Calcium/P53/Ninjurin 1 Signaling Mediates Plasma Membrane Rupture of Acinar Cells in Severe Acute Pancreatitis.

Ninjurin 1 (NINJ1) is a double-transmembrane cell-surface protein that might mediate plasma membrane rupture (PMR) and the diffusion of inflammatory factors. PMR is a characteristic of acinar cell injury in severe acute pancreatitis (SAP). However, the involvement of NINJ1 in mediating the PMR of acinar cells in SAP is currently unclear. Our study has shown that NINJ1 is expressed in acinar cells, and the expression is significantly upregulated in sodium-taurocholate-induced SAP. The knockout of NINJ1 delays PMR in acinar cells and alleviates SAP. Moreover, we observed that NINJ1 expression is mediated by Ca2+ concentration in acinar cells. Importantly, we found that Ca2+ overload drives mitochondrial stress to upregulate the P53/NINJ1 pathway, inducing PMR in acinar cells, and amlodipine, a Ca2+ channel inhibitor, can reduce the occurrence of PMR by decreasing the concentration of Ca2+. Our results demonstrate the mechanism by which NINJ1 induces PMR in SAP acinar cells and provide a potential new target for treatment of SAP.

NLRP3 inflammasome inhibitor MCC950 can reduce the damage of pancreatic and intestinal barrier function in mice with acute pancreatitis.

PURPOSE: Abnormal activation of NOD-like receptor protein 3 (NLRP3) inflammasome can lead to the occurrence and progression of acute pancreatitis. This study investigated the protective effect of MCC950 on pancreatitis mice. METHODS: Eighteen mice were randomly divided into control group, severe acute pancreatitis (SAP) group and SAP+MCC950 group. Serum interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α (TNF-α) were measured by ELISA. Hematoxylin and eosin (HE) staining was used to evaluate the pathological damage. Western blotting was used to detect the expression of NLRP3 inflammasome and tight junction proteins in the small intestine and pancreas. RESULTS: MCC950 could reduce the levels of IL-6 and IL-1ß in SAP mice. After treatment with MCC950, the expression levels of NLRP3 inflammasome in the pancreas of SAP mice were significantly reduced and the pathological damage to the pancreas and intestine was alleviated. Compared with the control group, the expression of tight junction protein (ZO-1,occludin and claudin-4) in the intestinal mucosa of SAP mice was decreased, and the expression of claudin-4 and occludin were upregulated after MCC950 treatment. CONCLUSIONS: MCC950 can inhibit NLRP3 inflammasome activation and significantly reduce the inflammatory response and delay the process of pancreatitis. It has therapeutic potential in the treatment of acute pancreatitis.

Triptolide Suppresses NF-κB-Mediated Inflammatory Responses and Activates Expression of Nrf2-Mediated Antioxidant Genes to Alleviate Caerulein-Induced Acute Pancreatitis.

Triptolide (TP), the main active ingredient of Tripterygium wilfordii Hook.f., displays potent anti-inflammatory, antioxidant, and antiproliferative activities. In the present study, the effect of TP on acute pancreatitis and the underlying mechanisms of the disease were investigated using a caerulein-induced animal model of acute pancreatitis (AP) and an in vitro cell model. In vivo, pretreatment with TP notably ameliorated pancreatic damage, shown as the improvement in serum amylase and lipase levels and pancreatic morphology. Meanwhile, TP modulated the infiltration of neutrophils and macrophages (Ly6G staining and CD68 staining) and decreased the levels of proinflammatory factors (TNF-α and IL-6) through inhibiting the transactivation of nuclear factor-κB (NF-κB) in caerulein-treated mice. Furthermore, TP reverted changes in oxidative stress markers, including pancreatic glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), in acute pancreatitis mice. Additionally, TP pretreatment inhibited intracellular reactive oxygen species (ROS) levels via upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes expression (HO-1, SOD1, GPx1 and NQO1) in vitro. Taken together, our data suggest that TP exert protection against pancreatic inflammation and tissue damage by inhibiting NF-κB transactivation, modulating immune cell responses and activating the Nrf2-mediated antioxidative system, thereby alleviating acute pancreatitis.

