Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis

Singh, Vijay; Saluja, Ashok K.; Bhagat, Lakshmi; Acker, Gijs J.D. van; Song, Albert M.; Soltoff, Stephen P.; Cantley, Lewis C.; Steer, Michael L.

doi:10.1172/jci12874

Cited by 106 publications

(57 citation statements)

References 33 publications

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“…Blocking the PI3K/Akt signal transduction pathway may therefore inhibit the activation of NF-jB, reduce the release of cytokines, alleviate the inflammatory response and achieve a therapeutic outcome for patients with UC. In fact, this hypothesis has been demonstrated in many previous studies [24][25][26][27]. All these studies further demonstrate that the PI3K/Akt signaling pathway plays an important role in inflammation.…”

Section: Discussionsupporting

confidence: 73%

PI3K/Akt signaling pathway is involved in the pathogenesis of ulcerative colitis

et al. 2011

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Section: Discussionsupporting

confidence: 73%

PI3K/Akt signaling pathway is involved in the pathogenesis of ulcerative colitis

et al. 2011

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“…Intrapancreatic activation of trypsinogen and other digestive zymogens is a critical event in the evolution of secretagogue-induced and other models of pancreatitis, and in previous studies, we have found that interventions that prevent trypsinogen activation lead to a reduction in pancreatitis severity (20). However, as shown in Fig.…”

Section: Discussionmentioning

confidence: 70%

Protection against acute pancreatitis by activation of protease-activated receptor-2

Sharma¹,

Tao²,

Gopal³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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Protease-activated receptor-2 (PAR-2) is a widely expressed tethered ligand receptor that can be activated by trypsin and other trypsin-like serine proteases. In the exocrine pancreas, PAR-2 activation modulates acinar cell secretion of digestive enzymes and duct cell ion channel function. During acute pancreatitis, digestive enzyme zymogens, including trypsinogen, are activated within the pancreas. We hypothesized that trypsin, acting via PAR-2, might regulate the severity of that disease, and to test this hypothesis, we examined the effect of either genetically deleting or pharmacologically activating PAR-2 on the severity of secretagogue-induced experimental pancreatitis. We found that experimental acute pancreatitis is more severe in PAR-2(-/-) than in wild-type mice and that in vivo activation of PAR-2, achieved by parenteral administration of the PAR-2-activating peptide SLIGRL-NH2, reduces the severity of pancreatitis. In the pancreas during the early stages of pancreatitis, the MAPK ERK1/2 is activated and translocated to the nucleus, but nuclear translocation is reduced by activation of PAR-2. Our findings indicate that PAR-2 exerts a protective effect on pancreatitis and that activation of PAR-2 ameliorates pancreatitis, possibly by inhibiting ERK1/2 translocation to the nucleus. Our observations suggest that PAR-2 activation may be of therapeutic value in the treatment and/or prevention of severe clinical pancreatitis, and they lead us to speculate that, from a teleological standpoint, PAR-2 may have evolved in the pancreas as a protective mechanism designed to dampen the injurious effects of intrapancreatic trypsinogen activation.

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“…Phosphatidylinositol 3-kinase (PI3K) is the best recognized upstream activator of Akt in mammalian cells. 4,32 Following stimulation of G protein-coupled receptors by agonists such as cytokines (TNF-a, interleukin-1b) and chemokines (interleukin 8, MCP-1, RANTES), activation of the PI3K/Akt axis modulates neutrophil activation, chemotaxis, and apoptosis. 5 However, others have shown that PI3K inhibitors such as wortmannin or LY294002 do not attenuate Akt activation after hyperstimlation with CCK-A receptor analog caerulein and suggest that PI3K-mediated production of inflammatory mediators does not involve Akt in the caerulein model.…”

Section: Discussionmentioning

confidence: 99%

“…5 However, others have shown that PI3K inhibitors such as wortmannin or LY294002 do not attenuate Akt activation after hyperstimlation with CCK-A receptor analog caerulein and suggest that PI3K-mediated production of inflammatory mediators does not involve Akt in the caerulein model. 32 On the other hand, upstream activators of Akt other than PI3K have recently been demonstrated, which include cAMP and b-adrenergic stimulation, and Akt activation by cAMP and b-adrenergic agonists was found to be PI3K independent (insensitive to PI3K inhibitor wortmannin). 28,33 Our current findings that bile-pancreatic juice replacement attenuates increased Akt/NF-kB pathway activation and chemokine production in the pancreas after duct ligation indicates that activation of this proinflammatory pathway is probably a response to acinar hyperstimulation, providing new insights into the mechanism of activation of proinflammatory pathways in this experimental model.…”

Section: Discussionmentioning

confidence: 99%

Bile-Pancreatic Juice Exclusion Promotes Akt/NF-κB Activation and Chemokine Production in Ligation-Induced Acute Pancreatitis

Samuel

Yorek

Zaheer

et al. 2006

Journal of Gastrointestinal Surgery

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Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis

Cited by 106 publications

References 33 publications

PI3K/Akt signaling pathway is involved in the pathogenesis of ulcerative colitis

PI3K/Akt signaling pathway is involved in the pathogenesis of ulcerative colitis

Protection against acute pancreatitis by activation of protease-activated receptor-2

Bile-Pancreatic Juice Exclusion Promotes Akt/NF-κB Activation and Chemokine Production in Ligation-Induced Acute Pancreatitis

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