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Yang X, Yao L, Fu X, Mukherjee R, Xia Q, Jakubowska MA, Ferdek PE, Huang W. Experimental Acute Pancreatitis Models: History, Current Status, and Role in Translational Research. Front Physiol 2020; 11:614591. [PMID: 33424638 PMCID: PMC7786374 DOI: 10.3389/fphys.2020.614591] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 11/30/2020] [Indexed: 02/05/2023] Open
Abstract
Acute pancreatitis is a potentially severe inflammatory disease that may be associated with a substantial morbidity and mortality. Currently there is no specific treatment for the disease, which indicates an ongoing demand for research into its pathogenesis and development of new therapeutic strategies. Due to the unpredictable course of acute pancreatitis and relatively concealed anatomical site in the retro-peritoneum, research on the human pancreas remains challenging. As a result, for over the last 100 years studies on the pathogenesis of this disease have heavily relied on animal models. This review aims to summarize different animal models of acute pancreatitis from the past to present and discuss their main characteristics and applications. It identifies key studies that have enhanced our current understanding of the pathogenesis of acute pancreatitis and highlights the instrumental role of animal models in translational research for developing novel therapies.
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Affiliation(s)
- Xinmin Yang
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Linbo Yao
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xianghui Fu
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Rajarshi Mukherjee
- Liverpool Pancreatitis Research Group, Liverpool University Hospitals National Health Service Foundation Trust and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Qing Xia
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | | | - Pawel E. Ferdek
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Wei Huang
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
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HOMA-estimated insulin resistance as an independent prognostic factor in patients with acute pancreatitis. Sci Rep 2019; 9:14894. [PMID: 31624312 PMCID: PMC6797758 DOI: 10.1038/s41598-019-51466-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 10/01/2019] [Indexed: 12/17/2022] Open
Abstract
This prospective study investigated the relationship between insulin resistance assessed using the homeostatic model assessment of insulin resistance (HOMA-IR) and the prognosis of acute pancreatitis (AP). A total of 269 patients with AP were recruited in this study. HOMA-IR scores were calculated using fasting insulin and plasma glucose levels. Patients were then categorized into the non-insulin-resistant group (HOMA-IR <2.5) and the insulin-resistant group (HOMA-IR ≥2.5). We performed multivariable logistic regression analysis to investigate the independent association between IR assessed using HOMA-IR and the severity of AP. We also conducted receiver operating characteristic analysis to investigate the predictive ability of HOMA-IR for severe AP. The proportion of patients with severe AP (according to the Atlanta classification) and the percentage of ICU admissions and mortality were higher in patients with insulin resistance than in those without insulin resistance. The area under the curve (AUC) of HOMA-IR for predicting severe AP was 0.719 (95% CI 0.59–0.85, P = 0.003). This value was not significantly different from the AUCs of other AP scoring systems such as CTSI, Ranson, and BISAP. Insulin resistance was the only independent factor for either ICU admission (OR 5.95, 95% CI 1.95–18.15, P = 0.002) or severe AP (OR 6.72, 95% CI 1.34–33.62, P = 0.020). Our findings suggest that the HOMA-IR score is an independent prognostic factor in patients with acute pancreatitis. This finding indicates that insulin resistance is potentially involved in the mechanism for severe AP.
