Human Pancreatic Acinar Cells: Proteomic Characterization, Physiologic Responses, and Organellar Disorders in ex Vivo Pancreatitis

Aurelia Lugea, Richard T. Waldron, Olga A. Mareninova, Natalia Shalbueva, Nan Deng, Hsin Yuan Su, Diane D. Thomas, Elaina K. Jones, Scott W. Messenger, Jiayue Yang, Cheng Hu, Ilya Gukovsky, Zhenqiu Liu, Guy E. Groblewski, Anna S. Gukovskaya, Fred S. Gorelick, Stephen J. Pandol

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Abstract

Knowledge of the molecular mechanisms of acute pancreatitis is largely based on studies using rodents. To assess similar mechanisms in humans, we performed ex vivo pancreatitis studies in human acini isolated from cadaveric pancreata from organ donors. Because data on these human acinar preparations are sparse, we assessed their functional integrity and cellular and organellar morphology using light, fluorescence, and electron microscopy; and their proteome by liquid chromatography–tandem mass spectrometry. Acinar cell responses to the muscarinic agonist carbachol (CCh) and the bile acid taurolithocholic acid 3-sulfate were also analyzed. Proteomic analysis of acini from donors of diverse ethnicity showed similar profiles of digestive enzymes and proteins involved in translation, secretion, and endolysosomal function. Human acini preferentially expressed the muscarinic acetylcholine receptor M3 and maintained physiological responses to CCh for at least 20 hours. As in rodent acini, human acini exposed to toxic concentrations of CCh and taurolithocholic acid 3-sulfate responded with trypsinogen activation, decreased cell viability, organelle damage manifest by mitochondrial depolarization, disordered autophagy, and pathological endoplasmic reticulum stress. Human acini also secreted inflammatory mediators elevated in acute pancreatitis patients, including IL-6, tumor necrosis factor-α, IL-1β, chemokine (C-C motif) ligands 2 and 3, macrophage inhibitory factor, and chemokines mediating neutrophil and monocyte infiltration. In conclusion, human cadaveric pancreatic acini maintain physiological functions and have similar pathological responses and organellar disorders with pancreatitis-causing treatments as observed in rodent acini.

Original languageEnglish (US)
Pages (from-to)2726-2743
Number of pages18
JournalAmerican Journal of Pathology
Volume187
Issue number12
DOIs
StatePublished - Dec 1 2017

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Acinar Cells
Pancreatitis
Proteomics
Carbachol
Rodentia
Muscarinic M3 Receptors
Tissue Donors
Trypsinogen
Chemokine CCL3
Muscarinic Agonists
Endoplasmic Reticulum Stress
Neutrophil Infiltration
Chemokine CCL2
Poisons
Autophagy
Muscarinic Receptors
Proteome
Bile Acids and Salts
Interleukin-1
Fluorescence Microscopy

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Lugea, Aurelia ; Waldron, Richard T. ; Mareninova, Olga A. ; Shalbueva, Natalia ; Deng, Nan ; Su, Hsin Yuan ; Thomas, Diane D. ; Jones, Elaina K. ; Messenger, Scott W. ; Yang, Jiayue ; Hu, Cheng ; Gukovsky, Ilya ; Liu, Zhenqiu ; Groblewski, Guy E. ; Gukovskaya, Anna S. ; Gorelick, Fred S. ; Pandol, Stephen J. / Human Pancreatic Acinar Cells : Proteomic Characterization, Physiologic Responses, and Organellar Disorders in ex Vivo Pancreatitis. In: American Journal of Pathology. 2017 ; Vol. 187, No. 12. pp. 2726-2743.
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abstract = "Knowledge of the molecular mechanisms of acute pancreatitis is largely based on studies using rodents. To assess similar mechanisms in humans, we performed ex vivo pancreatitis studies in human acini isolated from cadaveric pancreata from organ donors. Because data on these human acinar preparations are sparse, we assessed their functional integrity and cellular and organellar morphology using light, fluorescence, and electron microscopy; and their proteome by liquid chromatography–tandem mass spectrometry. Acinar cell responses to the muscarinic agonist carbachol (CCh) and the bile acid taurolithocholic acid 3-sulfate were also analyzed. Proteomic analysis of acini from donors of diverse ethnicity showed similar profiles of digestive enzymes and proteins involved in translation, secretion, and endolysosomal function. Human acini preferentially expressed the muscarinic acetylcholine receptor M3 and maintained physiological responses to CCh for at least 20 hours. As in rodent acini, human acini exposed to toxic concentrations of CCh and taurolithocholic acid 3-sulfate responded with trypsinogen activation, decreased cell viability, organelle damage manifest by mitochondrial depolarization, disordered autophagy, and pathological endoplasmic reticulum stress. Human acini also secreted inflammatory mediators elevated in acute pancreatitis patients, including IL-6, tumor necrosis factor-α, IL-1β, chemokine (C-C motif) ligands 2 and 3, macrophage inhibitory factor, and chemokines mediating neutrophil and monocyte infiltration. In conclusion, human cadaveric pancreatic acini maintain physiological functions and have similar pathological responses and organellar disorders with pancreatitis-causing treatments as observed in rodent acini.",
author = "Aurelia Lugea and Waldron, {Richard T.} and Mareninova, {Olga A.} and Natalia Shalbueva and Nan Deng and Su, {Hsin Yuan} and Thomas, {Diane D.} and Jones, {Elaina K.} and Messenger, {Scott W.} and Jiayue Yang and Cheng Hu and Ilya Gukovsky and Zhenqiu Liu and Groblewski, {Guy E.} and Gukovskaya, {Anna S.} and Gorelick, {Fred S.} and Pandol, {Stephen J.}",
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Lugea, A, Waldron, RT, Mareninova, OA, Shalbueva, N, Deng, N, Su, HY, Thomas, DD, Jones, EK, Messenger, SW, Yang, J, Hu, C, Gukovsky, I, Liu, Z, Groblewski, GE, Gukovskaya, AS, Gorelick, FS & Pandol, SJ 2017, 'Human Pancreatic Acinar Cells: Proteomic Characterization, Physiologic Responses, and Organellar Disorders in ex Vivo Pancreatitis', American Journal of Pathology, vol. 187, no. 12, pp. 2726-2743. https://doi.org/10.1016/j.ajpath.2017.08.017

