Platelet function in acute experimental pancreatitis.
Ontology highlight
ABSTRACT:
SUBMITTER: Hackert T
PROVIDER: S-EPMC1852387 | biostudies-other | 2007 Apr
REPOSITORIES: biostudies-other
Similar Datasets
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.
| S-EPMC6112120 | biostudies-literature
Project description:Platelet inositol hexakisphosphate kinase 1 (IP6K1) has been shown to control systemic inflammation. Herein, we examined if platelets and IP6K1 regulate pancreatic tissue injury via formation of NETs in experimental models of acute pancreatitis (AP) in mice. By use of electron microscopy abundant NET formation was observed in the inflamed pancreas. These NETs contained numerous microparticles (MP) expressing CD41 or Mac-1. Platelet depletion reduced deposition of NET-MP complexes in the inflamed pancreas. Circulating platelet-neutrophil aggregates (PNA) were increased and inhibition of P-selectin not only disrupted PNA formation but also reduced NETs formation in the inflamed pancreas. NETs depleted of MPs had lower capacity to provoke amylase secretion and STAT-3 phosphorylation in acinar cells. Taurocholate-induced NETs formation, inflammation and tissue damage in the pancreas were decreased in IP6K1-deficient mice. Thrombin stimulation of mixtures of wild-type platelets and neutrophils resulted in NETs formation but not when IP6K1-deficient platelets were incubated with wild-type neutrophils. Polyphosphate rescue restored thrombin-induced NET formation in mixtures of IP6K1-deficient platelets and wild-type neutrophils. Platelet IP6K1 regulates NET-MP complex formation in the pancreas of mice during induction of AP. Targeting platelet IP6K1 might useful to decrease NET-dependent pancreatic tissue inflammation and tissue injury in patients with AP.
| S-EPMC7032015 | biostudies-literature
Project description:Acute pancreatitis is a severe systemic disease triggered by a sterile inflammation and initial local tissue damage of the pancreas. Immune cells infiltrating into the pancreas are main mediators of acute pancreatitis pathogenesis. In addition to their antimicrobial potency, macrolides possess anti-inflammatory and immunomodulatory properties which are routinely used in patients with chronic airway infections and might also beneficial in the treatment of acute lung injury. We here tested the hypothesis that the macrolide antibiotic azithromycin can improve the course of acute experimental pancreatitis via ameliorating the damage imposed by sterile inflammation, and could be used as a disease specific therapy. However, our data show that azithromycin does not have influence on caerulein induced acute pancreatitis in terms of reduction of organ damage, and disease severity. Furthermore Infiltration of immune cells into the pancreas or the lungs was not attenuated by azithromycin as compared to controls or ampicillin treated animals with acute experimental pancreatitis. We conclude that in the chosen model, azithromycin does not have any beneficial effects and that its immunomodulatory properties cannot be used to decrease disease severity in the model of caerulein-induced pancreatitis in mice.
| S-EPMC6510415 | biostudies-literature
Project description:BackgroundInfectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs including the pancreas, exhibits anti-inflammatory effects by inhibiting NF-κB activation and is implicated in maintaining intestinal barrier integrity and preventing bacterial overgrowth and translocation. Here we explore, with the aid of complementary animal and human experiments, the potential role of FXR in acute pancreatitis.MethodsExperimental acute pancreatitis was induced using the CCK-analogue cerulein in wild-type and Fxr-/- mice. Severity of acute pancreatitis was assessed using histology and a semi-quantitative scoring system. Ileal permeability was analyzed in vitro by Ussing chambers and an in vivo permeability assay. Gene expression of Fxr and Fxr target genes was studied by quantitative RT-PCR. Serum FGF19 levels were determined by ELISA in acute pancreatitis patients and healthy volunteers. A genetic association study in 387 acute pancreatitis patients and 853 controls was performed using 9 tagging single nucleotide polymorphisms (SNPs) covering the complete FXR gene and two additional functional SNPs.ResultsIn wild-type mice with acute pancreatitis, ileal transepithelial resistance was reduced and ileal mRNA expression of Fxr target genes Fgf15, SHP, and IBABP was decreased. Nevertheless, Fxr-/- mice did not exhibit a more severe acute pancreatitis than wild-type mice. In patients with acute pancreatitis, FGF19 levels were lower than in controls. However, there were no associations of FXR SNPs or haplotypes with susceptibility to acute pancreatitis, or its course, outcome or etiology.ConclusionWe found no evidence for a major role of FXR in acute human or murine pancreatitis. The observed altered Fxr activity during the course of disease may be a secondary phenomenon.
