Pancreatic Edema Research Articles

Pressure-Enabled Drug Delivery Approach in the Pancreas with Retrograde Venous Infusion of Lipiodol with Ex Vivo Analysis

PurposeTo determine the safety and feasibility of pancreatic retrograde venous infusion (PRVI) utilizing a microvalvular infusion system (MVI) to deliver ethiodized oil (lipiodol) by means of the Pressure-Enabled Drug Delivery (PEDD) approach.MethodsUtilizing transhepatic access, mapping of the pancreatic body and head venous anatomy was performed in 10 swine. PEDD was performed by cannulation of veins in the head (n = 4) and body (n = 10) of the pancreas with a MVI (Surefire® Infusion System (SIS), Surefire Medical, Inc (DBA TriSalus™ Life Sciences)) followed by infusion with lipiodol. Sets of animals were killed either immediately (n = 8) or at 4 days post-PRVI (n = 2). All pancreata were harvested and studied with micro-CT and histology. We also performed three-dimensional volumetric/multiplanar imaging to assess the vascular distribution of lipiodol within the glands.ResultsA total of 14 pancreatic veins were successfully infused with an average of 1.7 (0.5–2.0) mL of lipiodol. No notable change in serum chemistries was seen at 4 days. The signal-to-noise ratio (SNR) of lipiodol deposition was statistically increased both within the organ in target relative to non-target pancreatic tissue and compared to extra pancreatic tissue (p < 0.05). Histological evaluation demonstrated no evidence of pancreatic edema or ischemia.ConclusionsPEDD using the RVI approach for targeted pancreatic infusions is technically feasible and did not result in organ damage in this pilot animal study.

Healing Effects of Single-Dose Triptolide in Rats with Severe Acute Pancreatitis

Aim: Severe acute pancreatitis (SAP) carries high morbidity and mortality risk. If the proinflammatory response phase of SAP cannot be controlled, it may result in multiorgan failure (MOF). Nuclear factor-kappa B (NF-κB) activation plays an important role in the development of MOF. In this study, it was aimed to investigate the healing effects of triptolide, an anti-inflammatory and immunosuppressive agent in rats with SAP.Material and Methods: A total of 20 Wistar-Albino rats were divided into two groups as the SAP and triptolide treatment (TT) groups. SAP was induced by intraperitoneal injection of cerulean (50 mg/kg) in both groups. TT group was administered a single dose (0.2 mg/kg) triptolide 24 hour after the induction of SAP. Serum ALT, AST, GGT, Lipase, Glucose, ALP and amylase levels and pancreatic tissue samples were examined.Results: Serum glucose and amylase levels were found to be significantly lower in the TT group (p=0.011 and p=0.035, respectively). There was no significant difference between the groups in terms of other biochemical parameters. Pancreatic edema, acinar cell degeneration, fat necrosis, intrapancreatic&amp;amp;perivascular inflammation, inflammation in the peripancreatic fat tissue were common histopathological findings in both groups. There was no significant difference between the groups in terms of histopathologic changes.Conclusion: Cerulein-induced pancreatitis is a successful method for experimental SAP. The healing effects of single-dose triptolide treatment are not evident in the early phase of SAP. The therapeutic effects of triptolide on inflammatory and oxidative stress were not significantly approved by histopathological and biochemical parameters by the pancreatic tissue.

Okra pectin relieves inflammatory response and protects damaged intestinal barrier in caerulein-induced acute pancreatic model.

Protecting the intestinal mucosa from being destroyed helps reduce the inflammation caused by acute pancreatitis (AP). In this study, whether okra pectin (OP) could attenuate the inflammation of AP through protecting the intestinal barrier was investigated. OP was obtained from crude okra pectin (COP) through the purification by DEAE cellulose 52 column. Supplementation with OP or COP in advance reduced the severity of AP, as revealed by lower serum amylase and lipase levels, abated pancreatic edema, attenuated myeloperoxidase activity and pancreas histology. OP or COP inhibited the production of pancreatic proinflammatory cytokines, including tumor necrosis factor-α and interleukin-6. In addition, the upregulation of AP-related proteins including ZO-1, occludin, the antibacterial peptide-defensin-1 (DEFB1) and cathelicidin-related antimicrobial peptide (CRAMP), as well as the histological examination of colon injuries, demonstrated that OP or COP provision could effectively maintain intestinal barrier function. Ultimately, dietary OP or COP supplementation could inhibit AP-induced intestinal inflammation. For the above, the effect of OP was better than COP. Dietary OP supplementation could be considered as a preventive method that effectively interferes with intestinal damage and attenuates inflammatory responses trigged by AP. © 2020 Society of Chemical Industry.

