title: Fibrosis reduces severity of acute-on-chronic pancreatitis in humans.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center Passavant, Pittsburgh, Pennsylvania, USA.
authors.forename: Chathur
authors.initials: C
authors.lastname: Acharya
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Cline
authors.forename: Deepthi
authors.initials: D
authors.lastname: Jaligama
authors.forename: Pawan
authors.initials: P
authors.lastname: Noel
authors.forename: James P
authors.initials: JP
authors.lastname: Delany
authors.forename: Kyongtae
authors.initials: K
authors.lastname: Bae
authors.forename: Alessandro
authors.initials: A
authors.lastname: Furlan
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Baty
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Karlsson
authors.forename: Bedda L
authors.initials: BL
authors.lastname: Rosario
authors.forename: Krutika
authors.initials: K
authors.lastname: Patel
authors.forename: Vivek
authors.initials: V
authors.lastname: Mishra
authors.forename: Chandra
authors.initials: C
authors.lastname: Dugampudi
authors.forename: Dhiraj
authors.initials: D
authors.lastname: Yadav
authors.forename: Sarah
authors.initials: S
authors.lastname: Navina
authors.forename: Vijay P
authors.initials: VP
authors.lastname: Singh
mesh_terms: D061354:Acinar Cells / Q000187:drug effects; D000208:Acute Disease; D017667:Adipocytes / Q000187:drug effects; D054392:Adipokines / Q000494:pharmacology; D000273:Adipose Tissue / Q000473:pathology*; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D005355:Fibrosis; D006801:Humans; D008875:Middle Aged; D009336:Necrosis; D009765:Obesity / Q000150:complications / Q000473:pathology*; D010179:Pancreas / Q000473:pathology*; D019283:Pancreatitis, Acute Necrotizing / Q000150:complications / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000150:complications / Q000473:pathology*; D012189:Retrospective Studies; D012720:Severity of Illness Index
chemical_list: D054392:Adipokines; D005230:Fatty Acids, Nonesterified
keywords: AP; ATP; BMI; CP; CT; FN; IPF; Inflammation; Mechanism; NEFA; Necrosis; PFAN; PI; Pancreas; SAP; UFA; acute pancreatitis; adenosine triphosphate; body mass index; chronic pancreatitis; computed tomography; fat necrosis; intrapancreatic fat; nonesterified fatty acid; peri-fat acinar necrosis; propidium iodide; severe acute pancreatitis; unsaturated fatty acid