Correlation Between Severity of Illness and Levels of Free Triiodothyronine, Interleukin-6, and Interleukin-10 in Patients with Acute Pancreatitis.

BACKGROUND Acute pancreatitis (AP) is a common acute abdominal disease. Rapid evaluation of the severity is important for AP prognosis and treatment. Free triiodothyronine (fT3) level is associated with the prognosis of AP patients. This study aimed to investigate the fT3 level in patients with acute pancreatitis; early warning signs of inflammation, including interleukin-6 (IL-6) and interleukin-10 (IL-10); and the correlation of fT3 level with illness severity. MATERIAL AND METHODS Enrolled AP patients (N=312) were divided into an SAP group (N=92) and a non-SAP group (N=220) according to the Revision of Atlanta classification. Blood or tissue samples and baseline clinical characteristics were recorded. The t test and chi-square test were used to evaluate differences between the 2 groups. Multivariate logistic regression analysis and receiver operating characteristic (ROC) curves were used to investigate protective factors. One-way repeated measures analysis of variance was used to evaluate the prognosis of SAP patients. RESULTS In our study, compared with APACHII score (AUC 0.829 [95% CIs 0.769-0.889]) and Ranson score (AUC 0.629 [95% CIs 0.542-0.715]), our predictive model (AUC 0.918 [95% CIs 0.875-0.961]) showed better prognostic performance in predicting poor patient outcomes. In the SAP group, changes in fT3 level were significantly associated with prognosis (P<0.05). CONCLUSIONS The predictive model can improve the diagnostic accuracy and prediction of the severity of disease. FT3 level could be used as an independent risk factor to predict the mortality of SAP patients.

Diallyl Disulfide Attenuates STAT3 and NF-κB Pathway Through PPAR-γ Activation in Cerulein-Induced Acute Pancreatitis and Associated Lung Injury in Mice.

We have previously shown that diallyl disulfide (DADS) protects mice against cerulein-induced acute pancreatitis (AP) and associated lung injury. However, the molecular mechanisms underlying its effect and the components involved have not been studied. We hypothesized that DADS may reduce TNF-α, CSE expression, H2S production, STAT3, and NF-κB activation and induce SOCS3 expression through peroxisome proliferator-activated receptor γ (PPAR-γ) pathway in cerulein-induced mice. Male Swiss mice were treated with hourly intraperitoneal injections of cerulein (50 µg/kg) for 6 h. Diallyl disulfide (200 µg/kg) was administered in the presence or absence of PPAR-γ antagonist GW9662 (0.3 mg/kg) (i.p) 1 h after the induction of AP. Our findings revealed that DADS blocked TNF-α, CSE expression, H2S production, and STAT3, and NF-κB activation was reversed by GW9662. Furthermore, GW9662 abrogated DADS-induced SOCS3 expression. The results show for the first that DADS-induced anti-inflammatory effect in acute pancreatitis is regulated through PPAR-γ.

Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis.

Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, pancreatic epithelial cells display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thereby limiting tissue damage through a rapid decrease of zymogen production. We propose that because activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis.

Comparison between prognostic indicators in organ insufficiency with acute pancreatitis.

