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The article discusses the role of the ORAI1 CRAC channel in immune cells as a therapeutic target for pancreatitis-associated acute lung injury. It highlights the importance of abnormal intracellular calcium signals in pancreatic acinar cells in initiating acute pancreatitis (AP) and the potential of ORAI1 inhibitors to prevent or ameliorate AP. The study focuses on the specific role of neutrophils and demonstrates that deletion of neutrophil ORAI1 reduces neutrophil infiltration and lung damage associated with AP. The findings suggest that targeting common mechanisms in multiple cell types may be more effective in treating AP. [Extracted from the article]

Glutathione peroxidase 4 (GPX4)-dependent ferroptosis in pancreatic acinar cells plays a critical role in acute pancreatitis (AP). However, potential upstream regulators of GPX4 are not well defined. Here, we observed a marked reduction in acinar GPX4 expression and ferroptotic cell death in mice with cerulein-induced AP. To determine the critical factors involved in acinar cell ferroptosis, pancreas transcriptome data from an AP mouse model were analyzed and overlapped with predicted transcription factors of Gpx4, and an upregulated transcription factor active protein 1 (AP-1) protein, Jun, was identified. The administration of a specific ferroptosis inhibitor liproxstatin-1 alleviated AP pathology and significantly decreased Jun levels. Bioinformatic analysis indicated that the Gpx4 promoter contains a putative AP-1 binding site. Jun binds directly to the Gpx4 promoter and inhibits Gpx4 transcription under pancreatic conditions. AP-1 inhibition by a selective inhibitor SR11302 reversed GPX4 reduction and ameliorated AP pathology in a GPX4-dependent manner. Collectively, our study demonstrates that the downregulation of GPX4 by AP-1 is critical in the aggravation of acinar cell ferroptosis during the progression of AP. Strategies targeting the AP-1/GPX4 axis may be potentially effective for the prevention and treatment of AP. [ABSTRACT FROM AUTHOR]

Background: Severe acute pancreatitis has a high mortality of 20%–40%, but there is a lack of optimal prognostic biomarker for the severity of acute pancreatitis (AP) or mortality. This study is designed to investigate the relationship between serum cholinesterase (ChE) level and poor outcomes of AP. Methods: A total of 1904 AP patients were screened in the study, and we finally got 692 patients eligible for analysis. Patients were divided into 2 groups based on serum ChE. The primary outcome was mortality, and multivariable logistic regression analysis for mortality was completed. Additionally, we used receiver operating characteristic (ROC) curve analysis to clarify the predictive value of serum ChE for mortality and organ failure. Results: Three hundred and seventy eight patients and 314 patients were included in the ChE‐low and ChE‐normal group, respectively. Patients in the ChE‐low group were older (46.68 ± 12.70 vs. 43.56 ± 12.13 years old, p =.001) and had a lower percentage of man (62.4% vs. 71.0%, p =.017) when compared to the ChE‐normal group. Mortality was significantly different in two groups (10.3% vs. 0.0%, p <.001). Moreover, organ failure also differed significantly in two groups (46.6% vs. 8.6%, p <.001). Decreased ChE level was independently associated with mortality in acute pancreatitis (odds ratio: 0.440; 95% confidence interval, 0.231, 0.838, p =.013). The area under the curve of serum ChE was 0.875 and 0.803 for mortality and organ failure, respectively. Conclusions: Lower level of serum ChE was independently associated with the severity and mortality of AP. [ABSTRACT FROM AUTHOR]

aimed to develop a nomogram based on available clinical parameters and validate its efficacy in predicting thrombocytopenia. Methods: This was a retrospective study. All the data were extracted from an electronic database from May 2018 to May 2019. Patients with a diagnosis of AP and staying in the intensive care unit for more than 3 days were retrospectively analyzed. A clinical signature was built based on reproducible features, using the least absolute shrinkage and selection operator method (LASSO), and logistic regression established the model (P < 0.05). Nomogram performance was determined by its discrimination, calibration, and clinical usefulness. Results: A total of 594 eligible patients were enrolled, of whom 399 were allocated to the training sets and the 195 in the test sets. The clinical features, including blood urea nitrogen (BUN), fibrinogen (FIB), and antithrombase III, were significantly associated with the incidence of thrombocytopenia after acute pancreatitis (p < 0.05) in training sets. The individualized nomogram showed good discrimination in the training sample (area under the receiver operating characteristic curve [AUC], 0.881) and in the validation sample (AUC, 0.883) with good calibration. Conclusion: The proposed nomogram has good performance for predicting thrombocytopenia in patients with acute pancreatitis and may facilitate clinical decision-making. [ABSTRACT FROM AUTHOR]