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Szentesi A, Párniczky A, Vincze Á, Bajor J, Gódi S, Sarlós P, Gede N, Izbéki F, Halász A, Márta K, Dobszai D, Török I, Farkas H, Papp M, Varga M, Hamvas J, Novák J, Mickevicius A, Maldonado ER, Sallinen V, Illés D, Kui B, Erőss B, Czakó L, Takács T, Hegyi P. Multiple Hits in Acute Pancreatitis: Components of Metabolic Syndrome Synergize Each Other's Deteriorating Effects. Front Physiol 2019; 10:1202. [PMID: 31620021 PMCID: PMC6763590 DOI: 10.3389/fphys.2019.01202] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 09/03/2019] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION The incidence of acute pancreatitis (AP) and the prevalence of metabolic syndrome (MetS) are growing worldwide. Several studies have confirmed that obesity (OB), hyperlipidemia (HL), or diabetes mellitus (DM) can increase severity, mortality, and complications in AP. However, there is no comprehensive information on the independent or joint effect of MetS components on the outcome of AP. Our aims were (1) to understand whether the components of MetS have an independent effect on the outcome of AP and (2) to examine the joint effect of their combinations. METHODS From 2012 to 2017, 1435 AP cases from 28 centers were included in the prospective AP Registry. Patient groups were formed retrospectively based on the presence of OB, HL, DM, and hypertension (HT). The primary endpoints were mortality, severity, complications of AP, and length of hospital stay. Odds ratio (OR) with 95% confidence intervals (CIs) were calculated. RESULTS 1257 patients (55.7 ± 17.0 years) were included in the analysis. The presence of OB was an independent predictive factor for renal failure [OR: 2.98 (CI: 1.33-6.66)] and obese patients spent a longer time in hospital compared to non-obese patients (12.1 vs. 10.4 days, p = 0.008). HT increased the risk of severe AP [OR: 3.41 (CI: 1.39-8.37)], renal failure [OR: 7.46 (CI: 1.61-34.49)], and the length of hospitalization (11.8 vs. 10.5 days, p = 0.020). HL increased the risk of local complications [OR: 1.51 (CI: 1.10-2.07)], renal failure [OR: 6.4 (CI: 1.93-21.17)], and the incidence of newly diagnosed DM [OR: 2.55 (CI: 1.26-5.19)]. No relation was found between the presence of DM and the outcome of AP. 906 cases (mean age ± SD: 56.9 ± 16.7 years) had data on all four components of MetS available. The presence of two, three, or four MetS factors increased the incidence of an unfavorable outcome compared to patients with no MetS factors. CONCLUSION OB, HT, and HL are independent risk factors for a number of complications. HT is an independent risk factor for severity as well. Components of MetS strongly synergize each other's detrimental effect. It is important to search for and follow up on the components of MetS in AP.
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Affiliation(s)
- Andrea Szentesi
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
- First Department of Medicine, University of Szeged, Szeged, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
| | - Andrea Párniczky
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
- Heim Pál National Institute of Pediatrics, Budapest, Hungary
| | - Áron Vincze
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Judit Bajor
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Szilárd Gódi
- Division of Translational Medicine, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Patricia Sarlós
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Noémi Gede
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Ferenc Izbéki
- Szent György Teaching Hospital of Fejér County, Székesfehérvár, Hungary
| | - Adrienn Halász
- Szent György Teaching Hospital of Fejér County, Székesfehérvár, Hungary
| | - Katalin Márta
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Dalma Dobszai
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
| | - Imola Török
- County Emergency Clinical Hospital – Gastroenterology and University of Medicine, Pharmacy, Sciences and Technology, Târgu Mureş, Romania
| | - Hunor Farkas
- County Emergency Clinical Hospital – Gastroenterology and University of Medicine, Pharmacy, Sciences and Technology, Târgu Mureş, Romania
| | - Mária Papp
- Division of Gastroenterology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary
| | - Márta Varga
- Dr. Réthy Pál Hospital of Békés County, Békéscsaba, Hungary
| | | | - János Novák
- Department of Gastroenterology, Pándy Kálmán Hospital of Békés County, Gyula, Hungary
| | - Artautas Mickevicius
- Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania
- Clinics of Abdominal Surgery, Nephrourology and Gastroenterology, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | | | - Ville Sallinen
- Department of Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Dóra Illés
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Balázs Kui
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Bálint Erőss
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
| | - László Czakó
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Tamás Takács
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
- First Department of Medicine, University of Szeged, Szeged, Hungary
- Division of Translational Medicine, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
- Hungarian Academy of Sciences – University of Szeged, Momentum Gastroenterology Multidisciplinary Research Group, Szeged, Hungary
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Alexandre-Heymann L, Mallone R, Boitard C, Scharfmann R, Larger E. Structure and function of the exocrine pancreas in patients with type 1 diabetes. Rev Endocr Metab Disord 2019; 20:129-149. [PMID: 31077020 DOI: 10.1007/s11154-019-09501-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In the last 10 years, several studies have shown that the pancreas of patients with type 1 diabetes (T1D), and even of subjects at risk for T1D, was smaller than the pancreas from healthy subjects. This arose the question of the relationships between the endocrine and exocrine parts of the pancreas in T1D pathogenesis. Our review underlines that histological anomalies of the exocrine pancreas are common in patients with T1D: intralobular and interacinar fibrosis, acinar atrophy, fatty infiltration, leucocytic infiltration, and pancreatic arteriosclerosis are all frequent observations. Moreover, 25% to 75% of adult patients with T1D present with pancreatic exocrine dysfunction. Our review summarizes the putative causal factors for these structural and functional anomalies, including: 1/ alterations of insulin, glucagon, somatostatin and pancreatic polypeptide secretion, 2/ global pancreatic inflammation 3/ autoimmunity targeting the exocrine pancreas, 4/ vascular and neural abnormalities, and 5/ the putative involvement of pancreatic stellate cells. These observations have also given rise to new theories on T1D: the primary event of T1D pathogenesis could be non-specific, e.g bacterial or viral or chemical, resulting in global pancreatic inflammation, which in turn could cause beta-cell predominant destruction by the immune system. Finally, this review emphasizes that it is advisable to evaluate pancreatic exocrine function in patients with T1D presenting with gastro-intestinal complaints, as a clinical trial has shown that pancreatic enzymes replacement therapy can reduce the frequency of hypoglycemia and thus might improve quality of life in subjects with T1D and exocrine failure.
