Sentinel Acute Pancreatitis Event Increases Severity of Subsequent Episodes in Mice.
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ABSTRACT:
SUBMITTER: Geisz A
PROVIDER: S-EPMC8545756 | biostudies-literature | 2021 Nov
REPOSITORIES: biostudies-literature
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Sentinel Acute Pancreatitis Event Increases Severity of Subsequent Episodes in Mice.
Geisz Andrea A Sahin-Tóth Miklós M
Gastroenterology 20210615 5
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Project description:Traditional approaches to understanding the origins of chronic pancreatitis (CP) and find treatments led to abysmal failure. Thus, no drugs now exists to meet this need. Outdated concepts of the etiopathogenesis of CP have been replaced with new insights and disease models that provide the framework for early detection of the pathogenic pancreatitis process. Application of these principals require a new paradigm in disease definition and management, i.e. personalized / precision medicine. The key is acute pancreatitis (AP) starting with the first (sentinel) acute pancreatitis (AP) event (SAPE). This event sensitizes the pancreas to recurrent acute pancreatitis (RAP) as ongoing stressors drive various inflammatory responses to cause CP. The problem is the complex etiologies of AP and the additional genetic and environmental factors that promote progression to RAP and CP. This paper provides a background on the key conceptual changes that facilitate new approaches and the rationale for using mechanism-specific therapies to prevent RAP and CP.
| S-EPMC9421067 | biostudies-literature
Project description:Background & aimsMutations in the human serine protease 1 gene (PRSS1), which encodes cationic trypsinogen, can accelerate its autoactivation and cause hereditary or sporadic chronic pancreatitis. Disruption of the locus that encodes cationic trypsinogen in mice (T7) causes loss of expression of the protein, but only partially decreases the severity of secretagogue-induced acute pancreatitis and has no effect on chronic pancreatitis. We investigated whether trypsinogen becomes pathogenic only when its activation is promoted by mutation.MethodsWe generated mice with knock-in of the p.K24R mutation (called T7K24R mice), which is analogous to human PRSS1 mutation p.K23R. We gave T7K24R and C57BL/6N (control) mice repeated injections of cerulein to induce pancreatitis. Plasma amylase activity, pancreatic edema, and myeloperoxidase content in pancreas and lungs were quantified. We expressed mutant and full-length forms of PRSS1 in Escherichia coli and compared their autoactivation.ResultsThe p.K24R mutation increased autoactivation of T7 5-fold. T7K24R mice developed no spontaneous pancreatitis. T7K24R mice given cerulein injections had increased pancreatic activation of trypsinogen and more edema, infiltration of lung and pancreas by inflammatory cells, and plasma amylase activity compared with control mice given cerulein injections. Injection of cerulein for 2 days induced progressive pancreatitis in T7K24R mice, but not in control mice, with typical features of chronic pancreatitis.ConclusionsIntroduction of a mutation into mice that is analogous to the p.K23R mutation in PRSS1 increases pancreatic activation of trypsinogen during secretagogue-induced pancreatitis. Higher pancreatic activity of trypsin increases the severity of pancreatitis, even though loss of trypsin activity does not prevent pancreatitis in mice.
| S-EPMC7062587 | biostudies-literature
Project description:BACKGROUND: Interleukin 10 (IL-10) decreases the severity of experimental acute pancreatitis. The role of endogenous IL-10 in modulating the course of pancreatitis is currently unknown. AIMS: To examine the systemic release of IL-10 and its messenger RNA production in the pancrease, liver, and lungs and analyse the effects of IL-10 neutralisation in caerulein induced acute pancreatitis in mice. METHODS: Acute necrotising pancreatitis was induced by intraperitoneal caerulein. Serum levels of IL-10 and tumour necrosis factor (TNF), and tissue IL-10 and TNF-alpha gene expression were assessed. After injecting control antibody or after blocking the activity of endogenous IL-10 by a specific monoclonal antibody, the severity of acute pancreatitis was assessed in terms of serum enzyme release, histological changes, and systemic and tissue TNF production. RESULTS: In control conditions, serum IL-10 levels increased and correlated with the course of pancreatitis, with a maximal value eight hours after induction. Both IL-10 and TNF-alpha messengers showed a similar course, and were identified in the pancreas, liver, and lungs. Neutralisation of endogenous IL-10 significantly increased the severity of pancreatitis and associated lung injury as well as serum TNF protein levels (+75%) and pancreatic, pulmonary, and hepatic TNF messenger expression (+33%, +29%, +43%, respectively). CONCLUSIONS: In this non-lethal model, systemic release of IL-10 correlates with the course of acute pancreatitis. This anti-inflammatory response parallels the release of TNF and both cytokines are produced multisystemically. Endogenous IL-10 controls TNF-alpha production and plays a protective role in the local and systemic consequences of the disease.