Background and Purpose: Pyroptosis is a lytic form of pro‐inflammatory cell death characterised as caspase 1 dependent with canonical NLRP3 inflammasome‐induced gasdermin D (GSDMD) activation. We aimed to investigate the role of acinar pyroptotic cell death in pancreatic injury and systemic inflammation in AP. Experimental Approach Pancreatic acinar pyroptotic cell death pathway activation upon pancreatic toxin stimulation in vitro and in vivo was investigated. Effects of pharmacological (NLRP3 and caspase‐1 inhibitors), constitutive (Nlrp3−/−, Casp1−/− and Gsdmd−/−) and acinar cell conditional (Pdx1CreNlrp3Δ/Δ and Pdx1CreGsdmdΔ/Δ) genetic inhibition on pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation were assessed using mouse AP models (caerulein, sodium taurocholate and l‐arginine). Effects of Pdx1CreGsdmdΔ/Δ versus myeloid conditional knockout (Lyz2CreGsdmdΔ/Δ) and Gsdmd−/− versus receptor‐interacting protein 3 (RIP3) inhibitor were compared in CER‐AP. Key Results: There was consistent pyroptotic acinar cell death upon pancreatic toxin stimulation both in vitro and in vivo, which was significantly reduced by pharmacological or genetic pyroptosis inhibition. Pdx1CreGsdmdΔ/Δ but not Lyz2CreGsdmdΔ/Δ mice showed significantly reduced pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation in caerulein‐AP. Co‐application of RIP3 inhibitor on Gsdmd−/− mice further increased protection on caerulein‐AP. Conclusion and Implications: This work demonstrates a critical role for NLRP3 inflammasome and GSDMD activation‐mediated pyroptosis in acinar cells, linking pancreatic necrosis and systemic inflammation in AP. Targeting pyroptosis signalling pathways holds promise for specific AP therapy. [ABSTRACT FROM AUTHOR]

Background: Vagus 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). Methods: Two 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. Results: VNS 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. Conclusions: VNS reduces disease severity and attenuates inflammation in AP mice. This effect is independent of spleen and is probably related to α7nAChR on macrophage. [ABSTRACT FROM AUTHOR]

The aim of this study was to describe the clinical characteristics and management of gastric outlet obstruction following acute pancreatitis(AP). Gastric outlet obstruction (GOO) is not uncommon in acute pancreatitis (AP) and can occur throughout the course. However, the clinical features and related treatment of GOO is rarely reported. A retrospective review of AP patients with a diagnosis of GOO from March 2017 to June 2020 was performed. The diagnosis and management of GOO, as well as the demographic characteristics and clinical outcomes of the study patients, were collected and analyzed. Over the three years, there were 60 AP patients developed GOO, constituting an incidence of 5.7%. Thirty-three patients (55.0%, 33/60) developed GOO in the first 4 weeks and 27 patients (45.0%, 27/60) after 4 weeks from onset. Pancreatic necrosis compression (60.6%; 20/33), gastric outlet gastrointestinal edema (27.3%, 9/33) are the main causes of early-onset GOO (≤4 weeks), while wall-off necrosis (92.6%, 25/27) is the leading cause in the late phase (>4 weeks). The management of GOO incorporates both supportive and specific treatment like gastric decompression, gastric juice reinfusion, percutaneous catheter drainage, etc. The mortality of AP patients with GOO (≤4 weeks) was 21.2% and none patients who developed GOO (>4 weeks) died. GOO, as a gastrointestinal complication developed in AP patients, has two peak incidences in the duration of AP and needs to be paid more attention to. [ABSTRACT FROM AUTHOR]