Posaconazole-Induced Acute Pancreatitis: A Rare Side Effect in a Child with Chronic Granulomatous Disease

Introduction: Pancreatitis is an inflammatory disease of the pancreas. Drug-induced pancreatitis is an important cause of pancreatitis. There are two pathological types of acute pancreatitis, including pancreatic edema with a mild course and pancreatic necrosis with a poor prognosis. Some agents can induce pancreatitis, but so far, posaconazole-induced pancreatitis in children has been not reported. Here, we describe the case of a child with acute pancreatitis who received posaconazole. Case Presentation: A 10-year-old girl with a three-year history of chronic granulomatous disease (CGD) was admitted to hospital due to epigastric pain, nausea, vomiting, loss of appetite, and fever for the last four days. The pain was persistent and prominent in the periumbilical area. The patient was on lifelong antifungal prophylaxis for her illness. On abdominal sonography, the head of the pancreas was inflated, which can indicate pancreatitis. All the medications were discontinued at the time of admission, and along with sufficient hydration, acetaminophen was administered for the patient’s pain. One, three, and twelve months after discharge, the patient was visited for follow-up with no signs of stomach discomfort, and the lab data was within the normal limits. CGD is a rare disease in which the phagocytes fail to produce hydrogen peroxide. Such patients are prone to bacterial and fungal infections. Conclusions: In conclusion, this is the second case of posaconazole-induced pancreatitis and the first case in children; thus, we recommend that physicians should be aware of the signs of pancreatitis in high-risk individuals like immunocompromised pediatric population.

CLINICAL EFFECTIVENESS OF ANTRAL IN PATIENTS WITH CHRONIC PANCREATITIS

The studies on the pathogenesis of chronic pancreatitis (CP) have proven the important role of systemic inflammation, factors of proteinase-inhibitory system with increasing damaging effects of systemic proteolysis, disturbance of oxidant-antioxidant homeostasis, changes in blood lipid and protein spectroscopic processes that collectively contribute to inhibition of reparative processes and the activation of pancreatic fibrosis processes. The aim of this study was to determine the effectiveness of applying Antral medicine in the treatment of CP in the exacerbation phase on the basis of a comprehensive assessment of clinical course of CP and structural and functional disorders of the pancreas. Material and methods. 52 patients with CP of mixed aetiology were examined in the exacerbation phase of moderate severity. The first group (group 1, control) included 24 people, who received standard treatment within 30 days. The main group (group 2) involved 28 people, who in addition to the standard therapy took Antral (Pharmak OAO, Kyiv) in a dose of 1 tablet (200 mg) 3 times a day for 30 days. The comparison group consisted of 30 healthy individuals of the same age and sex. Results. In 4 weeks since the beginning of the therapy, the astheno-vegetative syndrome was found as significantly less manifested in only 2 people (7.1%) of the 2 groups, whereas in the 1 group it remained in 17 patients. At the same time in all patients of group 2 (100.0%) the pain and feeling of heaviness in the epigastric region, pain in the left and right subcostal area were disappeared, they did not complain of nausea.&#x0D; The restoration of physical performance in 100.0% of patients in the 2 group can be regarded as a positive manifestation of the therapy efficacy. Analyzing the indicators, which characterize the phase of CP exacerbation, it is necessary to note the patients of the 2 group demonstrated higher efficacy of their treatment program. Thus, dynamic indicators of blood α-amylase activity against the background of hyperfermentemia diagnosed prior the treatment and in the phase of CP exacerbation significantly decreased in both groups of observation on the 30th day of the therapy; the syndrome of enzyme rejection in the blood was eliminated in 100% of patients of the 2 groups; whereas in group 1 this was observed only in 58.3% of the patients. The dynamic of indicators of the inflammation syndrome in patients with CP (by blood C-reactive protein content) indicates its complete elimination in 96.4% of the patients in group 2 vs. 29.2% of the patients in group 1. Analysis of the dynamic indicators of elastase-1 content in the faeces of the patients with CP on the 30th day of the therapy indicates a significant increase in this indicator in only group 2. Restoration of the secretory capacity of the pancreas was observed in 78.6% of patients in group 2 vs. 20.8% of the patients in group 1. Conclusions. Complex therapy of patients with chronic pancreatitis with applying Antral in addition to the integrated therapy has led to faster, when compared with only standard therapy, achieving clinical remission of chronic pancreatitis, elimination of inflammatory pancreatic oedema, hyperfermentemia and inflammation, restoration of the external secretion of the pancreas.