BACKGROUND: Organ failures that develop due to acute pancreatitis (AP), some laboratory values and the anthropometric characteristics of the patients have been shown to play a role in the prognosis AP and have been increasingly used to investigate the prognosis of the disease although classification systems, such as Ranson's criteria, are still used habitually. In this stud, we aimed to investigate the relationship of the organ failures observed during the course of AP, the biochemical parameters and the anthropometric characteristics of the patients and compare using Ranson's and Atlanta Classifica-tion (AC) systems. METHODS: Laboratory values, anthropometric data, including the waist circumference and body mass index, Systemic inflammatory response syndrome (SIRS) and organ failures developed during the course of the disease, were investigated prospectively in 153 AP patients and the Ranson and Modified Atlanta Classifications (MAC) were made. RESULTS: A relationship was observed between the organ failures that were established in the course of the disease (lung, liver, kidney, heart and MOF (multiple organ failure)) and higher Ranson's and MAC scores (p<0.05). Among the patients included in this study, 13 (8.4%) had multiple organ failure and 17 (11.1%) had SIRS. Exitus occurred in 10 patients (6.5%). A statistically significant relationship was found with organ failure, multiple organ failure and SIRS; and ensuing exitus (p<0.05). While no relationship was observed between the waist circumference, body mass index, Ranson's score, there was a significant relationship between the MAC and the waist circumference (p<0.01). Among the laboratory values, high urea and ALT values showed a relationship with the Ranson and MAC (p<0.001), while between the CRP values tested at the 0 time point and the 48th hour, only the CRP value at the 48th hour had a relationship with Ranson's score (p<0.05). Organ failure, MOF, and SIRS showed a correlation with both the severity scores and the mortality rate. In addition, a significant corre-lation was observed between the cholesterol, triglycerides and the CRP level at the time of hospitalisa-tion and mortality. On the contrary, no significant relationship was observed with the other laboratory results, including calcium, lipase and hematocrit. CONCLUSION: In conclusion, to determine the severity and prognosis of acute pancreatitis, and ex-pect the organ failures that may occur in severe pancreatitis, the body mass index, waist circumference and laboratory values, including cholesterol, triglycerides, ALT, and CRP may supply important prog-nostic data besides the conventional disease severity scoring methods.

Autoimmune pancreatitis: Current perspectives.

Over the last two decades, our knowledge and understanding regarding the pathogenesis and biology of autoimmune pancreatitis (AIP) have improved tremendously. Type 1 AIP or IgG4-related pancreatitis (IgG4-RP) is now believed to be the prototype of the multisystemic IgG4-related disease. In view of clinical features like obstructive jaundice and mass-forming lesions in the pancreas in elderly men, type 1 AIP often mimics pancreatic cancer. IgG4-related sclerosing cholangitis concomitantly involving the extrahepatic and intrahepatic biliary tree is the most common extrapancreatic involvement seen in up to 80% of these patients, which needs to distinguish from cholangiocarcinoma. Histology is characterised by lymphoplasmacytic inflammation, abundant IgG4 positive plasma cell infiltration, storiform fibrosis and obliterative phlebitis. Apart from histology, high serum IgG4 levels, pancreatic parenchymal and duct imaging findings and other organ involvement aid in diagnosis especially in cases where definitive histology is not evident. Also, these parameters lay the foundation of various diagnostic criteria proposed over last few years. On the contrary, histology alone is the mainstay for establishing diagnosis of idiopathic duct-centric pancreatitis (IDCP) as it lacks any specific serological marker or imaging. Since both types of AIP respond dramatically to corticosteroid treatment, a biopsy is crucial to establish the preoperative diagnosis and to exclude malignancy so as to avoid unnecessary surgery. This review discusses the morphologic spectrum, treatment and prognosis of IgG4-RP and IDCP with an emphasis on approach to diagnosis with relevant histologic features, differential diagnoses and the challenges faced during biopsy interpretation.

Clinical-radiological characteristics and intestinal microbiota in patients with pancreatic immune-related adverse events.

