PANCREAS ALERTS
Gastroenterology 2002; 122:1941-53. (AN 22050394, PMID 12055600)
Transporter-mediated bile acid uptake causes Ca2+-dependent cell death in rat pancreatic acinar cells.
Kim JY, Kim KH, Lee JA, Namkung W, Sun AQ, Ananthanarayanan M, et al.
Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine. Seoul, Korea.
The mechanism by which cholelithiasis increases the risk of acute pancreatitis remains obscure. Because bile acids can enter the pancreas either by luminal diffusion or by interstitial leakage during gallstone impaction and pancreatitis is associated with impaired Ca2+ signaling, the authors examined the effect of bile acids on pancreatic acinar cell signaling and the associated intracellular events.
Rat pancreatic acinar cells were isolated by collagenase digestion and the effects of bile acids on [Ca2+]i signaling, cell survival, inflammatory signals, and the molecular and functional expressions of bile uptake transporters were analyzed.
Bile acids specifically inhibited the sarco/endoplasmic reticulum Ca2+ ATPase pump to chronically deplete part of the Ca2+ stored in the endoplasmic reticulum. This in turn led to the activation of capacitative Ca2+ entry and a chronic [Ca2+]i load.
The Authors concluded that these results suggest that bile acids can be transported into pancreatic acinar cells through specific membrane transporters and induce cell death by impairing cellular Ca2+ signaling.
The increase in [Ca2+]i and Ca2+ load activated the inflammation-associated signals of c-Jun amino-terminal kinases and NF-kappaB and led to cell death, which was inhibited by buffering [Ca2+]i with 1,2-bis(2-aminophenoxy)ethane-N,N,N,N'-tetraacetic acid.
A comprehensive molecular analysis of bile acid transporters revealed that pancreatic acinar cells express the bile uptake transporters Na+-taurocholate co-transporting polypeptide and organic anion transporting polypeptide in the luminal and basolateral membranes, respectively. Bile acid uptake into acinar cells was in part Na+-dependent and in part Na+-independent, suggesting that both transporters contribute to bile acid influx into acinar cells.
Gastroenterology 2002; 122:1898-912. (AN 22050391, PMID 12055597)
Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells.
Wagner M, Weber CK, Bressau F, Greten FR, Stagge V, Ebert M, et al.
Department of Internal Medicine I, University of Ulm. Ulm, Germany.
The epidermal growth factor receptor family and the corresponding ligands are frequently overexpressed in pancreatic cancer. To compare the biological effects of transforming growth factor-alpha and amphiregulin on growth and differentiation of the exocrine pancreas, the authors have generated transgenic mice overexpressing amphiregulin under control of the elastase promoter.
Two independently generated transgenic mouse lines overexpressed 50-, 43-, 28-, 26-, and 16-kilodalton amphiregulin forms in the pancreas.
The authors concluded that these data suggest that amphiregulin induces a mitogenic response selectively in small duct cells through activation of Ras, CDK2, and CDK4, respectively.
Morphologic and immunohistochemical examinations suggested that small intralobular duct and centro-acinar cells proliferated in response to amphiregulin in these mice. Amphiregulin transgenic mice displaied increased Ras, Erk1/2, cyclin D/CDK4, and cyclin E/CDK2 activity and G1/S progression in pancreatic duct cells.
In contrast to transforming growth factor -alpha transgenic mice, amphiregulin neither induced tubular complex formation nor elicited a strong fibrogenic response.
Amphiregulin induced a slight induction of ErbB2 on duct cells, whereas transforming growth factor -alpha resulted in overexpression of the epidermal growth factor receptor in cells within tubular complexes.
Furthermore, amphiregulin and transforming growth factor-alpha displayed different effects on the differentiation of isolated acini in vitro comparable to the situation in vivo.
The closely related epidermal growth factor receptor ligands, amphiregulin and transforming growth factor -alpha, display different biological effects when overexpressed in the exocrine pancreas in vivo.
Arch Surg 2002; 137:730-6. (AN 22045017, PMID 12049546)
Severity scoring for prognostication in patients with severe acute pancreatitis: comparative analysis of the Ranson score and the APACHE III score.
Eachempati SR, Hydo LJ, Barie PS.
Department of Surgery, New York-Presbyterian Hospital. New York, NY (USA).
Despite a lack of validation, the Ranson score is still the most popular method for gauging the severity of pancreatitis. The authors hypothesized that the Ranson score more accurately predicts outcomes in patients with severe acute pancreatitis when compared with APACHE (Acute Physiology and Chronic Health Evaluation) III scores, and the individual components of the Ranson score differ in their capacities to predict outcome in patients with severe acute pancreatitis.
Patients with severe acute pancreatitis admitted to a university hospital surgical intensive care unit were studied prospectively.