The degree of pancreatic edema in ischemic damage during acute pancreatitis in the conditions of pharmacological correction with infliximab

The degree of pancreatic edema in ischemic damage during acute pancreatitis in the conditions of pharmacological correction with infliximab

No effects of a 6-week intervention with a glucagon-like peptide-1 receptor agonist on pancreatic volume and oedema in obese men without diabetes.

To investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA), liraglutide, on pancreatic volume, oedema, cellularity and DNA synthesis in humans. We performed an open-label study in 14 obese men (age 38 ± 11 years, body mass index 32 ± 4 kg/m2 ) without diabetes. Subjects were examined at baseline, during titration (week 4) of liraglutide towards 3.0 mg/day, and 2 weeks after steady-state treatment (week 6) of a final dose of liraglutide. The primary endpoint was pancreatic volume determined by magnetic resonance imaging. Secondary endpoints included pancreatic oedema and cellularity, positron emission tomography-based [18 F]fluorothymidine (FLT) uptake (DNA synthesis) and plasma pancreatic enzymes. Plasma amylase (+7 U/L [95% confidence intervals 3-11], P < .01) and lipase (+19 U/L [7-30], P < .01) increased during liraglutide treatment. Pancreatic volume did not change from baseline to steady state of treatment (+0.2 cm3 [-8-8], P = .96) and no change in pancreatic cellular infiltration was found (P = .22). During titration of liraglutide, FLT uptake in pancreatic tissue increased numerically (+0.08 [0.00-0.17], P = .0507). Six weeks of treatment with liraglutide did not affect pancreatic volume, oedema or cellularity in obese men without diabetes.

Acetyl-α-boswellic acid and Acetyl-β-boswellic acid protects against caerulein-induced pancreatitis via down-regulating MAPKs in mice

This study is to investigate the protective effect of Acetyl-α-boswellic acid and Acetyl-β-boswellic mixture(α/β-ABA), which is the active ingredients isolated from Frankincense, on actue pancreatitis and its mechanism. Our experimental results showed that 2 μM α/β-ABA reduced production of NO, TNF-α, IL-6, IL-10 and IL-1β in RAW264.7 cells that were stimulated with lipopolysaccharide (LPS) which indicates its anti-inflammatory role. In pancreatitis model induced by caerulein, intra-gastrical administration of 100 mg/kg α/β-ABA relieved inflammatory cells infiltration significantly and attenuated the serum elevation of amylase TNF-α and IL-6 remarkably in mice. Furthermore, α/β-ABA down-regulated mitogen-activated protein kinase (MAPK) family phosphorylated proteins in pancreas, including phosphorylated p38, ERK1/2 and JNK, to reduce the serum inflammatory factors. Finally, α/β-ABA alleviated the pancreatic edema and inflammatory cell infiltration in pancreatitis mice model. This study suggests that α/β-ABA may be targeted for drug development against pancreatitis via modulating MAPKs pathway.

355-OR: Effects of a Six-Week Intervention with Glucagon-Like Peptide-1 Analogue on Pancreatic Volume, Edema, and DNA Synthesis in Obese Men