| S-EPMC4255038 | biostudies-literature
Project description:Acute pancreatitis (AP) is an acute inflammation of the pancreas, mainly caused by gallstones and alcohol, and driven by changes in communication between cells. Heparin-binding proteins (HBPs) of the plasma membrane and extracellular matrix play a central role in cell communication. Therefore, we used heparin affinity proteomics to identify the extracellular HBPs in mouse normal pancreas (NP) and in a caerulein mouse model of AP. Many new HBPs (460) were discovered more than doubling their total number to 883. A number of the new HBPs are proteins with well-characterised intracellular functions, e.g. NDUFS4, NDUFS6, but which also have a documented extracellular presence with potential ‘moonlighting’ roles. The HBPs form highly interconnected protein-protein interaction networks in both NP and AP, as well as globally. Thus, HBPs may represent the most interconnected set of extracellular proteins and so those with the greatest regulatory potential. HBPs in NP are associated with biological functions such as molecular transport, cellular movement and tissue architecture that underlie pancreatic homeostasis. However, in AP HBPs are additionally associated with processes such as acute phase response signalling, complement system and mitochondrial dysfunction. By virtue of their extracellular location and heparin binding property, HBPs are easily accessible and are potential biomarkers and drug targets in AP.
2018-12-11 | PXD001950 | Pride
Project description:Various organosulfur compounds, such as dimethyl trisulfide (DMTS), display anti-inflammatory properties. We aimed to examine the effects of DMTS on acute pancreatitis (AP) and its mechanism of action in both in vivo and in vitro studies. AP was induced in FVB/n mice or Wistar rats by caerulein, ethanol-palmitoleic acid, or L-ornithine-HCl. DMTS treatments were administered subcutaneously. AP severity was assessed by pancreatic histological scoring, pancreatic water content, and myeloperoxidase activity measurements. The behaviour of animals was followed. Pancreatic heat shock protein 72 (HSP72) expression, sulfide, and protein persulfidation were measured. In vitro acinar viability, intracellular Ca2+ concentration, and reactive oxygen species production were determined. DMTS dose-dependently decreased the severity of AP. It declined the pancreatic infiltration of leukocytes and cellular damage in mice. DMTS upregulated the HSP72 expression during AP and elevated serum sulfide and low molecular weight persulfide levels. DMTS exhibited cytoprotection against hydrogen peroxide and AP-inducing agents. It has antioxidant properties and modulates physiological but not pathophysiological Ca2+ signalling. Generally, DMTS ameliorated AP severity and protected pancreatic acinar cells. Our findings indicate that DMTS is a sulfur donor with anti-inflammatory and antioxidant effects, and organosulfur compounds require further investigation into this potentially lethal disease.
| S-EPMC10556037 | biostudies-literature
Project description:Acute pancreatitis is a disease associated with suffering and high lethality. Although the disease mechanism is unclear, phospholipase A2 (PLA2) produced by pancreatic acinar cells is a known pathogenic trigger. Here, we show macrophage membrane-coated nanoparticles with a built-in 'lure and kill' mechanism (denoted 'MΦ-NP(L&K)') for the treatment of acute pancreatitis. MΦ-NP(L&K) are made with polymeric cores wrapped with natural macrophage membrane doped with melittin and MJ-33. The membrane incorporated melittin and MJ-33 function as a PLA2 attractant and a PLA2 inhibitor, respectively. These molecules, together with membrane lipids, work synergistically to lure and kill PLA2 enzymes. These nanoparticles can neutralize PLA2 activity in the sera of mice and human patients with acute pancreatitis in a dose-dependent manner and suppress PLA2-induced inflammatory response accordingly. In mouse models of both mild and severe acute pancreatitis, MΦ-NP(L&K) confer effective protection against disease-associated inflammation, tissue damage and lethality. Overall, this biomimetic nanotherapeutic strategy offers an anti-PLA2 treatment option that might be applicable to a wide range of PLA2-mediated inflammatory disorders.