Pancreatic necrosis occurs in a quarter of patients with acute pancreatitis, many of whom form an acute necrotic collection (ANC). The current standard treatment is to defer percutaneous catheter drainage (PCD) until the latter becomes "walled off," which takes approximately four weeks. The majority of patients that develop persistent organ failure (POF), the primary determinant of mortality, do so within four weeks. To defer PCD until after four weeks may result in a worse outcome because of a missed opportunity to treat early infection and thereby reduce the severity and/or duration of POF. This study is aimed to compare the clinical outcome of the current standard approach with early on-demand PCD in acute necrotizing pancreatitis (ANP) patients with ANC and POF. This is an open-label, multi-center, parallel, randomized, controlled trial. All patients with ANP who develop POF during the first week of onset will be screened for eligibility. In total, 120 study subjects will be randomized to either early on-demand PCD or standard care. Patients assigned to the former will receive PCD when they show signs of decompensation like new-onset OF, aggravation of pre-existent OF, and persistent OF for more than a week. The primary composite endpoint is major complication and/or death. Patients will be followed until discharge or death with an additional follow-up 90 days after randomization. This study challenges the standard 4-week delay before PCD and will answer the question whether early on-demand PCD is associated with a lower incidence of major complications and/or death. [ABSTRACT FROM AUTHOR]

Background: Patients could develop endocrine and exocrine pancreatic insufficiency after acute pancreatitis (AP), but the morbidity, risk factors and outcome remain unclear. The aim of the present study was to evaluate the incidence of endocrine and exocrine pancreatic insufficiency after AP and the risk factors of endocrine pancreatic insufficiency through a long-term follow-up investigation.Methods: Follow-up assessment of the endocrine and exocrine function was conducted for the discharged patients with AP episodes. Oral Glucose Tolerance Test (OGTT) and faecal elastase-1(FE-1) test were used as primary parameters. Fasting blood-glucose (FBG), fasting insulin (FINS), glycosylated hemoglobin HBA1c, 2-h postprandial blood glucose (2hPG), Homa beta cell function index (HOMA-β), homeostasis model assessment of insulin resistance (HOMA-IR) and FE-1 were collected. Abdominal contrast-enhanced computed tomography (CECT) was performed to investigate the pancreatic morphology and the other related data during hospitalization was also collected.Results: One hundred thirteen patients were included in this study and 34 of whom (30.1%) developed diabetes mellitus (DM), 33 (29.2%) suffered impaired glucose tolerance (IGT). Moreover, 33 patients (29.2%) developed mild to moderate exocrine pancreatic insufficiency with 100μg/gConclusion: The integrated morbidity of DM and IGT after AP was 59.25%, which was higher than exocrine pancreatic insufficiency. 6.2% and 29.2% of patients developed severe and mild to moderate exocrine pancreatic insufficiency, respectively. The extent of pancreatic necrosis>50%, WON and insulin resistance were the independent risk factors of new onset diabetes after AP. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to investigate the role of hypertriglyceridemia for acute kidney injury (AKI) in the course of acute pancreatitis. Methods Patients with acute pancreatitis were retrospectively divided into four groups according to admission triglyceride: normal group, mild HTG group, moderate HTG group and severe HTG group. Clinical characteristics were compared among these groups. Wild type (WT) mice and Human ApoC III transgenic (ApoCIIItg) mice were used in the next animal experiments. Severe acute pancreatitis (SAP) model was established by retrograde injection of 0.5% sodium taurocholate (0.1 ml/100 g) from duodenum to pancreatic duct. Histological scores, serum amylase, creatinine, usea nitrogen were compared between WT mice and ApoCIIItg mice. Results Two hundred and sixty-two patients were classified into 4 groups: normal TG (104, 39.7%), mild HTG (72, 27.5%), moderate HTG (47, 17.9%), and severe HTG (39, 14.9%) groups. The proportions of AKI were 13.5% (14/104, normal), 13.9% (10/72, mild), 21.3% (10/47, moderate), and 38.5% (15/39, severe), respectively. After establishing SAP model, the levels of serum amylase ( P < 0.05) and pancreatic histological score ( P < 0.05) of ApoCIII-SAP-9h group were significantly higher than that of WT-SAP-9h group, respectively. ApoCIII-SAP-9h group had significantly higher levels of serum creatinine ( P < 0.001), usea nitrogen ( P < 0.001), and kidney histological score ( P < 0.05) than that of WT-SAP-9h group, respectively. Conclusions Mild HTG has little adverse impact on disease severity of acute pancreatitis; severe HTG can aggravate kidney injury in the course of acute pancreatitis. ApoCIII-SAP mice have more serious pancreatic damage and kidney injury than WT-SAP mice. [ABSTRACT FROM AUTHOR]

