Necroptosis Is an Important Severity Determinant and Potential Therapeutic Target in Experimental Severe Pancreatitis

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• 作者：Johanna M. Louhimo¹ ; Michael L. Steer² ; George Perides² ; ^{peridesgeorge@gmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Acute Pancreatitis ; Biliary Pancreatitis ; Necroptosis ; Apoptosis ; Pancreatic Cell Death
• 刊名：CMGH Cellular and Molecular Gastroenterology and Hepatology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：2
• 期：4
• 页码：519-535
• 全文大小：3571 K

文摘

Severe acute pancreatitis is characterized by acinar cell death and inflammation. Necroptosis is an aggressive and proinflammatory mode of cell death that can be prevented by necrostatin-1 administration or receptor-interacting protein kinase (RIP3) deletion.

Methods

Mouse pancreatic acinar cells were incubated with supramaximally stimulating concentrations of caerulein or submicellar concentrations of taurolithocholic acid-3-sulfate (TLCS), and necroptosis was inhibited by either addition of necrostatin or by RIP3 deletion. Cell death was quantitated using either lactate dehydrogenase leakage from acini or propidium iodide staining of nuclei. Necrosome formation was tracked and quantitated using cell fractionation or immunoprecipitation. Pancreatitis was induced in mice by retrograde intraductal infusion of TLCS or by repetitive supramaximal stimulation with caerulein.

Results

Necroptosis was found to be the most prevalent mode of acinar cell in vitro death and little or no apoptosis was observed. Acinar cell death was associated with necrosome formation and prevented by either necrostatin administration or RIP3 deletion. Both of these interventions reduced the severity of TLCS- or caerulein-induced pancreatitis. Delaying necrostatin administration until after pancreatitis already had been established did not prevent its ability to reduce the severity of TLCS-induced pancreatitis.

Conclusions

Necroptosis is the predominant mode of acinar cell death in severe experimental mouse pancreatitis. The severity of pancreatitis can be reduced by administration of necrostatin, and necrostatin still can reduce the cell injury of pancreatitis even if it is administered after the disease already has been established. Inhibition of necroptosis may be an effective strategy for the treatment of severe clinical pancreatitis.