The number of positive Ranson variables was significantly higher in non-survivors compared with survivors, as were the APACHE III scores and intensive care unit stays.
The Ranson score remains a valid predictor of outcomes in patients with severe acute pancreatitis and individual Ranson variables determined 48 hours after hospital admission predicted adverse outcomes more accurately than early Ranson variables in patients with severe acute pancreatitis.
Each component and the total Ranson score were recorded. Also recorded were the APACHE II and III scores.
These Ranson variables were compared using univariate analysis of variance for mortality, need for operative debridement and need for an intensive care unit stay for longer than 7 days.
Significant variables were then analyzed by a multivariate analysis of variance to assess independent predictors of mortality, the need for debridement and prolonged length of stay.
Seventy-six patients were studied.
Ranson variables that predicted mortality included values for blood urea nitrogen, calcium, base deficit and fluid sequestration.
Endoscopy 2002; 34:464-8. (AN 22043097, PMID 12048629)
Preoperative laparoscopic examination using surgical manipulation and ultrasonography for pancreatic lesions.
Kwon AH, Inui H, Kamiyama Y.
First Department of Surgery, Kansai Medical University. Osaka, Japan.
Unnecessary laparotomies in patients with advanced pancreatic disease are unlikely to provide any benefits and may compromise both the quality and duration of survival.
The authors determined the contribution of laparoscopy and laparoscopic ultrasound to the diagnosis or staging, or both, of pancreatic lesions.
Fifty-two patients were diagnosed preoperatively with pancreatic cancer. The diagnoses made by laparoscopic ultrasonography were compared with those made prior to the operation. Laparoscopic visualization of the body of the pancreas was obtained via an infragastric approach. For the laparoscopic examination of the head of the pancreas, a retroduodenal approach was used.
In 52 patients with cancer of the pancreatic head and body, unresectable findings were observed in 13 patients. Portal vein displacement without other unresectable findings was evident in six patients using laparoscopic ultrasonography, and was confirmed at exploratory laparotomy in five patients.
The authors concluded that laparoscopic ultrasonography, when combined with laparoscopic manipulations, may overcome many of the limitations of laparoscopy alone in the investigation of pancreatic lesions by providing an accurate diagnosis and assessment of the size and extent of the local dissemination.
The surgical approaches were changed, with seven patients undergoing an open exploration for biliary drainage and the other six patients receiving endoscopic endoprostheses.
In six of the 52 patients, laparoscopic ultrasonography-guided needle biopsies and frozen-section examinations detected four cases of chronic pancreatitis, one malignant lymphoma and one abdominal tuberculosis, which had been diagnosed preoperatively as pancreatic cancers and cysts.
Only one patient undergoing the laparoscopic procedure had acute pancreatitis; this patient was treated conservatively.
Am J Physiol Gastrointest Liver Physiol 2002; 282: G1105-12. (AN 22011585, PMID 12016137)
Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis.
Demols A, Van Laethem JL, Quertinmont E, Degraef C, Delhaye M, Geerts A, Deviere J.
Department of Gastroenterology, Hopital Erasme and Laboratory of Experimental Gastroenterology, Universite Libre de Bruxelles. Brussels, Belgium.
Interleukin-10, a potent anti-inflammatory cytokine, limits the severity of acute pancreatitis and downregulates transforming growth factor-beta release by inflammatory cells on stimulation.
In this study, the authors evaluate the role of endogenous IL-10 in the modulation of the regeneration phase following acute pancreatitis and in the development of pancreatic fibrosis.
Interleukin-10 knockout mice and their C57BL/6 controls were submitted to repeated courses of cerulein-induced acute pancreatitis.
After repeated acute pancreatitis, interleukin-10 knockout mice had more severe histological lesions and fibrosis (intrapancreatic collagen content) than the controls.
The authors concluded that endogenous interleukin-10 controls the regeneration phase and limits the severity of fibrosis and glandular atrophy induced by repeated episodes of acute pancreatitis in mice.
Proinflammatory mediators, reactive oxygen species and transforming growth factor-beta can activate pancreatic stellate cells and their synthesis of collagen I and III.
Transforming growth factor-beta1 release was measured on plasma and its pancreatic expression was assessed by quantitative RT-PCR and immunohistochemistry; intrapancreatic interleukin-10 gene expression was assessed by semiquantitative RT-PCR and intrapancreatic collagen content was assessed by picrosirius staining; activated stellate cells were detected by immunohistochemistry and S phase intrapancreatic cells were marked using tritiated thymidine labeling.
Transforming growth factor-beta1 plasma levels, intrapancreatic transcription and expression by ductal and interstitial cells, as well as the number of activated stellate cells, were significantly higher.
Interleukin-10 knockout mice disclosed significantly fewer acinar cells in the S phase whereas the opposite was observed for pseudotubular cells.