NFATc3 Regulates Trypsinogen Activation, Neutrophil Recruitment, and Tissue Damage in Acute Pancreatitis in Mice

Awla, Darbaz; Zetterqvist, Anna V.; Abdulla, Aree; Camello-Almaraz, Cristina; Berglund, Lisa M.; Sartipy, Peter; Pozo, Marı́a J.; Camello, Pedro J.; Regnér, Sara; Gomez, Maria F.; Thorlacius, Henrik

doi:10.1053/j.gastro.2012.07.098

Cited by 56 publications

(54 citation statements)

References 47 publications

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“…Awla et al (61) examine late intrapancreatic protease activation, whereas our study examines early intra-acinar protease activation. The two phenomena appear to be independent and mediated by different factors (62)(63)(64).…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

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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Section: Discussionmentioning

confidence: 97%

“…A recent publication by Awla et al (61) has examined the calcineurin target NFAT in pancreatitis. The authors demonstrate using NFAT-luciferase-expressing transgenic mice that acinar cells exhibit calcineurin activation.…”

Section: Discussionmentioning

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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“…NFAT activity is generally considered to control aspects of tissue development during embryogenesis, including vasculogenesis, axonal outgrowth, muscle and bone formation, as well as maturation of the immune system (34)(35)(36)(37)(38). However, a growing body of literature also implicates NFAT signaling in inflammatory processes, such as atherosclerosis (39), autoimmune diseases (40), and acute pancreatitis (24). Here, we show that in vivo administration of the NFAT inhibitor (A-285222) readily blocked sepsis-induced NFAT-dependent tran- scriptional activity not only in the lung but also in the spleen, liver, and aorta, suggesting not only that NFAT is activated in sepsis but also that A-285222 is an effective inhibitor of NFAT.…”

Section: Discussionmentioning

confidence: 99%

“…twice daily for 7 consecutive days and in the morning of operation) and CLP mice pretreated with (iii) vehicle (PBS) or (iv) A-285222. Treatment with A-285222 was well tolerated and performed according to a previously established protocol (24). A-285222 was kindly provided by Abbott Laboratories.…”

Section: Animalsmentioning

confidence: 99%

Nuclear Factor of Activated T Cells Regulates Neutrophil Recruitment, Systemic Inflammation, and T-Cell Dysfunction in Abdominal Sepsis

et al. 2014

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The signaling mechanisms regulating neutrophil recruitment, systemic inflammation, and T-cell dysfunction in polymicrobial sepsis are not clear. This study explored the potential involvement of the calcium/calcineurin-dependent transcription factor, nuclear factor of activated T cells (NFAT), in abdominal sepsis. Cecal ligation and puncture (CLP) triggered NFAT-dependent transcriptional activity in the lung, spleen, liver, and aorta in NFAT-luciferase reporter mice. Treatment with the NFAT inhibitor A-285222 prior to CLP completely prevented sepsis-induced NFAT activation in all these organs. Inhibition of NFAT activity reduced sepsis-induced formation of CXCL1, CXCL2, and CXCL5 chemokines and edema as well as neutrophil infiltration in the lung. Notably, NFAT inhibition efficiently reduced the CLP-evoked increases in HMBG1, interleukin 6 (IL-6), and CXCL5 levels in plasma. Moreover, administration of A-285222 restored sepsis-induced T-cell dysfunction, as evidenced by markedly decreased apoptosis and restored proliferative capacity of CD4 T cells. Along these lines, treatment with A-285222 restored gamma interferon (IFN-␥) and IL-4 levels in the spleen, which were markedly reduced in septic mice. CLP-induced formation of regulatory T cells (CD4 ؉ CD25 ؉ Foxp3 ؉ ) in the spleen was also abolished in A-285222-treated animals. All together, these novel findings suggest that NFAT is a powerful regulator of pathological inflammation and T-cell immune dysfunction in abdominal sepsis. Thus, our data suggest that NFAT signaling might be a useful target to protect against respiratory failure and immunosuppression in patients with sepsis.

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“…Nevertheless, there is little belief that trypsinogen is responsible for all of the systemic complications. In experiments with pancreas-specific inducible trypsino-gen, maximum expression in homozygotes with continuous and rapid induction results in AP, whereas mild and repeated expressions (in heterozygotes) do not induce AP (7).…”

Section: Pathophysiologymentioning

confidence: 98%

Pathophysiology, classification and available guidelines of acute pancreatitis

İnce

Baysal²

2014

Turk J Gastroenterol

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Acute pancreatitis (AP) constitutes the majority of cases requiring hospital admission in gastroenterology. We are yet to know many things about its pathophysiology which is a certain drawback for the progress in its treatment. Prediction of severity is necessary for the plan of the management. The existing scoring systems are yet to be satisfactory. However our progress in the field was significant in the recent decade and a leap forward is expected in this cumbersome-to-manage condition which has many unmet needs. In this review, we are going to summarize the hitherto data in pathogenesis and would weigh the usefulnes and weaknes of each of existing scoring systems in the management of AP. Keywords: Acute pancreatitis, guideline, pathophysiology, scoring systems, classifications, insights Pancreas was first discovered by Herophilus, a Greek anatomist and surgeon, in Chalcedon (now Kadıkoy, Istanbul) in 336 BC. Despite the many years since its discovery, a lot remains unknown about pancreas. The coming decade would, probably, witness several advances in our understanding of pancreas and its diseases.This review aims to describe the hitherto knowledge in pancreas pathophysiology and classification systems of severity scoring. PATHOPHYSIOLOGYThe main reason for the lack of successful treatment in acute pancreatitis (AP) is that many aspects of this condition regarding the pathophysiology are still unknown. AP has a severe course in 20% of the cases and may be associated with high morbidity and mortality in 2-3%. Pancreatic autodigestion (trypsinogen-centered) theory has been in use in the AP pathogenesis for over a hundred year. In this theory, premature activation of pancreatic proenzymes (zymogens) induces autolysis, which triggers inflammatory events followed by continued damage to the pancreas and/or non-pancreatic tissues in some way.Experimental models (1,2) have demonstrated the involvement of trypsin activation in hereditary pancreatitis (3). Along with zymogen activation, natural factor kappa beta (NFkB) activation is also important in the development of AP. Whether both are involved or are independently-acting parallel factors in AP is controversial. It was shown, in vitro, that trypsinogen expression did not activate NFkB (4

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NFATc3 Regulates Trypsinogen Activation, Neutrophil Recruitment, and Tissue Damage in Acute Pancreatitis in Mice

Cited by 56 publications

References 47 publications

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

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

Nuclear Factor of Activated T Cells Regulates Neutrophil Recruitment, Systemic Inflammation, and T-Cell Dysfunction in Abdominal Sepsis

Pathophysiology, classification and available guidelines of acute pancreatitis

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