of the pancreas. The present study aimed to characterize the exosomes released by pancreas to pancreatitis-associated ascitic fluid (PAAF) as well as those circulatin ...[more]

PMID: 31882721

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Project description:BACKGROUND & AIMS:Acute pancreatitis (AP) is characterized by severe inflammation and acinar cell death. Transmembrane protein 173 (TMEM173 or STING) is a DNA sensor adaptor protein on immune cells that recognizes cytosolic nucleic acids and transmits signals that activate production of interferons and the innate immune response. We investigated whether leukocyte STING signaling mediates inflammation in mice with AP. METHODS:We induced AP in C57BL/6J mice (control) and C57BL/6J-Tmem173gt/J mice (STING-knockout mice) by injection of cerulein or placement on choline-deficient DL-ethionine supplemented diet. In some mice, STING signaling was induced by administration of a pharmacologic agonist. AP was also induced in C57BL/6J mice with bone marrow transplants from control or STING-knockout mice and in mice with disruption of the cyclic GMP-AMP synthase (Cgas) gene. Pancreata were collected, analyzed by histology, and acini were isolated and analyzed by flow cytometry, quantitative polymerase chain reaction, immunoblots, and enzyme-linked immunosorbent assay. Bone-marrow-derived macrophages were collected from mice and tested for their ability to detect DNA from dying acinar cells in the presence and absence of deoxyribonuclease (DNaseI). RESULTS:STING signaling was activated in pancreata from mice with AP but not mice without AP. STING-knockout mice developed less severe AP (less edema, inflammation, and markers of pancreatic injury) than control mice, whereas mice given a STING agonist developed more severe AP than controls. In immune cells collected from pancreata, STING was expressed predominantly in macrophages. Levels of cGAS were increased in mice with vs without AP, and cGAS-knockout mice had decreased edema, inflammation, and other markers of pancreatic injury upon induction of AP than control mice. Wild-type mice given bone marrow transplants from STING-knockout mice had less pancreatic injury and lower serum levels of lipase and pancreatic trypsin activity following induction of AP than mice given wild-type bone marrow. DNA from dying acinar cells activated STING signaling in macrophages, which was inhibited by addition of DNaseI. CONCLUSIONS:In mice with AP, STING senses acinar cell death (by detecting DNA from dying acinar cells) and activates a signaling pathway that promotes inflammation. Macrophages express STING and activate pancreatic inflammation in AP.

Project description:InductionLiver transplantation (LT) is the only final therapy for patients with acute liver failure (ALF) that cannot be controlled by conservative treatment. Acute pancreatitis (AP) is a recognized complication of ALF. The pathogenesis of AP in ALF patients has not yet been elucidated. The appearance of AP complicates the patients condition and causes a significantly increased risk of mortality.Patient concernsWe report 2 fatal cases who were both admitted with yellowing of skin and sclera with general weakness lasting for 2 weeks.DiagnosisAfter admission, the laboratory examination of case 1 showed liver dysfunction with serum levels of total bilirubin (TB) 270 μmol/l, alanine aminotransferase (ALT) 106 U/l. Abdominal computed tomography (CT) showed pelvic and peritoneal cavity fluids, occupation of left lateral lobe of liver and unclear margin of pancreas. The clinical laboratory findings of case 2 revealed TB 351.1 μmol/l, ALT 252 U/l, blood lactic acid 18 mmol/l, ammonia 209 μmol/l. And abdominal CT showed pancreatic exudation. They were both diagnosed with acute liver failure, hepatic encephalopathy and AP which was confirmed during the operation.InterventionsThey were both received a routine orthotopic LT.OutcomesAfter the surgery, their liver functions recovered well, and they received conventional conservative treatment for pancreatitis. However, the treatment was not adequately effective, and the infection was too serious and both died of multiple organ failure despite emergency rescue efforts on day 21 and day 19 after LT.ConclusionAP is a serious complication that can contribute to prohibitive morbidity and mortality in LT patients. For this reason, the vulnerable state of the pancreas and the scoring system must be defined to help clinicians decide whether a patient is suitable for liver transplantation, and the clinical experience in the treatment of pancreatitis after LT needs to be summarized as an optimal treatment guideline to facilitate better treatment.

Project description:The currently used diagnostic criteria for acute pancreatitis in Japan are presentation with at least two of the following three manifestations: (1) acute abdominal pain and tenderness in the upper abdomen; (2) elevated levels of pancreatic enzyme in the blood, urine, or ascitic fluid; and (3) abnormal imaging findings in the pancreas associated with acute pancreatitis. When a diagnosis is made on this basis, other pancreatic diseases and acute abdomen can be ruled out. The purpose of this article is to review the conventional criteria and, in particular, the various methods of diagnosis based on pancreatic enzyme values, with the aim of improving the quality of diagnosis of acute pancreatitis and formulating common internationally agreed criteria. The review considers the following recommendations: Better even than the total blood amylase level, the blood lipase level is the best pancreatic enzyme for the diagnosis of acute pancreatitis and its differentiation from other diseases. A pivotal factor in the diagnosis of acute pancreatitis is identifying an increase in pancreatic enzymes in the blood. Ultrasonography (US) is also one of the procedures that should be performed in all patients with suspected acute pancreatitis. Magnetic resonance imaging (MRI) is one of the most important imaging procedures for diagnosing acute pancreatitis and its intraperitoneal complications. Computed tomography (CT) is also one of the most important imaging procedures for diagnosing acute pancreatitis and its intraabdominal complications. CT should be performed when a diagnosis of acute pancreatitis cannot be established on the basis of the clinical findings, results of blood and urine tests, or US, or when the etiology of the pancreatitis is unknown. When acute pancreatitis is suspected, chest and abdominal X-ray examinations should be performed to determine whether any abnormal findings caused by acute pancreatitis are present. Because the etiology of acute pancreatitis can have a crucial influence on both the treatment policy and severity assessment, it should be evaluated promptly and accurately. It is particularly important to differentiate between gallstone-induced acute pancreatitis, which requires treatment of the biliary system, and alcohol-induced acute pancreatitis, which requires a different form of treatment.

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Acute pancreatitis promotes the generation of two different exosome populations.

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Acute pancreatitis promotes the generation of two different exosome populations.

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