| S-EPMC1727255 | biostudies-other
Project description:Background & aimsAcute pancreatitis (AP) of different etiologies is associated with the activation of different signaling pathways in pancreatic cells, posing challenges to the development of targeted therapies. We investigated whether local pancreatic hypothermia, without systemic hypothermia, could lessen the severity of AP induced by different methods in rats.MethodsA urethane balloon with 2 polyurethane tubes was placed inside the stomach of rats. AP was induced in Wistar rats by the administration of cerulein or glyceryl tri-linoleate (GTL). Then, cold water was infused into the balloon to cool the pancreas. Pancreatic temperatures were selected based on those found to decrease acinar cell injury. An un-perfused balloon was used as a control. Pancreatic and rectal temperatures were monitored, and an infrared lamp or heating pad was used to avoid generalized hypothermia. We collected blood, pancreas, kidney, and lung tissues and analyzed them by histology, immunofluorescence, immunoblot, cytokine and chemokine magnetic bead, and DNA damage assays. The effect of hypothermia on signaling pathways initiated by cerulein and GTL was studied in acinar cells.ResultsRats with pancreatic cooling developed less severe GTL-induced AP compared with rats that received the control balloon. In acinar cells, cooling decreased the lipolysis induced by GTL, increased the micellar form of its fatty acid, lowered the increase in cytosolic calcium, prevented the loss of mitochondrial membrane potential (by 70%-80%), and resulted in a 40%-50% decrease in the uptake of a fatty acid tracer. In rats with AP, cooling decreased pancreatic necrosis by 48%, decreased serum levels of cytokines and markers of cell damage, and decreased markers of lung and renal damage. Pancreatic cooling increased the proportions of rats surviving 6 hours after induction of AP (to 90%, from <10% of rats that received the control balloon). In rats with cerulein-induced AP, pancreatic cooling decreased pancreatic markers of apoptosis and inflammation.ConclusionsIn rats with AP, transgastric local pancreatic hypothermia decreases pancreatic necrosis, apoptosis, inflammation, and markers of pancreatitis severity and increases survival.
| S-EPMC6368865 | biostudies-literature
Project description:Background & aimsAcute pancreatitis is characterized by premature intracellular activation of digestive proteases within pancreatic acini and a consecutive systemic inflammatory response. We investigated how these processes interact during severe pancreatitis in mice.MethodsPancreatitis was induced in C57Bl/6 wild-type (control), cathepsin B (CTSB)-knockout, and cathepsin L-knockout mice by partial pancreatic duct ligation with supramaximal caerulein injection, or by repetitive supramaximal caerulein injections alone. Immune cells that infiltrated the pancreas were characterized by immunofluorescence detection of Ly6g, CD206, and CD68. Macrophages were isolated from bone marrow and incubated with bovine trypsinogen or isolated acinar cells; the macrophages were then transferred into pancreatitis control or cathepsin-knockout mice. Activities of proteases and nuclear factor (NF)-κB were determined using fluorogenic substrates and trypsin activity was blocked by nafamostat. Cytokine levels were measured using a cytometric bead array. We performed immunohistochemical analyses to detect trypsinogen, CD206, and CD68 in human chronic pancreatitis (n = 13) and acute necrotizing pancreatitis (n = 15) specimens.ResultsMacrophages were the predominant immune cell population that migrated into the pancreas during induction of pancreatitis in control mice. CD68-positive macrophages were found to phagocytose acinar cell components, including zymogen-containing vesicles, in pancreata from mice with pancreatitis, as well as human necrotic pancreatic tissues. Trypsinogen became activated in macrophages cultured with purified trypsinogen or co-cultured with pancreatic acini and in pancreata of mice with pancreatitis; trypsinogen activation required macrophage endocytosis and expression and activity of CTSB, and was sensitive to pH. Activation of trypsinogen in macrophages resulted in translocation of NF-kB and production of inflammatory cytokines; mice without trypsinogen activation (CTSB-knockout mice) in macrophages developed less severe pancreatitis compared with control mice. Transfer of macrophage from control mice to CTSB-knockout mice increased the severity of pancreatitis. Inhibition of trypsin activity in macrophages prevented translocation of NF-κB and production of inflammatory cytokines.ConclusionsStudying pancreatitis in mice, we found activation of digestive proteases to occur not only in acinar cells but also in macrophages that infiltrate pancreatic tissue. Activation of the proteases in macrophage occurs during endocytosis of zymogen-containing vesicles, and depends on pH and CTSB. This process involves macrophage activation via NF-κB-translocation, and contributes to systemic inflammation and severity of pancreatitis.