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Affiliation(s)
- Laure Alexandre-Heymann
- Service de Diabétologie, Hôpital Cochin, 123 boulevard de Port-Royal, 75014, Paris, France
- Département Hospitalo Universitaire, INSERM U 1016, Université Paris Descartes, Paris, France
| | - Roberto Mallone
- Service de Diabétologie, Hôpital Cochin, 123 boulevard de Port-Royal, 75014, Paris, France
- Département Hospitalo Universitaire, INSERM U 1016, Université Paris Descartes, Paris, France
| | - Christian Boitard
- Service de Diabétologie, Hôpital Cochin, 123 boulevard de Port-Royal, 75014, Paris, France
- Département Hospitalo Universitaire, INSERM U 1016, Université Paris Descartes, Paris, France
| | - Raphaël Scharfmann
- Service de Diabétologie, Hôpital Cochin, 123 boulevard de Port-Royal, 75014, Paris, France
- Département Hospitalo Universitaire, INSERM U 1016, Université Paris Descartes, Paris, France
| | - Etienne Larger
- Service de Diabétologie, Hôpital Cochin, 123 boulevard de Port-Royal, 75014, Paris, France.
- Département Hospitalo Universitaire, INSERM U 1016, Université Paris Descartes, Paris, France.
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Effect of acute pancreatitis on the pharmacokinetics of Chinese herbal micron Liuhe Pill ointment in rats. Chin J Integr Med 2015; 21:922-7. [PMID: 26138330 DOI: 10.1007/s11655-015-2080-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2011] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To explore the effect of acute pancreatitis (AP) on the pharmacokinetics of herbal ointment micron Liuhe Pill, MLHP) components in anesthetized rats. METHODS Rats were randomly divided into a AP model group (n=6) and a normal group as a control (n=6). The rat model of AP was induced by intraperitoneal injection of L-arginine in rats (15 mg/kg, twice, interval 1 h). Chinese herbal ointment MLHP was used externally on the belly after the 2nd injection for 48 h in both groups. Emodin, rhein, aloe emodin, physcion, chrysophanol from MLHP were detected and quantified in rat serum and pancreas (at 48 h) by high performance liquid chromatography-tandem mass spectrometry. RESULTS Among the five components, only emodin, aloe emodin and physcion from MLHP were detected in all rat serum and most of the rats' pancreas. Rhein and chrysophanol were not detected in both serum and pancreas. T1/2α of emodin and physcion in MLHP were obviously shorter in the AP model group than those in the normal group (P<0.05), while there was no difference for T1/2α of aloe emodin. The peak concentration and area under curve of all three components were much higher in the AP group than those in the normal group with MLHP in external application for 48 h (P<0.05). Furthermore, the mean residence time (MRT) and maximum plasma concentration (Tmax) of emodin and aloe emodin were obviously longer in the AP model group than those in the normal control group (P<0.05). There was no significant difference for Ka of all components between the two groups. Emodin could be detected in all rats' pancreas at 48 h in both groups, while its mean pancreatic concentration was higher in the AP model group than in the normal group (0.61±0.54 ng/mL, 0.42±0.37 ng/mL, respectively,P<0.05). Aloe emodin could be detected in all rats' pancreas at 48 h in both groups and their mean pancreatic concentration were similar (0.31±0.24 ng/mL, 0.33±0.17 ng/mL, respectively,P>0.05). Physcion could be detected in pancreas of most rats in the AP model while only two rats in the normal group. CONCLUSION AP could significantly affect the pharmacokinetics of absorbed components of Chinese herbal MLHP ointment in rats.
