Protease activation during in vivo pancreatitis is dependent on calcineurin activation

Shah, Akeesha A.; Sarwar, Amna; Orabi, Abrahim I.; Gautam, Samir; Grant, Wayne; Park, Alexander J; Shah, Adnan; Li, Jun; Mistry, Pramod K.; Jain, Dhanpat; Husain, Sohail Z.

doi:10.1152/ajpgi.00181.2009

Cited by 61 publications

(41 citation statements)

References 56 publications

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“…6D), the concept is proof of principal that apparently subtle biophysical changes in the Ca 2ϩ signal can translate to biologically important outcomes. Putative targets of acinar cell Ca 2ϩ pathology could include the Ca 2ϩ -activated phosphatase calcineurin, which has recently been shown to mediate protease activation and pancreatitis (17,44) (25,26,29). Our results, demonstrating that RYR inhibition abrogates the acceleration of Ca 2ϩ waves by ethanol, support the latter possibility.…”

Section: Discussionsupporting

confidence: 69%

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: Discussionsupporting

confidence: 69%

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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“…25 Pancreatic enzymes, such as trypsin, elastase and lipase, induce TNF-α secretion in peritoneal macrophages in vitro. 19 In addition, macrophage depletion by injecting liposome-encapsulated dichloromethylenedi-phosphonate in mice demonstrated protection against virus-induced pancreatitis. 26 In this study, to gain deeper insight into the antiinflammatory mechanisms of the G4.5-COOH and G5-OH PAMAM dendrimers in AP mice, macrophage infiltration in the pancreas, inflammatory factor expression in pancreatic tissues and peritoneal macrophages were investigated.…”

Section: ■ Introductionmentioning

confidence: 99%

Protective Effects and Mechanisms of G5 PAMAM Dendrimers against Acute Pancreatitis Induced by Caerulein in Mice

et al. 2014

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In this study, generation 5 (G5) polyamidoamine (PAMAM) dendrimers with two different surface groups, G4.5-COOH and G5-OH, were investigated for their protective effects on pancreas injury in a caerulein-induced acute pancreatitis (AP) mouse model. Both dendrimers significantly decreased pathological changes in the pancreas and reduced the inflammatory infiltration of macrophages in pancreatic tissues. In addition, the expression of pro-inflammatory cytokines was significantly inhibited by the two dendrimers, not only in pancreatic tissues from AP mice but also in vitro in mouse peritoneal macrophages with LPS-induced inflammation. G4.5-COOH, which had better in vivo protective effects for AP than G5-OH, led to a significant reduction in the total number of plasma white blood cells (WBCs) and monocytes in AP mice, and its anti-inflammatory mechanism was related to inhibition of the nuclear translocation of NF-κB in macrophages.

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“…About 10-20 % of AP patients develop severe acute pancreatitis (SAP), which is associated with poor prognosis and mortality rates as high as 15-25 % (Berezina et al 2005). SAP is initiated by the premature activation of digestive enzymes within the pancreatic acinar cells, leading to self-digestion of the pancreatic tissue (Shah et al 2009). During the early phase of SAP, inflammatory responses occur in the ductal cells and lead to systemic inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effect of human clonal bone marrow-derived mesenchymal stem cells in severe acute pancreatitis

Jung

Son

et al. 2014

Arch. Pharm. Res.

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Severe acute pancreatitis (SAP), a common necroinflammatory disease initiated by the premature activation of digestive enzymes within the pancreatic acinar cells, is associated with significant morbidity and mortality. In this study, we investigated whether human bone marrow-derived clonal mesenchymal stem cells (hcMSCs), isolated from human bone marrow aspirate according to our newly established isolation protocol, have potential therapeutic effects in SAP. SAP was induced by three intraperitoneal (i.p.) injections of cerulein (100 μg/kg) and sequential LPS (10 mg/kg) in Sprague-Dawley (SD) rats. hcMSCs (1 × 10(6)/head) were infused on 24 h after LPS injection via the tail vein. The rats were sacrificed 3 days after infusion of hcMSCs. We observed that infused hcMSCs reduced the levels of serum amylase and lipase. Infused hcMSCs ameliorated acinar cell necrosis, pancreatic edema, and inflammatory infiltration. Also, infused hcMSCs decreased the level of malondialdehyde, and increased the levels of glutathione peroxidase and superoxide dismutase. The number of TUNEL positive acinar cells was reduced after hcMSCs infusion. In addition, hcMSCs reduced the expression levels of pro-inflammation mediators and cytokines, and increased the expression of SOX9 in SAP. Taken together, hcMSCs could effectively relieve injury of pancreatitis as a promising therapeutics for SAP.

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Protease activation during in vivo pancreatitis is dependent on calcineurin activation

Cited by 61 publications

References 56 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

Protective Effects and Mechanisms of G5 PAMAM Dendrimers against Acute Pancreatitis Induced by Caerulein in Mice

Therapeutic effect of human clonal bone marrow-derived mesenchymal stem cells in severe acute pancreatitis

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