BACKGROUND: The pancreatic immune-related adverse event (irAE) is a rare but increasingly occurrence disease with limited knowledge, which was associated with the use of immune checkpoint inhibitors (ICIs). METHODS: In this case series study of pancreatic irAE patients, clinical and radiological manifestations are summarized. Baseline and post-treatment fecal microbiota of immune-related acute pancreatitis (irAP) patients were analyzed by the 16 s rDNA amplicon sequencing method. RESULTS: A total of six patients were enrolled into the study, and the onset of pancreatic irAEs occurred a median of 105 days after a median of 4.5 cycles with immune checkpoint inhibitors (ICIs). All patients had an effective response to ICIs. Abdominal pain was the main clinical manifestation. Serum amylase (sAMY) and lipase (sLIP) had dynamic changes parallel to clinical severity. Contrast-enhanced computed tomography (CT) did not accurately reveal the level of inflammation. However, magnetic resonance imaging (MRI) was a sensitive imaging method which showed decreased and increased signal intensity of pancreatic parenchyma in T1-weighted fat-saturated and diffusion-weighted imaging, respectively. Glucocorticoids were the main treatment with a rapid initial effect followed by a slow improvement. After reinitiation of ICI therapy, pancreatic irAEs either deteriorated, remained stable or the patient developed severe pancreatic ß-cell destruction without irAP recurrence. The baseline microbiota of irAP had low Bacteroidetes/Firmicutes ratio at phylum level, low relative abundance of Alistipes, Bacteroides and high Lachnospiraceae at genus level, compared to levels of pancreatic ß-cell destruction and post-treatment of irAP. CONCLUSIONS: Pancreatic irAE patients had corresponding abdominal pain and increase in sAMY/sLIP. MRI was found to be an ideal imaging modality. Treatment with glucocorticoids were the main approach. The microbiota showed relative changes at baseline and during treatment.

[Pancreatic panniculitis with polyarthritis: PPP syndrome]. / Polyartritis, panniculitis en pancreatitis.

BACKGROUND: Diseases of the pancreas may present with extrapancreatic symptoms, such as (poly)arthritis or necrosis of subcutaneous fat. A combination of pancreatitis, panniculitis and (poly)arthritis is referred to as the PPP syndrome, which is associated with acute and chronic pancreatitis, as well as pancreatic malignancies. CASE DESCRIPTION: This article describes a patient which was admitted to our hospital with severe polyarthritis and panniculitis. A meticulous work-up revealed an underlying focal alcoholic pancreatitis. The clinical course in our patient illustrates the severity of the PPP syndrome and emphasizes the need of a multidisciplinary approach. CONCLUSION: Panniculitis and/or (poly)arthritis may be the first symptom of underlying pancreatic disease. Timely recognition and diagnosis is imperative for successful treatment and outcome. The multi-organ involvement in the PPP syndrome requires close collaboration across different medical departments.

Poly(ADP-Ribose) Polymerase 1 Promotes Inflammation and Fibrosis in a Mouse Model of Chronic Pancreatitis.

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by ductal obstructions, tissue fibrosis, atrophy and exocrine and endocrine pancreatic insufficiency. However, our understanding is very limited concerning the disease's progression from a single acute inflammation, via recurrent acute pancreatitis (AP) and early CP, to the late stage CP. Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor enzyme activated mostly by oxidative DNA damage. As a co-activator of inflammatory transcription factors, PARP1 is a central mediator of the inflammatory response and it has also been implicated in acute pancreatitis. Here, we set out to investigate whether PARP1 contributed to the pathogenesis of CP. We found that the clinically used PARP inhibitor olaparib (OLA) had protective effects in a murine model of CP induced by multiple cerulein injections. OLA reduced pancreas atrophy and expression of the inflammatory mediators TNFα and interleukin-6 (IL-6), both in the pancreas and in the lungs. Moreover, there was significantly less fibrosis (Masson's trichrome staining) in the pancreatic sections of OLA-treated mice compared to the cerulein-only group. mRNA expression of the fibrosis markers TGFß, smooth muscle actin (SMA), and collagen-1 were markedly reduced by OLA. CP was also induced in PARP1 knockout (KO) mice and their wild-type (WT) counterparts. Inflammation and fibrosis markers showed lower expression in the KO compared to the WT mice. Moreover, reduced granulocyte infiltration (tissue myeloperoxidase activity) and a lower elevation of serum amylase and lipase activity could also be detected in the KO mice. Furthermore, primary acinar cells isolated from KO mice were also protected from cerulein-induced toxicity compared to WT cells. In summary, our data suggest that PARP inhibitors may be promising candidates for repurposing to treat not only acute but chronic pancreatitis as well.

Dihydrokaempferol (DHK) ameliorates severe acute pancreatitis (SAP) via Keap1/Nrf2 pathway.