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Das SLM, Kennedy JIC, Murphy R, Phillips ARJ, Windsor JA, Petrov MS. Relationship between the exocrine and endocrine pancreas after acute pancreatitis. World J Gastroenterol 2014; 20:17196-17205. [PMID: 25493036 PMCID: PMC4258592 DOI: 10.3748/wjg.v20.i45.17196] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 07/09/2014] [Accepted: 07/30/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the prevalence and time course of pancreatic exocrine insufficiency in individuals with newly diagnosed prediabetes or diabetes mellitus after acute pancreatitis.
METHODS: Relevant literature cited in three major biomedical journal databases (EMBASE, MEDLINE, and Scopus) was reviewed independently by two authors. There were no language constraints but the search was limited to human studies. Studies included were cohort studies of adult patients who were discharged after an attack of acute pancreatitis. Patients were excluded if they were under 18 years of age or had a previous diagnosis of prediabetes or diabetes mellitus, pancreatic exocrine insufficiency, or chronic pancreatitis. The main outcome measure was the prevalence of concomitant pancreatic exocrine insufficiency in patients who were diagnosed with prediabetes and diabetes mellitus after an attack of acute pancreatitis. Subgroup analysis was conducted for patients who were diagnosed with prediabetes only and those who were diagnosed with diabetes mellitus only. Subgroup analysis looking at the time course of concomitant pancreatic exocrine and endocrine insufficiency was also conducted. Pooled prevalence and corresponding 95% confidence intervals were calculated for all outcome measures and P-values < 0.05 were deemed statistically significant.
RESULTS: Eight clinical studies comprising of 234 patients met all eligibility criteria. The pooled prevalence of newly diagnosed prediabetes or diabetes in individuals after acute pancreatitis was 43% (95%CI: 30%-56%). The pooled prevalence of pancreatic exocrine insufficiency in individuals after acute pancreatitis was 29% (95%CI: 19%-39%). The prevalence of concomitant pancreatic exocrine insufficiency in individuals with newly diagnosed prediabetes or diabetes was 40% (95%CI: 25%-55%). The prevalence of concomitant pancreatic exocrine insufficiency among individuals with prediabetes alone and diabetes mellitus alone was 41% (95%CI: 12%-75%) and 39% (95%CI: 28%-51%), respectively. Further analysis showed that the prevalence of concomitant pancreatic exocrine insufficiency in individuals with prediabetes or diabetes decreases over time after an attack of acute pancreatitis.
CONCLUSION: Pancreatic exocrine insufficiency occurs in 40% of individuals with newly diagnosed prediabetes or diabetes mellitus after acute pancreatitis. Further studies are needed to investigate the pathogenesis of diabetes in this setting.
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Bachmann K, Freitag M, Lohalm H, Tomkötter L, Dupree A, Koops S, Strate T, Izbicki JR, Mann O. Effects of hydroxyethyl starch and cell-free hemoglobin on microcirculation, tissue oxygenation, and survival in severe acute porcine pancreatitis: results of a randomized experimental trial. Pancreas 2014; 43:855-62. [PMID: 24809409 DOI: 10.1097/mpa.0000000000000146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Severe acute pancreatitis is a life-threatening disease with a high mortality; so far, no causal treatment is known. The aim of this study was to evaluate the therapeutic potential of hydroxyethyl starch (HES) and cell-free hemoglobin in an experimental model. METHODS Thirty-nine pigs were randomly assigned into 3 groups. Severe acute pancreatitis was induced by intraductal injection of glycodeoxycholic acid in combination with intravenous administration of cerulein. All animals were kept in isovolemic conditions by application of Ringer solution, 10% HES, or cell-free hemoglobin. The pancreatic microcirculation was evaluated over 8 hours. Thereafter, the animals were observed for 6 days followed by killing of the animals and histopathologic examination. RESULTS The administration of HES and cell-free hemoglobin led to improved microcirculation and tissue oxygenation compared with the Ringer's group. Consequently, the histopathologic damage was reduced (5.5 [3-8.5] vs 9.5 [7.5-11]; P < 0.001). In addition, the mean survival was significantly longer at 121 hours (95% confidence interval, 102-139) versus the Ringer group's 57 hours (95% confidence interval, 32-82; P < 0.001). CONCLUSIONS The administration of HES and cell-free hemoglobin can improve microcirculation in severe acute porcine pancreatitis, with consequent reduction in histopathologic damage and mortality. Therefore, this might represent an interesting therapeutic option in the treatment of severe acute pancreatitis.
