The epidemiology and impact of pancreatic diseases in the United States

Lowenfels, Albert B.; Sullivan, Terri N.; Fiorianti, John; Maisonneuve, Patrick

doi:10.1007/s11894-005-0045-6

Cited by 72 publications

(44 citation statements)

References 42 publications

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“…Pancreatitis is a life-threatening inflammatory disorder of the pancreas that leads to more than 30,000 deaths per year (1). Alcohol-associated pancreatitis accounts for 30% of acute cases and 70 -90% of chronic cases.…”

Section: From the Yale University School Of Medicine New Haven Connmentioning

confidence: 99%

Ethanol Enhances Carbachol-induced Protease Activation and Accelerates Ca2+ Waves in Isolated Rat Pancreatic Acini

Orabi¹,

Shah²,

Muili

et al. 2011

Journal of Biological Chemistry

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Alcohol abuse is a leading cause of pancreatitis, accounting for 30% of acute cases and 70 -90% of chronic cases, yet the mechanisms leading to alcohol-associated pancreatic injury are unclear. An early and critical feature of pancreatitis is the aberrant signaling of Ca 2؉ within the pancreatic acinar cell. An important conductor of this Ca 2؉ is the basolaterally localized, intracellular Ca 2؉ channel ryanodine receptor (RYR). In this study, we examined the effect of ethanol on mediating both pathologic intra-acinar protease activation, a precursor to pancreatitis, as well as RYR Ca 2؉ signals. We hypothesized that ethanol sensitizes the acinar cell to protease activation by modulating RYR Ca 2؉ . Acinar cells were freshly isolated from rat, pretreated with ethanol, and stimulated with the muscarinic agonist carbachol (1 M). Ethanol caused a doubling in the carbachol-induced activation of the proteases trypsin and chymotrypsin (p < 0.02). The RYR inhibitor dantrolene abrogated the enhancement of trypsin and chymotrypsin activity by ethanol (p < 0.005 for both proteases). Further, ethanol accelerated the speed of the apical to basolateral Ca 2؉ wave from 9 to 18 m/s (p < 0.0005; n ‫؍‬ 18 -22 cells/group); an increase in Ca 2؉ wave speed was also observed with a change from physiologic concentrations of carbachol (1 M) to a supraphysiologic concentration (1 mM) that leads to protease activation. Dantrolene abrogated the ethanol-induced acceleration of wave speed (p < 0.05; n ‫؍‬ 10 -16 cells/group). Our results suggest that the enhancement of pathologic protease activation by ethanol is dependent on the RYR and that a novel mechanism for this enhancement may involve RYR-mediated acceleration of Ca 2؉ waves.Pancreatitis is a life-threatening inflammatory disorder of the pancreas that leads to more than 30,000 deaths per year (1). Alcohol-associated pancreatitis accounts for 30% of acute cases and 70 -90% of chronic cases. Further, alcoholic pancreatitis carries the highest mortality rate among all etiologies (2). However, the mechanisms by which ethanol mediates pathology are largely unknown.Alcohol can exert diverse effects on the pancreas. Ethanol exposure has been linked to abnormal blood flow, leading to ischemic changes, and increased sphincter of Oddi dysfunction, resulting in pancreatic duct hypertension (2).In addition, ethanol appears to directly predispose the acinar cell to pathological changes including oxidant stress (3), membrane fragility (4), mitochondrial uncoupling (5, 6), and basolateral exocytosis (7). Several lines of evidence also link ethanol to aberrant Ca 2ϩ 3 signaling (6). High amplitude, aberrant, intracellular Ca 2ϩ waves that propagate from the apical to basolateral region of the acinar cell predispose to early features of pancreatitis, particularly intra-acinar protease activation (8, 9). We know that intracellular Ca 2ϩ release is responsible for the onset of this aberrant Ca 2ϩ signal (10). In addition, we have previously shown that the ryanodine receptor (RYR), 4 a major intracel...