Severe acute pancreatitis (SAP) is a non-bacterial inflammatory disease that clinically causes a very high rate of mortality. Dihydrokaempferol (DHK) is a natural flavonoid extracted from Bauhinia championii. Our research aimed to establish the treatment function of DHK on SAP-induced pancreas injury and delve into its potential mechanism. In this study, SAP was induced by caerulein (CER) and Lipopolysaccharide (LPS). DHK was administered orally at different doses of 20, 40, or 80 mg/kg. Results from serum amylase/lipase, pancreas hematoxylin-eosin staining technique, pancreas malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) showed the therapeutic effect of DHK in a mice SAP model. MTT revealed DHK alleviated CER + LPS induced cytotoxicity in a dose-dependent manner in the pancreatic acinar cells of mice. Next, we verified DHK suppressed the level of Keap1 and promoted transcriptional activation of nuclear Nrf2 in the presence of CER + LPS. The molecular docking study suggested that there is a potential interaction between DHK and Keap1. To further look at the role of Keap1 using in vitro and in vivo models, Keap1 overexpression adenovirus (ad-Keap1) was performed. The results revealed that ad-Keap1suppressed the nuclear translocation of Nrf2 which is enhanced by DHK, and suppressed the antioxidative functionality of DHK both in mice and cell models. Collectively, this research demonstrated that DHK bettered the SAP induced pancreas injury by regulating the Keap1/Nrf2 pathway and regulating oxidative stress injury.

Validation of the clinical utility of 4 guidelines in the initial triage of mucinous cystic lesions of the pancreas based on cross-sectional imaging: Experience with 188 surgically-treated patients.

INTRODUCTION: Over the years, several guidelines have been introduced to guide management of mucinous pancreatic cystic neoplasms (mPCN). In this study, we aimed to evaluate and compare the clinically utility of the Sendai-06, Fukuoka-12, Fukuoka-17 and European-18 guidelines in predicting malignancy of mPCN. METHODS: One hundred and eighty-eight patients with mucinous cystic neoplasms (MCN) or intraductal papillary mucinous neoplasm (IPMN) who underwent surgery were retrospectively reviewed and classified under the 4 guidelines. Malignancy was defined as high grade dysplasia and invasive carcinoma. RESULTS: Raised CA19-9>37U/ml, enhancing mural nodule≥5 mm and main pancreatic duct≥10 mm were significantly associated with malignancy on multivariate analysis. Increasing number of high risk features, absolute indications (European-18), worrisome risk or relative indications (European-18) were significantly associated with an increased likelihood of malignancy. The positive predictive values (PPV) of high risk features for Sendai-06, Fukuoka-12, Fukuoka-17 and absolute indications (European-18) for malignancy were 53%, 76%, 78% and 78% respectively. The negative predictive values (NPV) of the Sendai-06, Fukuoka-12 and Fukuoka-17 were 100%, while that of the European-18 was 92%. Risk of malignancy for patients with ≥4 worrisome features (Fukuoka-17) and ≥3 relative indications (European-18) was 66.7% and 75.0% respectively. CONCLUSIONS: All 4 guidelines studied were useful in the initial triage of mPCN for the risk stratification of malignancy. The Fukuoka-17 had the highest PPV and NPV.

The Severity of Acute Pancreatitis According to Modified Balthazar Classification in Patients With Pancreatic Cancer.

OBJECTIVE: Although acute pancreatitis (AP) is a self-limited disease under supportive and medical treatment, it can have life-threatening potential in some patients. Results of studies reporting outcomes of AP-associated pancreatic malignancy are controversial. The aim of this study was to evaluate the severity and prognosis of pancreatic cancer (PC)-related AP by modified Balthazar score. METHODS: A total of 354 patients hospitalized and followed up in our clinic between 2013 and 2019 were included in the study. Demographic data of all patients were recorded. The etiology of all cases was determined. According to the etiology, the cases were divided into 2 groups: AP related to pancreatic malignancy and AP due to nonmalignant causes. The patients underwent computed tomography of the abdomen within the first 12 hours of admission and after 3 to 7 days. Patients were evaluated and classified by modified Balthazar classification. RESULTS: Malignancy-related AP was detected in 18 (5.1%) patients. A total of 336 cases (94.9%) were related to nonmalignant causes. There was no statistically significant difference in the severity of AP in both groups at admission and after 3 days (p > 0.05). The changes (regression, progression, or no change) in the disease severity at the first and the subsequent imaging were examined. There was no significant relationship between the 2 groups (p > 0.05). CONCLUSION: AP may be the clinical manifestation of PC or PC may induce AP in various ways. It was shown that the underlying malignancy did not adversely affect the severity and course of AP.