Background Endothelial injury is believed to play an important role in the evolution of pancreatic microcirculatory dysfunction and pancreatic necrosis (PN) in patients with acute pancreatitis (AP). The aim of this study was to investigate the role of three endothelial markers (von Willebrand factor, vWF; E-selectin; endothelial protein C receptor, EPCR) in the early phase of AP, especially the relationship between endothelial markers and PN. Methods From March 2015 to March 2016, 57 AP patients admitted within 72 h of symptom onset in our hospital were included for this study. Blood samples were taken on admission and the clinical characteristics and outcomes of these patients were recorded. The levels of vWF, E-selectin and EPCR were measured using ELISA for analysis and compared with other severity markers of AP. Results All the three markers were significantly different in healthy control, mild, moderate and severe AP patients. Moreover, the endothelial markers, especially vWF, also showed significant difference in patients with different extent of PN, as well as those with or without MODS. Additionally, the levels of endothelial markers correlated well with other commonly used markers of AP severity. Conclusion Elevated endothelium-related mediators (vWF, E-selectin and EPCR) appear to participate in the development of PN and may be a potential indicator of overall prognosis. Our results may help clinicians better understand the pathophysiological process of the development of PN. [ABSTRACT FROM AUTHOR]

Background: Early occurrence of immunosuppression is a risk factor for infected pancreatic necrosis (IPN) in the patients with acute pancreatitis (AP). However, current measures for the immune systems are too cumbersome and not widely available. Significantly decreased lymphocyte count has been shown in patients with severe but not mild type of AP. Whereas, the correlation between the absolute lymphocyte count and IPN is still unknown. We conduct this study to reveal the exact relationship between early lymphocyte count and the development of IPN in the population of AP patients.Methods: One hundred and fifty-three patients with acute pancreatitis admitted to Jinling Hospital during the period of January 2012 to July 2014 were included in this retrospective study. The absolute lymphocyte count and other relevant parameters were measured on admission. The diagnosis of IPN was based on the definition of the revised Atlanta classification.Results: Patients were divided into two groups according to the presence of IPN. Thirty patients developed infected necrotizing pancreatitis during the disease course. The absolute lymphocyte count in patients with IPN was significantly lower on admission (0.62 × 10(9)/L, interquartile range [IQR]: 0.46-0.87 × 10(9)/L vs. 0.91 × 10(9)/L, IQR: 0.72-1.27 × 10(9)/L, p < 0.001) and throughout the whole clinical course than those without IPN. Logistic regression indicated that reduced lymphocyte count was an independent risk factor for IPN. The optimal cut-offs from ROC curve was 0.66 × 10(9)/L giving sensitivity of 83.7 % and specificity of 66.7 %.Conclusions: Reduced lymphocyte count within 48 h of AP onset is significantly and independently associated with the development of IPN. [ABSTRACT FROM AUTHOR]

