TY - JOUR
T1 - Fibrosis reduces severity of acute-on-chronic pancreatitis in humans
AU - Acharya, Chathur
AU - Cline, Rachel A.
AU - Jaligama, Deepthi
AU - Noel, Pawan
AU - Delany, James P.
AU - Bae, Kyongtae
AU - Furlan, Alessandro
AU - Baty, Catherine J.
AU - Karlsson, Jenny M.
AU - Rosario, Bedda L.
AU - Patel, Krutika
AU - Mishra, Vivek
AU - Dugampudi, Chandra
AU - Yadav, Dhiraj
AU - Navina, Sarah
AU - Singh, Vijay P.
N1 - Funding Information:
Funding The project described was supported by grants R01 DK092460 (to V.P.S.) and UL1 RR024153 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research (V.P.S, S.N.), and the Clinical Translational Science Institute supported by the NIH through grants UL1 RR024153 and UL1 TR000005 . The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or NIH. Information on the NCRR is available at http://www.ncrr.nih.gov/ . Information on Re-engineering the Clinical Research Enterprise is available at http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp . Funding was also provided by a startup package from the University of Pittsburgh Department of Medicine (to V.P.S.).
PY - 2013/8
Y1 - 2013/8
N2 - Background & Aims Acute pancreatitis (AP) and chronic pancreatitis (CP) share etiologies, but AP can be more severe and is associated with a higher rate of mortality. We investigated features of CP that protect against severe disease. The amount of intrapancreatic fat (IPF) is increased in obese patients and fibrosis is increased in patients with CP, so we studied whether fibrosis or fat regulate severity of AP attacks in patients with CP. Methods We reviewed records from the University of Pittsburgh Medical Center/Presbyterian Hospital Autopsy Database (1998-2008) for patients with a diagnosis of AP (n = 23), CP (n = 35), or both (AP-on-CP; n = 15). Pancreatic histology samples from these patients and 50 randomly selected controls (no pancreatic disease) were analyzed, and IPF data were correlated with computed tomography data. An adipocyte and acinar cell Transwell coculture system, with or without collagen type I, was used to study the effects of fibrosis on acinar-adipocyte interactions. We studied the effects of nonesterified fatty acids (NEFAs) and adipokines on acinar cells in culture. Results Levels of IPF were significantly higher in nonobese patients with CP than in nonobese controls. In patients with CP or AP-on-CP, areas of IPF were surrounded by significantly more fibrosis than in controls or patients with AP. Fat necrosis-associated peri-fat acinar necrosis (PFAN, indicated by NEFA spillage) contributed to most of the necrosis observed in samples from patients with AP; however, findings of peri-fat acinar necrosis and total necrosis were significantly lower in samples from patients with CP or AP-on-CP. Fibrosis appeared to wall off the fat necrosis and limit peri-fat acinar necrosis, reducing acinar necrosis. In vitro, collagen I limited the lipolytic flux between acinar cells and adipocytes and prevented increases in adipokines in the acinar compartment. This was associated with reduced acinar cell necrosis. However, NEFAs, but not adipokines, caused acinar cell necrosis. Conclusions Based on analysis of pancreatic samples from patients with CP, AP, or AP-on-CP and in vitro studies, fibrosis reduces the severity of acute exacerbations of CP by reducing lipolytic flux between adipocytes and acinar cells.
AB - Background & Aims Acute pancreatitis (AP) and chronic pancreatitis (CP) share etiologies, but AP can be more severe and is associated with a higher rate of mortality. We investigated features of CP that protect against severe disease. The amount of intrapancreatic fat (IPF) is increased in obese patients and fibrosis is increased in patients with CP, so we studied whether fibrosis or fat regulate severity of AP attacks in patients with CP. Methods We reviewed records from the University of Pittsburgh Medical Center/Presbyterian Hospital Autopsy Database (1998-2008) for patients with a diagnosis of AP (n = 23), CP (n = 35), or both (AP-on-CP; n = 15). Pancreatic histology samples from these patients and 50 randomly selected controls (no pancreatic disease) were analyzed, and IPF data were correlated with computed tomography data. An adipocyte and acinar cell Transwell coculture system, with or without collagen type I, was used to study the effects of fibrosis on acinar-adipocyte interactions. We studied the effects of nonesterified fatty acids (NEFAs) and adipokines on acinar cells in culture. Results Levels of IPF were significantly higher in nonobese patients with CP than in nonobese controls. In patients with CP or AP-on-CP, areas of IPF were surrounded by significantly more fibrosis than in controls or patients with AP. Fat necrosis-associated peri-fat acinar necrosis (PFAN, indicated by NEFA spillage) contributed to most of the necrosis observed in samples from patients with AP; however, findings of peri-fat acinar necrosis and total necrosis were significantly lower in samples from patients with CP or AP-on-CP. Fibrosis appeared to wall off the fat necrosis and limit peri-fat acinar necrosis, reducing acinar necrosis. In vitro, collagen I limited the lipolytic flux between acinar cells and adipocytes and prevented increases in adipokines in the acinar compartment. This was associated with reduced acinar cell necrosis. However, NEFAs, but not adipokines, caused acinar cell necrosis. Conclusions Based on analysis of pancreatic samples from patients with CP, AP, or AP-on-CP and in vitro studies, fibrosis reduces the severity of acute exacerbations of CP by reducing lipolytic flux between adipocytes and acinar cells.
KW - Pancreas Inflammation Necrosis Mechanism
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U2 - 10.1053/j.gastro.2013.05.012
DO - 10.1053/j.gastro.2013.05.012
M3 - Article
C2 - 23684709
AN - SCOPUS:84880635038
SN - 0016-5085
VL - 145
SP - 466
EP - 475
JO - Gastroenterology
JF - Gastroenterology
IS - 2
ER -