Plasma concentrations of the two pancreatic enzymes, amylase and lipase, are increased within the normal physiological range after initiation of glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment. An association between the use of GLR-1RA and incidence of acute pancreatitis or pancreatic cancer has not been found - neither in rodent studies nor in preclinical studies or in the large cardiovascular outcome trials with GLP-1RAs. The increased concentrations of pancreatic enzymes have been suggested to be explained by increased DNA or protein synthesis found in rodent and acinar cell studies. However, whether this translates into humans is unknown. We therefore investigated the effect of liraglutide, a GLP-1RA, on pancreatic volume, edema and DNA synthesis reflected by 18F-flourothymidine (FLT)-uptake using state-of-the-art positron emission tomography (PET)-magnetic resonance imaging (MRI) before initiation, after four weeks during titration of liraglutide and after six weeks during steady state on maximum dose of liraglutide 3.0 mg in 14 obese men (age 38 ± 3 years, BMI 32 ± 1 kg/m2) without diabetes. Plasma concentrations of amylase and lipase were assessed in parallel. Amylase (+7 U/L [95% confidence intervals, 3 - 11] p&amp;lt;0.01) and lipase (+19 U/L [7-30] p&amp;lt;0.01) increased during liraglutide treatment while body weight decreased (-4.5 kg [-5,9 - -3,1] p&amp;lt;0.01). Pancreatic volume did not change from baseline to steady state of treatment (+2.1 cm3 [-10 - 14] p=0.72]) and no signs of change in cellular infiltration of the pancreas were found (p=0.22). During titration of liraglutide, FLT-uptake increased (+0.09 g/mL [0.000 - 0.17], p=0.05). In conclusion, six weeks of treatment with liraglutide did not affect pancreatic volume, edema or cellularity in obese individuals. Increased DNA synthesis reflected by FLT-uptake in the pancreas seen after four weeks of liraglutide treatment may be responsible for the increase in pancreatic enzymes. Disclosure M.S. Svane: None. H.H. Johannesen: None. C. Martinussen: None. K.N. Bojsen-Moller: None. M.L. Hansen: None. A.E. Hansen: None. C.F. Deacon: Employee; Spouse/Partner; Merck &amp; Co., Inc. Stock/Shareholder; Spouse/Partner; Merck &amp; Co., Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Novartis AG, Novo Nordisk A/S. B. Hartmann: None. S.H. Keller: None. T.L. Klausen: None. A. Loft: None. A. Kjaer: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. J.O. Löfgren: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker’s Bureau; Self; Merck Sharp &amp; Dohme Corp.

Dehydrocholic Acid Ameliorates Sodium Taurocholate-Induced Acute Biliary Pancreatitis in Mice.

Acute biliary pancreatitis (ABP) with a high mortality rate is an incurable digestive system disease induced by abnormal bile acid regurgitation due to the biliary obstruction. Dehydrocholic acid (DA) alleviates the severity of cholestatic hepatitis related to biliary inflammation, suggesting DA is potential to develop for the incurable ABP management. Here we identified DA potency and explored the underlying mechanism in ABP. Our data showed that DA administration not only reduced typically clinicopathological parameters including serum levels of amylase and lipase but also suppressed pancreatic tissue edema, necrosis and trypsin activation in ABP mice. We also found that DA significantly reduced the necrosis of pancreatic acinar cells induced by sodium taurocholate (NaT). Further experimental data showed the significant inhibitions of DA on mitochondrial membrane potential depolarization, ATP exhaustion, calcium overload and reactive oxygen species (ROS) erupted in acinar cells induced by NaT, indicating DA could avert acinar cell death through protecting the mitochondrial function, scavenging excessive oxidative stress and balancing calcium. The comprehensive study found DA elevated the expression of transcription factor EB (TFEB) in vitro thus to increase the functional lysosome content. Indeed, DA decreased the Microtubule-associated protein light chain 3 (LC3) II/I ratio as well as ubiquitin-binding protein p62 and Parkin expressions in vivo and in vitro, revealing autophagy restoration maybe through the improvement of TFEB-mediated lysosome biogenesis. These data indicate that DA improves ABP through the mitochondrial protection, antioxidant ability enhancement and autophagy recovery. In conclusion, our study proposes a potential therapy strategy for the incurable ABP.

Emerging Phenotype of Severe Acute Respiratory Syndrome-Coronavirus 2–associated Pancreatitis

Emerging Phenotype of Severe Acute Respiratory Syndrome-Coronavirus 2–associated Pancreatitis

Pretreatment with Warfarin Attenuates the Development of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats.