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Affiliation(s)
- Kai Bachmann
- From the *Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf; †Department of Anesthesiology and Intensive Care Medicine, Israelitic Hospital; and ‡Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Pharmacokinetic and pharmacodynamic comparison of chinese herbal ointment liu-he-dan and micron liu-he-dan ointment in rats with acute pancreatitis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:389576. [PMID: 24693322 PMCID: PMC3947679 DOI: 10.1155/2014/389576] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 12/05/2013] [Accepted: 12/26/2013] [Indexed: 02/05/2023]
Abstract
Aim. To compare the pharmacokinetics and pharmacodynamics of herbal ointment Liu-He-Dan (LHD) and micron LHD (MLHD) in rats with acute pancreatitis (AP). Methods. Twenty rats were allocated into normal, AP, LHD, and MLHD groups. LHD or MLHD was applied on rats' abdomens. Plasma levels of emodin, rhein, aloe emodin, physcion, and chrysophanol were determined by high performance liquid chromatography-mass spectrometry-mass spectrometry (HPLC-MS-MS) at different time points, and the pharmacokinetic parameters were calculated. Serum amylase, TNF- α , IL-6, and IL-10 levels, and the pancreatic pathological scores were determined at 48 h after LHD or MLHD treatment. Results. T 1/2 α and area under the curve (AUC) of emodin in the MLHD group were lower than those in the LHD group, while T 1/2 α and AUC of aloe emodin in the MLHD group were higher than those in the LHD group (P < 0.05). T 1/2 α and T max of physcion in the MLHD group were significantly shorter than those in the LHD group (P < 0.05). Compared with the AP group, the amylase, malondialdehyde (MDA), TNF- α , and IL-6 levels decreased significantly after three days of treatment in LHD and MLHD groups, while the levels of superoxide dismutase (SOD), TNF- α , and the pancreatic pathological score, were similar. The pharmacodynamic parameters between the LHD and MLHD groups were similar. Conclusion. MLHD had better pharmacokinetics than, and similar pharmacodynamics to, LHD in the management of rats with AP, which indicated that MLHD might be substituted for LHD in the treatment of AP and thus reduce the amount of medicinal herbs used.
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Kui B, Balla Z, Végh ET, Pallagi P, Venglovecz V, Iványi B, Takács T, Hegyi P, Rakonczay Z. Recent advances in the investigation of pancreatic inflammation induced by large doses of basic amino acids in rodents. J Transl Med 2014; 94:138-149. [PMID: 24365745 DOI: 10.1038/labinvest.2013.143] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 11/13/2013] [Accepted: 11/19/2013] [Indexed: 12/16/2022] Open
Abstract
It has been known for approximately 30 years that large doses of the semi-essential basic amino acid L-arginine induce severe pancreatic inflammation in rats. Recently, it has been demonstrated that L-arginine can also induce pancreatitis in mice. Moreover, other basic amino acids like L-ornithine and L-lysine can cause exocrine pancreatic damage without affecting the endocrine parenchyma and the ducts in rats. The utilization of these noninvasive severe basic amino acid-induced pancreatitis models is becoming increasingly popular and appreciated as these models nicely reproduce most laboratory and morphological features of human pancreatitis. Consequently, the investigation of basic amino acid-induced pancreatitis may offer us a better understanding of the pathogenesis and possible treatment options of the human disease.