• The incidence rate of recurrent HTG-AP attack was 23 % during the 2-3 year follow-up period. • Age <40 years and a history of diabetes were potential predictor factors for recurrence of HTG-AP. • Recurrence necessitated more readmissions and was associated with compromised quality of life. There are scarce prospective data on recurrent hypertriglyceridemia-associated acute pancreatitis (HTG-AP). This study aimed to investigate the incidence, potential prognostic factors, and clinical relevance of recurrent HTG-AP. This study is a multicenter, prospective cohort study. Adult patients with the first HTG-AP attack enrolled in the PERFORM registry between November 2020 and December 2021 were involved. All the study patients were followed up for more than two years with a two-round schedule. The Cox proportional-hazards model was applied to analyze the potential factors. Quality of life was evaluated using the EuroQol five-dimensional five-level health scale (EQ-5D-5L). A total of 184 patients from 25 sites were included in the study, and 161 patients completed the two-round follow-up. Among them, the mean follow-up time for the study patients was 31±4 months, and the incidence rate of recurrent HTG-AP attack was 23 % (37/161). All patients with recurrent episodes required readmission to the hospital. The EQ visual analog scale (VAS) score was significantly lower in patients with recurrent episodes compared to those without (76±10 vs. 82±12; P = 0.02) at the latest follow-up. Age <40 years old (hazard ratio [HR], 3.6; 95 % confidence interval [CI], 1.5–8.7; P = 0.004) and a history of diabetes (HR, 2.6; 95 %CI, 1.3–5.1; P = 0.005) were identified as potential predictor factors for recurrence. Recurrence of HTG-AP is common, especially for younger patients with diabetes. Recurrence necessitated additional hospital readmissions and was associated with compromised quality of life. [ABSTRACT FROM AUTHOR]

• More than one-fifth of AP patients (21%) experienced recurrence after discharge. • Alcoholic and hypertriglyceridemia etiologies have the highest recurrence rates. • Addressing the underlying causes post-discharge may reduce the risk of recurrence. • Smoking, alcoholic etiology, gender and local complications affect AP recurrence. There are a certain number of acute pancreatitis (AP) patients who may suffer from multiple episodes and develop recurrent acute pancreatitis (RAP), but recurrence rates and associated risk factors for RAP vary significantly in the published literature. We searched PubMed, Web of Science, Scopus, and Embase databases to identify all publications reporting AP recurrence until October 20th, 2022. Meta-analysis and meta-regression were performed to calculate the pooled estimates using the random-effects model. A total of 36 studies met the inclusion criteria and all were used in pooled analyses. The overall rate of recurrence after first-time AP was 21% (95% CI, 18%- 24%), and pooled rates in biliary, alcoholic, idiopathic, and hypertriglyceridemia etiology patients were 12%, 30%, 25%, and 30%, respectively. After managing underlying causes post-discharge, the recurrence rate decreased (14% versus 4% for biliary, 30% versus 6% for alcoholic, and 30% versus 22% for hypertriglyceridemia AP). An increased risk of recurrence was reported in patients with a smoking history (odds ratio [OR] = 1.99), alcoholic etiology (OR = 1.72), male sex (hazard ratio [HR] = 1.63), and local complications (HR = 3.40), while biliary etiology was associated with lower recurrence rates (OR = 0.38). More than one-fifth of AP patients experienced recurrence after discharge, with the highest recurrence rate in alcoholic and hypertriglyceridemia etiologies, and managing underlying causes post-discharge was related to decreased incidence. In addition, smoking history, alcoholic etiology, male gender, and presence of local complications were independent risks for the recurrence. [ABSTRACT FROM AUTHOR]

NQDI-1, an inhibitor of ASK1, has been reported to have protective effects in several experimental human disease models. However, the role of NQDI-1 in acute pancreatitis (AP) has not been reported. In this study, we found that NQDI-1 could attenuate histological damage of pancreatic tissue as well as the levels of serum amylase and lipase in a mouse model of AP induced by caerulein. Moreover, the production of reactive oxygen species (ROS) and the expression of necrosis-related proteins (RIP3 and p-MLKL) were also reduced after NQDI-1 administration. Correspondingly, we elucidated the effect of NQDI-1 in vitro and found that NQDI-1 protected against pancreatic acinar cells necrosis via decreasing the ROS production and RIP3 and p-MLKL expression. In addition, we identified the protective effect of NQDI-1 on AP through two other mouse models induced by l -arginine and pancreatic duct ligation. Taken together, these findings showed that NQDI-1 could reduce the acinar cells necrosis and alleviate the severity of AP, which may afford a new therapeutic target on pancreatic necrosis in AP clinically. • NQDI-1 alleviates acinar cell necrosis of acute pancreatitis in three experimental mouse models. • NQDI-1 inhibits ROS aggregation and down-regulate the necrosis pathway. • NQDI-1 may be a therapeutic candidate for acute pancreatitis in clinical. [ABSTRACT FROM AUTHOR]