In acute pancreatitis (AP), pancreatic damage leads to local vascular injury, manifesting as endothelial damage and activation, increased vascular permeability, leukocyte rolling, sticking and transmigration to pancreatic tissue as well as activation of coagulation. Previous studies have shown that pretreatment with heparin or acenocoumarol inhibits the development of AP. The aim of the present study was to check the impact of pretreatment with warfarin, an oral vitamin K antagonist, on the development of ischemia/reperfusion-induced AP in rats. AP was induced by pancreatic ischemia followed by reperfusion of the gland. Warfarin (90, 180 or 270 µg/kg/dose) or vehicle were administered intragastrically once a day for 7 days before induction of AP. The effect of warfarin on the severity of AP was assessed 6 h after pancreatic reperfusion. The assessment included histological, functional, and biochemical analyses. Pretreatment with warfarin given at a dose of 90 or 180 µg/kg/dose increased the international normalized ratio and reduced morphological signs of pancreatic damage such as pancreatic edema, vacuolization of acinar cells, necrosis and the number of hemorrhages. These effects were accompanied by an improvement of pancreatic blood flow and a decrease in serum level amylase, lipase, pro-inflammatory interleukin-1β and plasma level of D-dimer. In contrast, pretreatment with warfarin given at a dose of 270 µg/kg/dose led to an increase in severity of pancreatic damage and biochemical indicators of AP. In addition, this dose of warfarin resulted in deaths in some animals. Pretreatment with low doses of warfarin inhibits the development of AP induced by pancreatic ischemia followed by reperfusion.

The use of the synthetic analogue of leucin-encephaline in complementary therapy of dogs with chronic pancreatitis

Abstract. A review of the problem of treating dogs for pancreatitis with peptide drugs is presented. The main attention is paid to the analysis of the use of somatostatin, octreotide and the synthetic analogue of leucine-enkephalin – dalargin. Despite numerous studies of the therapeutic effects of these agents for acute pancreatitis and pancreatic necrosis in humane medicine, there is no definitive answer about their efficacy in dogs due to the lack of work performed in accordance with the criteria of evidence-based medicine. The use of dalargin in the complex therapy of dogs with chronic pancreatitis, eliminates or reduces pain and dyspeptic phenomena, contributes to the onset of positive changes at the same time a number of positive changes in the functional state of the pancreas manifested by decreased serum amylase activity 3 times, pancreatic lipase in the 1 , 9 times. Studies carried out on dogs, patients with chronic pancreatitis, it is determined that against the background of treatment of synthetic analogue Leukin-enkefaline – Dalagin. The intensity of pain decreased (up to 5 days in 90% of patients), decreased amylase and pancreatic lipase activity and TBK-active product (mal on ic dialdehyde, MDA) in their blood serum. Ultrasound showed data on the reduction of pancreatic edema, in 7 sick dogs, its sizes were restored to indicators in healthy animals. Keywords : chronic pancreatitis, acute pancreatitis, dogs, dalargin, serum amylase, pancreatic lipase

OPTIMIZATION OF SURGICAL TREATMENT OF PATIENTS WITH ACUTE PANCREATITIS USING MINIINVASIVE TECHNIQUES

Summary. The aim of the study. To improve the results of surgical treatment of patients with acute pancreatitis using minimal invasive techniques.&#x0D; Matherials and Methods of the study. The results of surgical treatment of 75 patients with different forms of acute pancreatitis were analyzed. All patients were examined and operated on.&#x0D; Results of the study. Minimally invasive interventions were performed in 92 % of the analyzed patients. Intraoperatively acute pancreatic edema was observed in 43 % of patients, hemorrhagic pancreatic necrosis – in 24 %, infected pancreatic necrosis – in 33 %. The postoperative period was complicated by 13.3 %, the mortality rate was 9.3 %.&#x0D; Conclusions. The use of minimally invasive techniques for treating acute pancreatitis can significantly improve the results of surgical treatment of patients with this pathology. The frequency of complications and lethality decreases. Also, it is possible to significantly reduce operational trauma, and hence the number of bed-days of stay in hospital treatment. This contributes to reducing the financial cost of treatment in patients with acute pancreatitis, as well as improving the quality of life of this category of patients.

Current trends in pharmacological approaches for treatment and management of acute pancreatitis - a review.