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Affiliation(s)
- Balázs Kui
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Zsolt Balla
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Eszter T Végh
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Petra Pallagi
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Viktória Venglovecz
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| | - Béla Iványi
- Department of Pathology, University of Szeged, Szeged, Hungary
| | - Tamás Takács
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Péter Hegyi
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Zoltán Rakonczay
- First Department of Medicine, University of Szeged, Szeged, Hungary
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Guo L, Sans MD, Hou Y, Ernst SA, Williams JA. c-Jun/AP-1 is required for CCK-induced pancreatic acinar cell dedifferentiation and DNA synthesis in vitro. Am J Physiol Gastrointest Liver Physiol 2012; 302:G1381-96. [PMID: 22461029 PMCID: PMC3378092 DOI: 10.1152/ajpgi.00129.2010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Endogenous CCK plays an important role in pancreatic regeneration after pancreatitis. We used primary culture of mouse pancreatic acinar cells to evaluate the effect of CCK on acinar cell morphology and gene expression and to determine signaling pathways required for proliferation of acinar cells in vitro. Over 4 days in culture, cells grew out from acini and formed patches of monolayer, which displayed a reduced expression of acinar cell markers including digestive enzymes and Mist1 and an increased expression of ductal and embryonic markers, including cytokeratin 7, β-catenin, E-cadherin, pdx-1, and nestin. There was no appearance of stellate cell markers. CCK enhanced cellular spreading, DNA synthesis, and cyclin D1 expression. When signaling pathways were evaluated, CCK stimulation increased c-Jun expression, JNK and ERK activity, and AP-1 activation. Chemical inhibitors of JNK and ERK pathways, dominant-negative JNK and c-Jun, and c-Jun shRNA significantly inhibited CCK-induced DNA synthesis, CCK-induced AP-1 activation, and cyclin D1 expression. Furthermore, dominant-negative c-Jun reduced the increased expression of β-catenin and the decreased expression of amylase during culture. These results show that MAPK/c-Jun/AP-1 pathway plays an important role in pancreatic acinar cell dedifferentiation and proliferation in culture. Monolayer culture can serve as a model to study acinar cell proliferation similar to regeneration after pancreatitis in vivo.
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Affiliation(s)
- Lili Guo
- 1Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, Michigan,
| | - Maria Dolors Sans
- 1Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, Michigan,
| | - Yanan Hou
- 1Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, Michigan,
| | - Stephen A. Ernst
- 2Department of Cellular and Developmental Biology, The University of Michigan Medical School, Ann Arbor, Michigan, and
| | - John A. Williams
- 1Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, Michigan, ,3Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, Michigan
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Khan MW, Priyamvada S, Khan SA, Khan S, Naqshbandi A, Yusufi ANK. Protective effect of ω-3 polyunsaturated fatty acids onL-arginine-induced nephrotoxicity and oxidative damage in rat kidney. Hum Exp Toxicol 2012; 31:1022-34. [DOI: 10.1177/0960327112440110] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- MW Khan
- Department of Biochemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - S Priyamvada
- Department of Biochemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - SA Khan
- Department of Biochemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - S Khan
- Department of Biochemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - A Naqshbandi
- Department of Biochemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - ANK Yusufi
- Department of Biochemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
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González AM, Garcia T, Samper E, Rickmann M, Vaquero EC, Molero X. Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis. Am J Physiol Gastrointest Liver Physiol 2011; 301:G846-55. [PMID: 21852363 DOI: 10.1152/ajpgi.00485.2010] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tocotrienols exhibit anti-inflammatory properties over macrophages and promote cytotoxicity in activated pancreatic stellate cells, suggesting that they may limit chronic pancreatitis progression. We aimed to quantitate the effect of oral tocotrienols on a rat model of chronic pancreatic injury. Chronic-like pancreatitis was induced by repeated arginine pancreatitis. Palm oil tocotrienol-rich fraction (TRF) was given by gavage before and after pancreatitis inductions. Amylase and hydroxyproline were determined in pancreatic homogenates; collagen, fibronectin, α-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and phosphorylated Smad3 were assessed by Western blotting. Transforming growth factor (TGF)-β1 was