• Genetic apolipoprotein A-I deletion aggravated acinar NLRP3 inflammasome activation in acute pancreatitis. • Pharmacological high-density lipoprotein and apoA-I treatment inhibited acinar NLRP3 inflammasome activation and pyroptosis in acute pancreatitis. • Apolipoprotein -I mimic peptide D4F may be a promising drug in clinical treatment for acute pancreatitis patients. Recent clinical studies have shown that serum high-density lipoprotein (HDL) levels are correlated with acute pancreatitis (AP) severity. We aimed to investigate the role of HDL in pancreatic necrosis in AP. ApoA-I is the main constitution and function component of HDL. The roles of healthy human-derived HDL and apoA-I mimic peptide D4F were demonstrated in AP models in vivo and in vitro. Constitutive Apoa1 genetic inhibition on AP severity, especially pancreatic necrosis was assessed in both caerulein and sodium taurocholate induced mouse AP models. In addition, constitutive (Casp1 -/-) and acinar cell conditional (Pdx1 Cre Nlrp 3Δ/Δ and Pdx1 Cre Gsdmd Δ/Δ) mice were used to explore the effects of HDL on acinar cell pyroptosis in AP. Apoa1 knockout dramatically aggravated pancreatic necrosis. Human-derived HDL protected against acinar cell death in vivo and in vitro. We found that mimic peptide D4F also protected against AP very well. Constitutive Casp1 or acinar cell-conditional Nlrp3 and Gsdmd genetic inhibition could counteract the protective effects of HDL, implying HDL may exert beneficial effects on AP through inhibiting acinar cell pyroptosis. This work demonstrates the protective role of HDL and apoA-I in AP pathology, potentially driven by the inhibition of NLRP3 inflammasome signaling and acinar cell pyroptosis. Mimic peptides have promise as specific therapies for AP. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is one of the most common digestive tract diseases, but effective drug therapy is still lack. Regenerating gene protein 3α (Reg3α) administration significantly reduced the severity of AP in mice. HTD4010 is a new 15 amino acid long synthetic peptide and its biological activities are similar to Reg3α. This study aimed to explore whether HTD4010 could protect pancreatic acinar cells against necrosis and decrease the inflammatory response in AP, and thus to explore underlying mechanisms. It was shown that administration of HTD4010 alleviated significantly the severity of biliary AP (BAP), characterized as less degree of pancreatic histological damage and acinar cell injury (both apoptosis and necroptosis), lower levels of serum amylase and pro-inflammatory cytokines. Moreover, HTD4010 down-regulated the expression of toll-like receptor 4 (TLR4) protein, and TLR4 deficiency eliminated the protective effect of HTD4010 on BAP in mice. In conclusion, these results showed that HTD4010 could alleviate the severity of pancreatitis, reduce the acinar cells necrosis and inflammatory response possibly by TLR4 signaling pathway in AP. • HTD4010 is a new 15 amino acid long synthetic peptide. • HTD4010 reduced the inflammatory response and acinar cells necrosis in BAP mice. • HTD4010 could alleviate the severity of AP by TLR4 signaling pathway. [ABSTRACT FROM AUTHOR]

Bile acids receptor TGR5 and its agonist INT-777, which has been found to be involved in the NLRP3 inflammasome pathway, play an important role in inflammatory diseases. However, the role of INT-777 in acute pancreatitis (AP) has not been reported. In this present study, we found that TGR5 was expressed in pancreatic tissue and increased after AP onset induced by caerulein and further evaluated the impact of INT-777 on the severity of AP. The results showed that INT-777 could reduce the severity of AP in mice, which was manifested as decreased pancreatic tissue damage as well as the decrease of serum enzymes (amylase and lipase), pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and the expression of necrosis related proteins (RIP3 and p-MLKL). Furthermore, we found that INT-777 reduced the reactive oxygen species (ROS) production in pancreatic acinar cells and inhibited the activation of NLRP3 inflammasome pathway. In conclusion, our data showed that INT-777 could protect pancreatic acinar cell against necrosis and reduce the severity of AP, which may be mediated by inhibiting ROS/NLRP3 inflammasome pathway. [ABSTRACT FROM AUTHOR]

