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 language | English (US) |
|---|---|
| Pages (from-to) | 2726-2743 |
| Number of pages | 18 |
| Journal | American Journal of Pathology |
| Volume | 187 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2017 |
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All Science Journal Classification (ASJC) codes
- Pathology and Forensic Medicine
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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 journal › Article
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.
UR - http://www.scopus.com/inward/record.url?scp=85034264142&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85034264142&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2017.08.017
DO - 10.1016/j.ajpath.2017.08.017
M3 - Article
C2 - 28935577
AN - SCOPUS:85034264142
VL - 187
SP - 2726
EP - 2743
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 12
ER -