| S-EPMC6663074 | biostudies-literature
Project description:Nuclear factor-?B (NF-?B) is activated during early stages of pancreatitis. This transcription factor regulates genes that control many cell activities, including inflammation and survival. There is evidence that activation of NF-?B protects against pancreatitis, and, in other cases, that it promotes this disease. We compared the effects of NF-?B in different mouse models of pancreatitis to understand these complications.To model constitutive activation of NF-?B, we expressed a transgene that encodes its p65 subunit or the inhibitor of ?B kinase (IKK)2 in pancreatic acinar cells of mice. We analyzed effects on pancreatic tissues and levels of NF-?B target genes in these mice and compared them with mice that did not express transgenic p65 or IKK2 (controls).Transgenic expression of p65 led to compensatory expression of the inhibitory subunit IKB-? and, therefore, no clear phenotype. However, p65 transgenic mice given injections of cerulein, to induce acute pancreatitis, had higher levels of NF-?B activity in acinar cells, greater levels of inflammation, and more severe outcomes than control mice. In contrast, constitutive expression of IKK2 directly increased the activity of NF-?B in acinar cells and induced pancreatitis. Prolonged activity of IKK2 (3 months) resulted in activation of stellate cells, loss of acinar cells, and fibrosis, which are characteristics of chronic pancreatitis. Co-expression of IKK2 and p65 greatly increased the expression of inflammatory mediators and the severity of pancreatitis, compared with control mice.The level of NF-?B activation correlates with the severity of acute pancreatitis in mice. Longer periods of activation (3 months) lead to chronic pancreatitis. These findings indicate that strategies to inactivate NF-?B might be used to treat patients with acute or chronic pancreatitis.
| S-EPMC3769090 | biostudies-literature
Project description:BackgroundVagus nerve stimulation (VNS) is effective in reducing inflammation in various diseases, such as rheumatoid arthritis, colitis and acute kidney injury. The anti-inflammatory effect of vagus nerve in these diseases necessitates the interactions of neural activation and α7 nicotinic acetylcholine receptors (α7nAChRs) on splenic macrophages. In this study, we aimed to investigate the effect of VNS on severity in experimental acute pancreatitis (AP).MethodsTwo independent AP models were used, which induced in ICR mice with caerulein or pancreatic duct ligation (PDL). Thirty minutes after modeling, the left cervical carotid sheath containing the vagus nerve was electrically stimulated for 2 min. Plasma lipase and amylase activities, TNF-α levels and pancreas histologic damage were evaluated. In caerulein mice, the percentages of α7nAChR+ macrophage in pancreas and spleen were assessed by flow cytometry. Furthermore, splenectomy and adoptive transfer of VNS-conditioned α7nAChR splenocytes were performed in caerulein mice to evaluate the role of spleen in the protective effect of VNS.ResultsVNS reduced plasma lipase and amylase activities, blunted the concentrations of TNF-α and protected against pancreas histologic damage in two AP models. Survival rates were improved in the PDL model after VNS. In caerulein AP mice, VNS increased the percentages of α7nAChR+ macrophages in pancreas and spleen. Adoptive transfer of VNS-treated α7nAChR splenocytes provided protection against pancreatitis in recipient mice. However, splenectomy did not abolish the protective effect of VNS.ConclusionsVNS reduces disease severity and attenuates inflammation in AP mice. This effect is independent of spleen and is probably related to α7nAChR on macrophage.