Time intervals to diagnosis and chemotherapy do not influence survival outcome in patients with advanced pancreatic adenocarcinoma.

BACKGROUND: The effect of treatment delay on survival in pancreatic ductal adenocarcinoma (PDAC) remains unclear. AIMS: This study aimed to assess the prognostic impact of time to diagnosis and chemotherapy in advanced PDAC and factors influencing the time intervals. METHODS: advanced PDAC patients receiving chemotherapy in five centers in the decade 2007-2016 were included. Key time points during care pathway from clinical presentation to beginning of chemotherapy were retrospectively collected. Multivariate Cox proportional hazard model was performed. RESULTS: A total of 409 patients were included (mean age 66.1 ± 10.3 years; 250 metastatic (61%); 139 received FOLFIRINOX chemotherapy (34%). The median overall survival (OS) was 7.2 months. The median times from first symptoms and from first specialist visit to the beginning of chemotherapy were respectively 100 days and 47 days. None of time intervals was significantly associated with OS. Significant prognostic factors were FOLFIRINOX chemotherapy (HR 0.6 [0.5-0.8]; P < 0.001), metastasis (HR 1.6 [1.3-2.0]; P = 0.001), WHO PS ≥ 2 (HR 1.6 [1.2-2.1]; P < 0.001) and acute pancreatitis as first symptom (HR 2.9 [1.7-4.9]; P < 0.001). Jaundice shortened time to diagnosis (P < 0.001). Acute pancreatitis (P < 0.001) and diabetes (P = 0.01) increased time to treatment. CONCLUSION: Wait times from clinical presentation to beginning of chemotherapy do not influence survival in advanced PDAC.

Controversias en la terapia nutricional de la pancreatitis aguda grave / Controversies in nutrition therapy of severe acute pancreatitis

La clasificación de la severidad de la pancreatitis aguda ha cambiado con la actualización de Atlanta del 2012. Las recomendaciones de terapia nutricional en los casos de pancreatitis aguda grave no están sustentadas en estudios con alto nivel de evidencia, en los estudios se incluyen pacientes con los diferentes grados de severidad, se usa la clasificación de Atlanta 2002 para definir la pancreatitis aguda grave y, en la mayoría de los estudios experimentales, los controles son pacientes con nutrición parenteral. Se realiza una revisión narrativa de la evidencia actual publicada, analizando las características clínico epidemiológica de los pacientes y los resultados obtenidos. Así, se proponen características que deben ser consideradas en estudios futuros sobre el tema.

The classification of the severity of acute pancreatitis has changed with respect to the Atlanta update of 2012. The recommendations for nutritional therapy in cases of severe acute pancreatitis are not supported by high-level studies, as studies contain a mix of patients with different degrees of severity. The Atlanta 2002 classification is used to define severe acute pancreatitis and, in most of experimental studies, controls are patients with parenteral nutrition. A narrative review of the current published evidence is carried out analyzing the clinical and epidemiological characteristics of the patients in these results and characteristics to be included in future studies are proposed.

TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activation.