Acute pancreatitis (AP) is an inimical disorder associated with overall mortality rates between 10-15%. It is a disorder of the exocrine pancreas which is characterized by local and systemic inflammatory responses primarily driven by oxidative stress and death of pancreatic acinar cells. The severity of AP ranges from mild pancreatic edema with complete recuperative possibilities to serious systemic inflammatory response resulting in peripancreatic/pancreatic necrosis, multiple organ failure, and death. We have retrieved the potential alternative approaches that are developed lately for efficacious treatment of AP from the currently available literature and recently reported experimental studies. This review summarizes the need for alternative approaches and combinatorial treatment strategies to deal with AP based on literature search using specific key words in PubMed and ScienceDirect databases. Since AP results from perturbations of multiple signaling pathways, the so called "monotargeted smart drugs" of the past decade is highly unlikely to be effective. Also, the conventional treatment approaches were mainly involved in providing palliative care instead of curing the disease. Hence, many researchers are beginning to focus on developing alternate therapies to treat AP effectively. This review also summarizes the recent trends in the combinatorial approaches available for AP treatment.

Loss of RE-1 silencing transcription factor accelerates exocrine damage from pancreatic injury

Regulation of pancreas plasticity is critical for preventing injury and promoting regeneration upon tissue damage. The intricate process of pancreatic differentiation is governed by an orchestrated network of positive and negative transcription factors for appropriate gene expression. While the transcriptional repressor REST is well characterized as a silencer of neuronal genes in non-neuronal cells, the role of REST in regulating exocrine pancreas cell identity remains largely unexplored. Rest expression is increased upon injury in the mouse pancreas, such as induced acute and chronic pancreatitis and ductal adenocarcinoma. At the cellular level, Rest expression is lower in mature acinar cells compared with pancreas progenitor and ductal cells. To investigate the role of REST activity in pancreatic transdifferentiation and homeostasis, we developed a novel mouse model (Cre/RESTfl/fl) with conditional knockout (KO) of Rest expression within pancreas cells. The high Cre-mediated excision efficiency of Rest exon two KO caused decreased Rest expression and activity within the pancreas. Short-term organoid cultures of pancreatic acini to undergo acinar-to-ductal metaplasia (ADM) showed that loss of REST impedes induced ADM, while overexpression of REST increases ADM. Interestingly, REST ablation accelerated acute pancreatitis in mice treated with the cholecystokinin analog caerulein, as indicated by cellular morphology, elevated serum amylase levels and pancreatic edema. Furthermore, Cre/RESTfl/fl mice were more sensitive to acute pancreatitis injury and displayed augmented tissue damage and cellular lesions. These results suggest REST has a novel protective role against pancreatic tissue damage by acting as a regulator of exocrine cell identity.

Preventive Effects of Gardenia jasminoides on Cerulein-Induced Chronic Pancreatitis.

Our previous report revealed that Gardenia jasminoides (GJ) has protective effects against acute pancreatitis. So, we examined whether aqueous extract of GJ has anti-inflammation and antifibrotic effects even against cerulein-induced chronic pancreatitis (CP). CP was induced in mice by an intraperitoneal injection of a stable cholecystokinin (CCK) analogue, cerulein, six times a day, four days per week for three weeks. GJ extract (0.1 or 1[Formula: see text]g/kg) or saline (control group) were intraperitoneally injected 1[Formula: see text]h before first cerulein injection. After three weeks of stimulation, the pancreas was harvested for the examination of several fibrotic parameters. In addition, pancreatic stellate cells (PSCs) were isolated using gradient methods to examine the antifibrogenic effects of GJ. In the cerulein-induced CP mice, the histological features of the pancreas showed severe tissue damage such as enlarged interstitial spaces, inflammatory cell infiltrate and glandular atrophy, and tissue fibrosis. However, treatment of GJ reduced the severity of CP such as pancreatic edema and inflammatory cell infiltration. Furthermore, treatment of GJ increased pancreatic acinar cell survival, and reduced pancreatic fibrosis and activation of PSC in vivo and in vitro. In addition, GJ treatment inhibited the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) in the PSCs. These results suggest that GJ attenuated the severity of CP and the pancreatic fibrosis by inhibiting JNK and ERK activation during CP.

Critical Role of TFEB-Mediated Lysosomal Biogenesis in Alcohol-Induced Pancreatitis in Mice and Humans.