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Section: From the Yale University School Of Medicine New Haven Connmentioning

confidence: 99%

Ethanol Enhances Carbachol-induced Protease Activation and Accelerates Ca2+ Waves in Isolated Rat Pancreatic Acini

Orabi¹,

Shah²,

Muili

et al. 2011

Journal of Biological Chemistry

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“…The most common inciting factor in both children and adults accounting for 30 -50% of cases (2)(3)(4) is the presence of gallstones or sludge within the distal common bile duct (5). A dominant mechanism for this etiology of pancreatitis known as acute biliary pancreatitis is thought to be the reflux of bile into the pancreatic duct (6,7).…”

mentioning

confidence: 99%

“…Most bile acids are conjugated to either taurine or glycine. Administration of submillimolar concentrations of chenodeoxycholic acid (CDC) 3 to the lumen of ex vivo ducts elicits reactive mechanisms within the pancreatic duct cell to stimulate bicarbonate secretion (10,11). However, higher concentrations of CDC induce acinar cell pathology, leading to pancreatitis (12,13).…”

mentioning

confidence: 99%

Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

Muili

Wang

Orabi

et al. 2013

Journal of Biological Chemistry

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“…Pancreatitis affects hundreds of thousands of people in the U.S. annually and is characterized by inappropriate activation of digestion enzymes within the pancreas, leading to inflammation, fibrosis, and, in the chronic form, the eventual destruction of both the exocrine and endocrine pancreas (1,2). Pancreatitis is associated with alcohol abuse, cystic fibrosis, inherited polymorphisms affecting pancreatic enzyme regulation, and, more recently, type 1 and type 2 diabetes (1,3).…”

mentioning

confidence: 99%

Critical Roles for Macrophages in Islet Angiogenesis and Maintenance During Pancreatic Degeneration

et al. 2008

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OBJECTIVE-Chronic pancreatitis, characterized by pancreatic exocrine tissue destruction with initial maintenance of islets, eventually leads to insulin-dependent diabetes in most patients. Mice deficient for the transcription factors E2F1 and E2F2 suffer from a chronic pancreatitis-like syndrome and become diabetic. Surprisingly, onset of diabetes can be prevented through bone marrow transplantation. The goal of the described studies was to determine the hematopoietic cell type responsible for maintaining islets and the associated mechanism of this protection.RESEARCH DESIGN AND METHODS-Mouse models of acute and chronic pancreatitis, together with mice genetically deficient for macrophage production, were used to determine roles for macrophages in islet angiogenesis and maintenance.RESULTS-We demonstrate that macrophages are essential for preventing endocrine cell loss and diabetes. Macrophages expressing matrix metalloproteinase-9 migrate to the deteriorating pancreas. E2f1/E2f2 mutant mice transplanted with wild-type, but not macrophage-deficient colony stimulating factor 1 receptor mutant (Csf1r Ϫ/Ϫ ), bone marrow exhibit increased angiogenesis and proliferation within islets, coinciding with increased islet mass. A similar macrophage dependency for islet and islet vasculature maintenance is observed during caerulein-induced pancreatitis.CONCLUSIONS-These findings demonstrate that macrophages promote islet angiogenesis and protect against islet loss during exocrine degeneration, could explain why most patients with chronic pancreatitis develop diabetes, and suggest an avenue for preventing pancreatitis-associated diabetes.

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The epidemiology and impact of pancreatic diseases in the United States

Cited by 72 publications

References 42 publications

Ethanol Enhances Carbachol-induced Protease Activation and Accelerates Ca2+ Waves in Isolated Rat Pancreatic Acini

Ethanol Enhances Carbachol-induced Protease Activation and Accelerates Ca2+ Waves in Isolated Rat Pancreatic Acini

Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

Critical Roles for Macrophages in Islet Angiogenesis and Maintenance During Pancreatic Degeneration

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