Objective Previous studies have shown that acute inflammation is associated with increased sympathetic activity, which in turn increases the inflammatory response and leads to organ damage. The present study aimed to investigate whether dexmedetomidine administration during acute pancreatitis (AP) lessens pancreatic pathological and functional injury and the inflammatory response, and to explore the underlying mechanisms. Methods Mild pancreatitis was induced in mice with caerulein, and severe pancreatitis was induced with caerulein plus lipopolysaccharide (LPS). After pancreatitis induction, dexmedetomidine at 10 or 20 μg/kg was injected via the tail vein. Pancreatic pathological and functional injury was assessed by histology and serum levels of amylase and lipase, respectively. The inflammatory response was evaluated by determining serum levels of inflammatory factors. The expression of myeloperoxidase (MPO) was examined by immunohistochemistry. The expression of norepinephrine transporter (NET), NLRP3, pro-IL-1β, and interleukin (IL)-1β in pancreatic tissue was detected by Western blot and real-time PCR. Results Dexmedetomidine at 20 μg/kg significantly attenuated pancreatic pathological injury, reduced serum levels of amylase, lipase, IL-1β, IL-6, and tumor necrosis factor (TNF)-α, and decreased the expression of MPO in pancreatic tissue in both mouse models of pancreatitis. In addition, dexmedetomidine at 20 μg/kg significantly down-regulated the expression of NLRP3, pro-IL-1β, and IL-1β in pancreatic tissue, but up-regulated the expression of NET in both mouse models. Conclusion Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis possibly by reducing NLRP3 activation and up-regulating NET expression. [ABSTRACT FROM AUTHOR]

• PD1 alleviates severity of acute pancreatitis in three experimental mouse models. • PD1 inhibits NETs formation by downregulating PAD4 expression in neutrophils. • PD1 may be a therapeutic candidate for acute pancreatitis in clinical. Docosahexaenoic acid-derived protectin D1 (PD1) was identified critical in the resolution of inflammation in vivo, where it modulates the innate immune response and stimulates resolution. Acute pancreatitis (AP) is characterized by local pancreatic inflammation with mild forms whereas systemic inflammation with severe forms. Herein we investigate the impact of PD1 in murine models of pancreatitis. Three independent AP models, which induced in male mice via intraperitoneal injection of caerulein, L-arginine or pancreatic duct ligation, were used to confirm the protective effect of PD1. Infiltrations of neutrophils and macrophages in pancreas were detected by flow cytometry and immunohistochemistry. In vitro and in vivo neutrophil extracellular traps formation was detected by immunofluorescence staining. Expression of peptidylarginine deiminase 4 (PAD4) in activated neutrophils was evaluated by western blotting. Systemic treatment with PD1 reduced serum activities of amylase and lipase, blunted the concentrations of tumor necrosis factor-α and interleukin-6 in serum and protected against pancreas histologic damage in three AP models. PD1 also prolonged the survival in the pancreatic duct ligation model. Moreover, pancreatic infiltration of neutrophils and neutrophil CitH3 expression were reduced after PD1 administration. In vitro studies revealed PD1 decreased supernatant cell-free DNA and CitH3 levels and downregulated PAD4 expression in mouse bone-marrow derived neutrophils. However, in the caerulein mice pretreated with GSK484 hydrochloride, an inhibitor of PAD4, PD1 treatment showed no more protective effect. PD1 ameliorates AP by decreasing early infiltration of neutrophils into the pancreas and neutrophil extracellular traps formation through PAD4. These results supply the foundation to consider PD1 as a therapy for AP. [ABSTRACT FROM AUTHOR]