measured in plasma. Morphological assessment included light microscopy, fibrosis area fraction, and collagen network fractal analysis. Arginine pancreatitis induced pancreatic atrophy and increased hydroxyproline that ameliorated after TRF. Arginine increased TGF-β1 (185 ± 40 vs. 15 ± 2 ng/ml; P <0.01) that was blunted by TRF (53 ± 19; P < 0.01). TRF reduced protease and Smad3 activation, collagen, and fibronectin. α-SMA increased and GFAP diminished in arginine pancreatitis, consistent with long-term stellate cell activation, and TRF reverted these changes to basal. Arginine pancreatitis increased fibrosis area fraction (4.5 ± 0.3% vs. 0.2 ± 0.2%), collagen network complexity (fractal dimension 1.52 ± 0.03 vs. 1.42 ± 0.01; P < 0.001), and inhomogeneity (lacunarity 0.63 ± 0.03 vs. 0.40 ± 0.02; P < 0.001), which were all reduced by TRF (1.3 ± 0.4%, 1.43 ± 0.02%, and 0.51 ± 0.03%, respectively; P < 0.01). Best correlation coefficients were obtained when comparing fibrosis area fraction with lacunarity (r = 0.88) and both parameters with pancreatic weight (r = -0.91 and -0.79, respectively). TRF administered only before pancreatitis best, but not fully, recapitulated the beneficial effects of TRF. Tocotrienols improve quantitative measures of chronic pancreatic damage. They may be of benefit in human chronic pancreatitis.
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Affiliation(s)
- Ana María González
- Grup de Recerca en Patologia Pancreàtica Exocrina, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, CIBER-EHD, Barcelona, Spain
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Sidhu S, Pandhi P, Malhotra S, Vaiphei K, Khanduja KL. Rosiglitazone promotes pancreatic regeneration in experimental model of acute pancreatitis. Fundam Clin Pharmacol 2011; 25:237-47. [PMID: 20408879 DOI: 10.1111/j.1472-8206.2010.00827.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Acute pancreatitis is an inflammatory disease of the pancreas caused by release of activated digestive enzymes in the pancreas. A number of therapeutic options have been explored for acute pancreatitis, but none has been unambiguously proven to be effective. Rosiglitazone has been shown to be efficacious in acute pancreatitis; thus, the present study was planned to evaluate the effect of rosiglitazone on pancreatic regeneration. Pancreatitis was induced by l-arginine in rats which were divided into three groups: cholecystokinin (CCK-8), rosiglitazone and vehicle. Rats were sacrificed at four time points after induction of pancreatitis i.e. 24h, day 3, day 14 and day 28 for determination of biochemical parameters and histological examination. Rate of DNA synthesis, immunohistochemistry and RT-PCR were performed at day 3 and day 7. Drug administration was started 2h after last L-arginine injection and continued till the day of sacrifice. The lower levels of enzyme in rosiglitazone-treated group compared to vehicle group proved the efficacy of rosiglitazone treatment in reducing severity of acute pancreatitis. The nucleic acid content and rate of DNA synthesis were significantly higher in rosiglitazone group indicating promotion of pancreatic regeneration. The histopathological score were lower in rosiglitazone group. Rosiglitazone treatment promoted pancreatic regeneration after acute injury. Currently, only symptomatic treatment is available, regeneration of pancreatic tissue can be a future strategy in the management of acute pancreatitis. Further studies are required to support the findings of the present study.
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Affiliation(s)
- Shabir Sidhu
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
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Abstract
OBJECTIVES There have been few epidemiological studies on pancreatic diabetes. In this study, we determined the incidence and pathology of pancreatic diabetes in Japan. METHODS We examined the epidemiology of pancreatic diabetes in Japan in 2005 by using a nationwide stratified random-sampling method. Especially, we focused on newly developed diabetes in association with the occurrence of pancreatic disease (true pancreatic diabetes). RESULTS A total of 19,500 individuals received treatment for true pancreatic diabetes, accounting for 0.8% of patients with diabetes. Prevalence was estimated to be 15.2 per 100,000 with an annual onset incidence of 1.1 per 100,000. With regard to the complications in true pancreatic diabetes, the incidence of retinopathy was lower than that in types 1 and 2 diabetes. Among true pancreatic diabetes with chronic pancreatitis, alcoholic pancreatitis was found in the largest sector. Furthermore, as many as 53.7% were continuous drinkers, and 66.7% received insulin therapy. The frequency of hypoglycemia was high in regular drinkers treated with insulin. Hypoglycemia was a major cause of death in patients who were on insulin and continuous drinkers. CONCLUSION We clarified the epidemiology of pancreatic diabetes in Japan. Patients with chronic pancreatitis-associated pancreatic diabetes should receive lifestyle guidance focused on drinking cessation.