Human Pancreatic Acinar Cells : Proteomic Characterization, Physiologic Responses, and Organellar Disorders in ex Vivo Pancreatitis. / Lugea, Aurelia; Waldron, Richard T.; Mareninova, Olga A.; Shalbueva, Natalia; Deng, Nan; Su, Hsin Yuan; Thomas, Diane D.; Jones, Elaina K.; Messenger, Scott W.; Yang, Jiayue; Hu, Cheng; Gukovsky, Ilya; Liu, Zhenqiu; Groblewski, Guy E.; Gukovskaya, Anna S.; Gorelick, Fred S.; Pandol, Stephen J.

In: American Journal of Pathology, Vol. 187, No. 12, 01.12.2017, p. 2726-2743.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Human Pancreatic Acinar Cells

T2 - Proteomic Characterization, Physiologic Responses, and Organellar Disorders in ex Vivo Pancreatitis

AU - Lugea, Aurelia

AU - Waldron, Richard T.

AU - Mareninova, Olga A.

AU - Shalbueva, Natalia

AU - Deng, Nan

AU - Su, Hsin Yuan

AU - Thomas, Diane D.

AU - Jones, Elaina K.

AU - Messenger, Scott W.

AU - Yang, Jiayue

AU - Hu, Cheng

AU - Gukovsky, Ilya

AU - Liu, Zhenqiu

AU - Groblewski, Guy E.

AU - Gukovskaya, Anna S.

AU - Gorelick, Fred S.

AU - Pandol, Stephen J.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Knowledge of the molecular mechanisms of acute pancreatitis is largely based on studies using rodents. To assess similar mechanisms in humans, we performed ex vivo pancreatitis studies in human acini isolated from cadaveric pancreata from organ donors. Because data on these human acinar preparations are sparse, we assessed their functional integrity and cellular and organellar morphology using light, fluorescence, and electron microscopy; and their proteome by liquid chromatography–tandem mass spectrometry. Acinar cell responses to the muscarinic agonist carbachol (CCh) and the bile acid taurolithocholic acid 3-sulfate were also analyzed. Proteomic analysis of acini from donors of diverse ethnicity showed similar profiles of digestive enzymes and proteins involved in translation, secretion, and endolysosomal function. Human acini preferentially expressed the muscarinic acetylcholine receptor M3 and maintained physiological responses to CCh for at least 20 hours. As in rodent acini, human acini exposed to toxic concentrations of CCh and taurolithocholic acid 3-sulfate responded with trypsinogen activation, decreased cell viability, organelle damage manifest by mitochondrial depolarization, disordered autophagy, and pathological endoplasmic reticulum stress. Human acini also secreted inflammatory mediators elevated in acute pancreatitis patients, including IL-6, tumor necrosis factor-α, IL-1β, chemokine (C-C motif) ligands 2 and 3, macrophage inhibitory factor, and chemokines mediating neutrophil and monocyte infiltration. In conclusion, human cadaveric pancreatic acini maintain physiological functions and have similar pathological responses and organellar disorders with pancreatitis-causing treatments as observed in rodent acini.

AB - Knowledge of the molecular mechanisms of acute pancreatitis is largely based on studies using rodents. To assess similar mechanisms in humans, we performed ex vivo pancreatitis studies in human acini isolated from cadaveric pancreata from organ donors. Because data on these human acinar preparations are sparse, we assessed their functional integrity and cellular and organellar morphology using light, fluorescence, and electron microscopy; and their proteome by liquid chromatography–tandem mass spectrometry. Acinar cell responses to the muscarinic agonist carbachol (CCh) and the bile acid taurolithocholic acid 3-sulfate were also analyzed. Proteomic analysis of acini from donors of diverse ethnicity showed similar profiles of digestive enzymes and proteins involved in translation, secretion, and endolysosomal function. Human acini preferentially expressed the muscarinic acetylcholine receptor M3 and maintained physiological responses to CCh for at least 20 hours. As in rodent acini, human acini exposed to toxic concentrations of CCh and taurolithocholic acid 3-sulfate responded with trypsinogen activation, decreased cell viability, organelle damage manifest by mitochondrial depolarization, disordered autophagy, and pathological endoplasmic reticulum stress. Human acini also secreted inflammatory mediators elevated in acute pancreatitis patients, including IL-6, tumor necrosis factor-α, IL-1β, chemokine (C-C motif) ligands 2 and 3, macrophage inhibitory factor, and chemokines mediating neutrophil and monocyte infiltration. In conclusion, human cadaveric pancreatic acini maintain physiological functions and have similar pathological responses and organellar disorders with pancreatitis-causing treatments as observed in rodent acini.

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