Fibrosis reduces severity of acute-on-chronic pancreatitis in humans

Chathur Acharya, Rachel A. Cline, Deepthi Jaligama, Pawan Noel, James P. Delany, Kyongtae Bae, Alessandro Furlan, Catherine J. Baty, Jenny M. Karlsson, Bedda L. Rosario, Krutika Patel, Vivek Mishra, Chandra Dugampudi, Dhiraj Yadav, Sarah Navina, Vijay Prem Singh

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)466-475
Number of pages10
JournalGastroenterology
Volume145
Issue number2
DOIs
StatePublished - Aug 2013

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Chronic Pancreatitis
Fibrosis
Pancreatitis
Acinar Cells
Fat Necrosis
Necrosis
Adipocytes
Fats
Adipokines
Nonesterified Fatty Acids
Pancreatic Diseases
Coculture Techniques
Collagen Type I
Autopsy
Histology
Collagen
Cell Culture Techniques

Keywords

  • Pancreas Inflammation Necrosis Mechanism

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Acharya, C., Cline, R. A., Jaligama, D., Noel, P., Delany, J. P., Bae, K., ... Singh, V. P. (2013). Fibrosis reduces severity of acute-on-chronic pancreatitis in humans. Gastroenterology, 145(2), 466-475. https://doi.org/10.1053/j.gastro.2013.05.012

Fibrosis reduces severity of acute-on-chronic pancreatitis in humans. / Acharya, Chathur; Cline, Rachel A.; Jaligama, Deepthi; Noel, Pawan; Delany, James P.; Bae, Kyongtae; Furlan, Alessandro; Baty, Catherine J.; Karlsson, Jenny M.; Rosario, Bedda L.; Patel, Krutika; Mishra, Vivek; Dugampudi, Chandra; Yadav, Dhiraj; Navina, Sarah; Singh, Vijay Prem.

In: Gastroenterology, Vol. 145, No. 2, 08.2013, p. 466-475.

Research output: Contribution to journalArticle

Acharya, C, Cline, RA, Jaligama, D, Noel, P, Delany, JP, Bae, K, Furlan, A, Baty, CJ, Karlsson, JM, Rosario, BL, Patel, K, Mishra, V, Dugampudi, C, Yadav, D, Navina, S & Singh, VP 2013, 'Fibrosis reduces severity of acute-on-chronic pancreatitis in humans', Gastroenterology, vol. 145, no. 2, pp. 466-475. https://doi.org/10.1053/j.gastro.2013.05.012
Acharya C, Cline RA, Jaligama D, Noel P, Delany JP, Bae K et al. Fibrosis reduces severity of acute-on-chronic pancreatitis in humans. Gastroenterology. 2013 Aug;145(2):466-475. https://doi.org/10.1053/j.gastro.2013.05.012
Acharya, Chathur ; Cline, Rachel A. ; Jaligama, Deepthi ; Noel, Pawan ; Delany, James P. ; Bae, Kyongtae ; Furlan, Alessandro ; Baty, Catherine J. ; Karlsson, Jenny M. ; Rosario, Bedda L. ; Patel, Krutika ; Mishra, Vivek ; Dugampudi, Chandra ; Yadav, Dhiraj ; Navina, Sarah ; Singh, Vijay Prem. / Fibrosis reduces severity of acute-on-chronic pancreatitis in humans. In: Gastroenterology. 2013 ; Vol. 145, No. 2. pp. 466-475.
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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 Prem

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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.

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