| S-EPMC8260623 | biostudies-literature
Project description:Acute pancreatitis (AP) is acute inflammation of the pancreas, mainly caused by gallstones and alcohol, driven by changes in communication between cells. Heparin-binding proteins (HBPs) play a central role in health and diseases. Therefore, we used heparin affinity proteomics to identify extracellular HBPs in pancreas and plasma of normal mice and in a caerulein mouse model of AP. Many new extracellular HBPs (360) were discovered in the pancreas, taking the total number of HBPs known to 786. Extracellular pancreas HBPs form highly interconnected protein-protein interaction networks in both normal pancreas (NP) and AP. Thus, HBPs represent an important set of extracellular proteins with significant regulatory potential in the pancreas. HBPs in NP are associated with biological functions such as molecular transport and cellular movement that underlie pancreatic homeostasis. However, in AP HBPs are associated with additional inflammatory processes such as acute phase response signalling, complement activation and mitochondrial dysfunction, which has a central role in the development of AP. Plasma HBPs in AP included known AP biomarkers such as serum amyloid A, as well as emerging targets such as histone H2A. Other HBPs such as alpha 2-HS glycoprotein (AHSG) and histidine-rich glycoprotein (HRG) need further investigation for potential applications in the management of AP. Pancreas HBPs are extracellular and so easily accessible and are potential drug targets in AP, whereas plasma HBPs represent potential biomarkers for AP. Thus, their identification paves the way to determine which HBPs may have potential applications in the management of AP.
| S-EPMC6581253 | biostudies-literature
Project description:Acute pancreatitis is a potentially severe inflammatory disease that may be associated with a substantial morbidity and mortality. Currently there is no specific treatment for the disease, which indicates an ongoing demand for research into its pathogenesis and development of new therapeutic strategies. Due to the unpredictable course of acute pancreatitis and relatively concealed anatomical site in the retro-peritoneum, research on the human pancreas remains challenging. As a result, for over the last 100 years studies on the pathogenesis of this disease have heavily relied on animal models. This review aims to summarize different animal models of acute pancreatitis from the past to present and discuss their main characteristics and applications. It identifies key studies that have enhanced our current understanding of the pathogenesis of acute pancreatitis and highlights the instrumental role of animal models in translational research for developing novel therapies.
| S-EPMC7786374 | biostudies-literature
Project description:Platelet factor 4 (PF4) is a pleiotropic inflammatory chemokine, which has been implicated in various inflammatory disorders including liver fibrosis. However, its role in acute liver diseases has not yet been elucidated. Here we describe an unexpected, anti-inflammatory role of PF4. Serum concentrations of PF4 were measured in patients and mice with acute liver diseases. Acute liver injury in mice was induced either by carbon tetrachloride or by D-galactosamine hydrochloride and lipopolysaccharide. Serum levels of PF4 were decreased in patients and mice with acute liver diseases. PF4-/- mice displayed increased liver damage in both models compared to control which was associated with increased apoptosis of hepatocytes and an enhanced pro-inflammatory response of liver macrophages. In this experimental setting, PF4-/- mice were unable to generate activated Protein C (APC), a protein with anti-inflammatory activities on monocytes/macrophages. In vitro, PF4 limited the activation of liver resident macrophages. Hence, the systemic application of PF4 led to a strong amelioration of experimental liver injury. Along with reduced liver injury, PF4 improved the severity of the pro-inflammatory response of liver macrophages and induced increased levels of APC. PF4 has a yet unidentified direct anti-inflammatory effect in two models of acute liver injury. Thus, attenuation of acute liver injury by systemic administration of PF4 might offer a novel therapeutic approach for acute liver diseases.
| S-EPMC6444115 | biostudies-literature