Background & AimsAlcohol abuse is the major cause of experimental and human pancreatitis but the molecular mechanisms remain largely unknown. We investigated the role of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, in the pathogenesis of alcoholic pancreatitis.MethodsUsing a chronic plus acute alcohol binge (referred to as Gao-binge) mouse model, we analyzed pancreas injury, autophagic flux, zymogen granule removal, TFEB nuclear translocation and lysosomal biogenesis in GFP-LC3 transgenic mice, acinar cell-specific Atg5 knockout (KO) and TFEB KO mice as well as their matched wild type mice.ResultsWe found that Gao-binge alcohol induced typical features of pancreatitis in mice with increased serum amylase and lipase activities, pancreatic edema, infiltration of inflammatory cells, accumulation of zymogen granules (ZGs) and expression of inflammatory cytokines. While Gao-binge alcohol increased the number of autophagosomes, it also concurrently inhibited TFEB nuclear translocation and TFEB-mediated lysosomal biogenesis resulting in insufficient autophagy. Acinar cell-specific Atg5 KO and acinar cell-specific TFEB KO mice developed severe inflammatory and fibrotic pancreatitis in both Gao-binge alcohol and control diet-fed mice. In contrast, TFEB overexpression inhibited alcohol-induced pancreatic edema, accumulation of zymogen granules and serum amylase and lipase activities. In line with our findings in mice, decreased LAMP1 and TFEB nuclear staining were also observed in human alcoholic pancreatitis tissues.Conclusionsour results indicate that TFEB plays a critical role in maintaining pancreatic acinar cell homeostasis. Impairment of TFEB-mediated lysosomal biogenesis by alcohol may lead to insufficient autophagy and promote alcohol-induced pancreatitis.

OPTIMIZATION OF SURGICAL TREATMENT OF PATIENTS WITH ACUTE PANCREATITIS USING MINIINVASIVE TECHNIQUES

Abstract. The aim of the study. To improve the results of surgical treatment of patients with acute pancreatitis using minimal invasive techniques. Matherials and Methods of the study. The results of surgical treatment of 75 patients with different forms of acute pancreatitis were analyzed. All patients were examined and operated on. Results of the study. Minimally invasive interventions were performed in 92% of the analyzed patients. Intraoperatively acute pancreatic edema was observed in 43% of patients, hemorrhagic pancreatic necrosis – in 24%, infected pancreatic necrosis – in 33%. The postoperative period was complicated by 13.3%, the mortality rate was 9.3%. Conclusions. The use of minimally invasive techniques for treating acute pancreatitis can significantly improve the results of surgical treatment of patients with this pathology. The frequency of complications and lethality decreases. Also, it is possible to significantly reduce operational trauma, and hence the number of bed-days of stay in hospital treatment. This contributes to reducing the financial cost of treatment in patients with acute pancreatitis, as well as improving the quality of life of this category of patients.

Butyrate ameliorates caerulein-induced acute pancreatitis and associated intestinal injury by tissue-specific mechanisms.

Acute pancreatitis (AP) is a common acute abdominal condition, frequently associated with intestinal barrier dysfunction, which aggravates AP retroactively. Butyrate exhibits anti-inflammatory effects in a variety of inflammatory diseases. However, its potential beneficial effect on AP and the underlying mechanisms have not been investigated. Experimental AP was induced by caerulein hyperstimulation in wild-type and GPR109A-/- mice. Sodium butyrate was administered intragastrically for 7 days prior to caerulein hyperstimulation. Anti-inflammatory mechanisms of butyrate were further investigated in peritoneal macrophages. Butyrate prophylaxis attenuated AP as shown by reduced serum amylase and lipase levels, pancreatic oedema, myeloperoxidase activity, and improved pancreatic morphology. Amelioration of pancreatic damage by butyrate was associated with reduced levels of TNF-α, IL-6, and CCL2 and suppressed activation of the NLRP3 inflammasome in both pancreas and colon. Further, butyrate ameliorated pancreatic inflammation by suppressing interactions between histone deacetylase 1 (HDAC1) and AP1 and STAT1 with increased histone acetylation at H3K9, H3K14, H3K18, and H3K27 loci, resulting in suppression of NLRP3 inflammasome activation and modulation of immune cell infiltration in pancreas. Additionally, butyrate mediated STAT1/AP1-NLRP3 inflammasome suppression via HDAC1 inhibition was demonstrated in peritoneal macrophage. In colon, butyrate inhibited NLRP3 inflammasome activation via GPR109A. Accordingly, the modulatory effects of butyrate on AP, AP-associated gut dysfunction, and NLRP3 inflammasome activation were diminished in GPR109A-/- mice. Our study dissected tissue-specific anti-inflammatory mechanisms of butyrate during AP, suggesting that increased colonic levels of butyrate may be a strategy to protect against AP.