| S-EPMC7840568 | biostudies-literature
Project description:Genetic susceptibility to chronic pancreatitis in humans is frequently associated with mutations that increase activation of the digestive protease trypsin. Intrapancreatic trypsin activation is an early event in experimental acute pancreatitis in rodents, suggesting that trypsin is a key driver of pathology. In contrast to trypsin, the pancreatic protease chymotrypsin serves a protective function by mitigating trypsin activation through degradation. In humans, loss-of-function mutations in chymotrypsin C (CTRC) are common risk factors for chronic pancreatitis; however, the pathogenic effect of CTRC deficiency has not been corroborated in animal models yet. Here we report that C57BL/6 mice that are widely used for genetic manipulations do not express functional CTRC due to a single-nucleotide deletion in exon 2 of the Ctrc gene. We restored a functional Ctrc locus in C57BL/6N mice and demonstrated that in the novel Ctrc+ strain the severity of cerulein-induced experimental acute and chronic pancreatitis was significantly ameliorated. Improved disease parameters were associated with reduced intrapancreatic trypsin activation suggesting a causal link between CTRC-mediated trypsinogen degradation and protection against pancreatitis. Taken together with prior human genetic and biochemical studies, the observations provide conclusive evidence for the protective role of CTRC against pancreatitis.
| S-EPMC6675558 | biostudies-literature
Project description:Cannabis is the most commonly and widely used illicit drug in the world and is also the most commonly used drug of abuse in alcohol drinkers. Experimental studies have shown conflicting results of the effects of cannabis on the severity of acute pancreatitis (AP). The purpose of this study is to ascertain the clinical effects of simultaneous alcohol and cannabis use on severity at presentation and outcomes of acute alcoholic pancreatitis (AAP).A retrospective review was conducted on the patients discharged with principle or secondary diagnosis of AP using ICD-9 & ICD-10 codes during the time period from January 2006 to December 2015 at a large community-based hospital in Central Georgia. Patients with alcoholic pancreatitis with cannabis (CB+) and without cannabis (CB-) use were identified and were matched with sex and age.Our study findings showed that a greater percentage of CB+ patients did not have a systemic inflammatory response syndrome (SIRS) score (P=0.043), had a lower BISAP score (P=0.031), and had a significantly lower BUN level (P=0.033), but there was no difference in the Balthazar Index and revised Atlanta classification severity between the two groups. CB+ patients tended to need less ICU care than CB- patients (P=0.059).Based on our findings, we found that CB+ patients had less severe presentation of AAP indicating that cannabis could modulate the inflammatory effect of alcohol on the pancreas. Further large scale prospective studies are needed to confirm our results.
| S-EPMC5539398 | biostudies-other
Project description:BackgroundThe effect of diet on risk of acute pancreatitis (AP) has been suggested by prior studies, but the association of dietary habits with severity of AP has not been previously evaluated.ObjectiveThe objective of the study was to assess differences in reported dietary habits in patients with severe AP compared with those with mild or moderate AP.MethodsA prospectively maintained cohort of patients with AP was utilized. A brief questionnaire on dietary habits was implemented. Dietary habits were categorized based on the overall type of diet, fruit/vegetable servings, fat content, dairy consumption, dessert/sweets consumption, and fluid intake. Patients were grouped into mild/moderate and severe AP. Multivariate analysis was used to determine whether dietary habits have an independent association with AP severity.Results407 patients with AP were studied. Mean patient age was 51 y, and 202 (50%) were men. 29% of patients were smokers and 46% actively consumed alcohol. 225 patients had mild AP, 103 moderate AP, and 79 developed severe AP. The 3 groups were comparable in race, body mass index, etiology of AP, and comorbidities. Dietary factors were overall comparable between the groups except for diet type: subjects with severe AP had a higher percentage of consuming a meat-rich diet (84%) than patients with mild AP (72%) and moderate AP (67%) (P = 0.04). Based on multivariable logistic regression, the OR of developing severe AP was 2.5 (95% CI: 1.24-5.32, P = 0.01) between patients who eat a meat-rich diet and those who consume a vegetable-based diet.ConclusionsA meat-rich diet is independently associated with the development of persistent organ failure (severe disease) in patients with AP. These findings require further evaluation and could be useful for patient counseling, risk stratification, and disease prevention. This study is registered at clinicaltrials.gov as NCT03075605.
| S-EPMC6295618 | biostudies-literature