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Sidhu S, Pandhi P, Malhotra S, Vaiphei K, Khanduja KL. Melatonin treatment is beneficial in pancreatic repair process after experimental acute pancreatitis. Eur J Pharmacol 2009; 628:282-9. [PMID: 19958759 DOI: 10.1016/j.ejphar.2009.11.058] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2009] [Revised: 11/14/2009] [Accepted: 11/24/2009] [Indexed: 02/07/2023]
Abstract
Current treatment options for acute pancreatitis are supportive and symptomatic. Due to lack of agents targeting the underlying pathophysiology a large amount of experimental work is going on to identify novel therapeutic agents. The present study was carried out to explore if melatonin can modulate the spontaneous regeneration process of the pancreas after experimentally induced acute pancreatitis. Rats were given two i.p. injections of l-arginine in a dose of 200mg/100g at an interval of 1h for induction of pancreatitis. After this rats were randomly divided into three groups i.e. saline, CCK-8 and melatonin. Drug treatment was started 2h after the last l-arginine injection and continued till the day of sacrifice. An additional only saline treated control group was included for comparison. Animals in each group were sacrificed at 24h, days 3, 14 and 28 after pancreatitis induction for determination of biochemical parameters (serum amylase, lipase and IL-10 and pancreatic amylase, total proteins and nucleic acid content) and histological examination. For rate of DNA synthesis and immunohistochemical studies animals were sacrificed at day 3 and day 7. Melatonin treatment was found to be beneficial in acute pancreatitis. Severity of acute pancreatitis was significantly reduced in melatonin group. Nucleic acid content, rate of DNA synthesis, pancreatic proteins and pancreatic amylase content were significantly improved. Histopathological examination showed significantly lower total scores in melatonin group. Results of melatonin group were comparable to that of positive control, CCK-8 group. Thus melatonin treatment was found to promote the spontaneous regeneration process of pancreatic tissue.
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Affiliation(s)
- Shabir Sidhu
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
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Czakó L, Hegyi P, Rakonczay Z, Wittmann T, Otsuki M. Interactions between the endocrine and exocrine pancreas and their clinical relevance. Pancreatology 2009; 9:351-359. [PMID: 19454837 DOI: 10.1159/000181169] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In consequence of the close anatomical and functional links between the exocrine and endocrine pancreas, any disease affecting one of these parts will inevitably affect the other. Pancreatic conditions which might cause diabetes mellitus include acute and chronic pancreatitis, pancreatic surgery, cystic fibrosis and pancreatic cancer. The development of diabetes greatly influences the prognosis and quality of life of patients with exocrine pancreatic diseases. It may cause life-threatening complications, such as hypoglycemia, due to the lack of glucagon and the impaired absorption of nutrients, or the micro- and macrovascular complications may impair the organ functions. Diabetes mellitus is an independent risk factor of mortality in those with exocrine pancreatic diseases. The treatment of pancreatic diabetes, a distinct metabolic and clinical form of diabetes, requires special knowledge. Diet and pancreatic enzyme replacement therapy may be sufficient in the early stages. Oral antidiabetic drugs are not recommended. If the diet proves inadequate to reach the glycemic goals, insulin treatment with multiple injections is required. Impairments of the exocrine pancreatic function and morphology in diabetic patients are frequent and well known. Atrophy of the exocrine tissue may be caused by the lack of trophic insulin, whereas pancreatic fibrosis can result from activation of stellate cells by hyperglycemia, or from microangiopathy and neuropathy. The regulation of the exocrine pancreatic function is also damaged because of the impaired effect of islet hormones. In the event of a proven impairment of the pancreatic exocrine function in diabetes mellitus, pancreatic enzyme replacement therapy is indicated. This may improve the nutritional condition of the patient and decrease the metabolic instability.
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Affiliation(s)
- László Czakó
- First Department of Medicine, University of Szeged, Szeged, Hungary.
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