Dataset Information

HIF1-alpha Regulates Acinar Cell Function and Response to Injury in Mouse Pancreas.

ABSTRACT: We investigated whether intrapancreatic coagulation, with deposition of the fibrinogen-? dimer (Fib-?D) and hypoxia, affect the severity of acute pancreatitis (AP) in mice. Pancreata of mice with AP induced by administration of cerulein or by L-arginine, or from patients with pancreatitis, had increased deposition of Fib-?D compared with control pancreata. Heparin administration protected mice from cerulein-induced AP and prevented Fib-?D formation. Cerulein administration resulted in activation and stabilization of hypoxia-inducible factor-1? (HIF1?) in pancreata of oxygen-dependent degradation domain-luciferase HIF1? reporter mice. Cerulein also led to induction of genes regulated by HIF1?, including Vegfa and Ero1a, before evidence of Fib-?D deposition or histologic features of AP. Expression of tissue factor, which is regulated by vascular endothelial growth factor, also increased following cerulein administration. Mice with acinar cell-specific disruption of Hif1a (Hif1aAc-/-) developed spontaneous endoplasmic reticulum stress and less severe AP, but did not accumulate Fib-?D following administration of cerulein. Feeding mice increased pancreatic expression of HIF1?, indicating a physiologic role in the exocrine pancreas. Therefore, HIF1? has bifunctional roles, in exocrine pancreas homeostasis and progression of AP that is promoted by intrapancreatic coagulation.

SUBMITTER: Park MJ

PROVIDER: S-EPMC5927829 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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HIF1-alpha Regulates Acinar Cell Function and Response to Injury in Mouse Pancreas.

Park Min-Jung MJ Iyer Sapna S Xue Xiang X Bragazzi Cunha Juliana J Gu Shufang S Moons David D Pipe Steven W SW Williams John A JA Simeone Diane M DM Shah Yatrik M YM Omary M Bishr MB

Gastroenterology 20180201 6

We investigated whether intrapancreatic coagulation, with deposition of the fibrinogen-γ dimer (Fib-γD) and hypoxia, affect the severity of acute pancreatitis (AP) in mice. Pancreata of mice with AP induced by administration of cerulein or by L-arginine, or from patients with pancreatitis, had increased deposition of Fib-γD compared with control pancreata. Heparin administration protected mice from cerulein-induced AP and prevented Fib-γD formation. Cerulein administration resulted in activation ...[more]

PMID: 29409830

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Project description:The physiology and pathophysiology of the exocrine pancreas are in close connection to changes in intra-cellular Ca2+ concentration. Most of our knowledge is based on in vitro experiments on acinar cells or acini enzymatically isolated from their surroundings, which can alter their structure, physiology, and limit our understanding. Due to these limitations, the acute pancreas tissue slice technique was introduced almost two decades ago as a complementary approach to assess the morphology and physiology of both the endocrine and exocrine pancreas in a more conserved in situ setting. In this study, we extend previous work to functional multicellular calcium imaging on acinar cells in tissue slices. The viability and morphological characteristics of acinar cells within the tissue slice were assessed using the LIVE/DEAD assay, transmission electron microscopy, and immunofluorescence imaging. The main aim of our study was to characterize the responses of acinar cells to stimulation with acetylcholine and compare them with responses to cerulein in pancreatic tissue slices, with special emphasis on inter-cellular and inter-acinar heterogeneity and coupling. To this end, calcium imaging was performed employing confocal microscopy during stimulation with a wide range of acetylcholine concentrations and selected concentrations of cerulein. We show that various calcium oscillation parameters depend monotonically on the stimulus concentration and that the activity is rather well synchronized within acini, but not between acini. The acute pancreas tissue slice represents a viable and reliable experimental approach for the evaluation of both intra- and inter-cellular signaling characteristics of acinar cell calcium dynamics. It can be utilized to assess many cells simultaneously with a high spatiotemporal resolution, thus providing an efficient and high-yield platform for future studies of normal acinar cell biology, pathophysiology, and screening pharmacological substances.

Dataset Information

HIF1-alpha Regulates Acinar Cell Function and Response to Injury in Mouse Pancreas.

Publications

HIF1-alpha Regulates Acinar Cell Function and Response to Injury in Mouse Pancreas.

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