Elevated pressure in the pancreatic gland is the central cause of pancreatitis following abdominal trauma, surgery, endoscopic retrograde cholangiopancreatography, and gallstones. In the pancreas, excessive intracellular calcium causes mitochondrial dysfunction, premature zymogen activation, and necrosis, ultimately leading to pancreatitis. Although stimulation of the mechanically activated, calcium-permeable ion channel Piezo1 in the pancreatic acinar cell is the initial step in pressure-induced pancreatitis, activation of Piezo1 produces only transient elevation in intracellular calcium that is insufficient to cause pancreatitis. Therefore, how pressure produces a prolonged calcium elevation necessary to induce pancreatitis is unknown. We demonstrate that Piezo1 activation in pancreatic acinar cells caused a prolonged elevation in intracellular calcium levels, mitochondrial depolarization, intracellular trypsin activation, and cell death. Notably, these effects were dependent on the degree and duration of force applied to the cell. Low or transient force was insufficient to activate these pathological changes, whereas higher and prolonged application of force triggered sustained elevation in intracellular calcium, leading to enzyme activation and cell death. All of these pathological events were rescued in acinar cells treated with a Piezo1 antagonist and in acinar cells from mice with genetic deletion of Piezo1. We discovered that Piezo1 stimulation triggered transient receptor potential vanilloid subfamily 4 (TRPV4) channel opening, which was responsible for the sustained elevation in intracellular calcium that caused intracellular organelle dysfunction. Moreover, TRPV4 gene-KO mice were protected from Piezo1 agonist- and pressure-induced pancreatitis. These studies unveil a calcium signaling pathway in which a Piezo1-induced TRPV4 channel opening causes pancreatitis.

Protective Effects of Bone Marrow-Derived Mesenchymal Stem Cells on Insulin Secretion and Inflammation in the Treatment of Severe Acute Pancreatitis in Rats.

OBJECTIVE: The present study aims to demonstrate the protective effect of bone marrow mesenchymal stem cells (bmMSCs) on transplanted islets and its potential therapeutic role of severe acute pancreatitis (SAP) in rat model. MATERIALS AND METHODS: Mesenchymal stem cells (MSCs) were isolated from 6 male SD rats, and were identified. The Islets isolated from 20 SD rats were evenly and randomly divided into co-culture group, and basic culture group (control group), in which the islets were cultured in DMEM/F12 medium, so as to compare the insulin secretion and stimulation index. Severe AP was induced in SD rats by retrograde injection of sodium taurocholate. Ninety rats were randomly and evenly assigned into 5 groups: control group (healthy rats), SAP group, tail vein injection group, intraperitoneal injection group and combined injection (tail vein + intraperitoneal) group. Rats were sacrificed on day 1, 2, and 3. The pancreatic tissues and blood were collected. The plasma levels of IL-10, IL-1ß, TNF-α, IL-6 were determined using ELISA. Pathologic changes of the pancreas were observed using HE staining, and the positioning of DAPI labeled bmMSCs in vivo were detected. RESULTS: Insulin secretion and the stimulation index of co-culture group were significantly higher than those of basic culture group (P < .05), after 7 and 14 days of culture. Inflammation, edema, hemorrhage and necrosis in each model of pancreatitis were reduced significantly in BMMSCs injection group as compared to SAP group (P < .05). Infused BMMSCs through combined injection indicated improved outcome than that of tail-vein injection or intraperitoneal injection alone. CONCLUSION: Co-culture of BMMSCs with transplanted islets prolongs the survival time of islets and maintains in vitro activity. In the rat model of SAP, combined injection of BMMSCs through tail vein and intraperitoneal significantly suppresses the inflammatory reaction and alleviates pancreatic injury in rat SAP model.

Life with the pancreas: A personal experience.

This review article has primary objective to summarize pancreatic research which has been done in our laboratory since 1965, the first year of the author's registration in the Ph.D. program at the University of Sherbrooke (Canada). It covers the following major topics of pancreatic physiology: controls of pancreatic adaptation to diet, control of pancreatic enzyme secretion, control of pancreatic enzyme synthesis, control of pancreatic growth, intracellular events stimulated during pancreatic growth, pancreas regeneration after pancreatitis and pancreatectomy, the pancreatic cholecystokinin receptor types 1 and 2, growth control and cell signaling in pancreatic cancer cells and finally, cystic fibrosis.