title: Release of Cathepsin B in Cytosol Causes Cell Death in Acute Pancreatitis.
abstract: Experimental studies in acute pancreatitis (AP) suggest a strong association of acinar cell injury with cathepsin B-dependent intracellular activation of trypsin. However, the molecular events subsequent to trypsin activation and their role, if any, in cell death is not clear. In this study, we have explored intra-acinar events downstream of trypsin activation that lead to acinar cell death.
  
  
  
  Acinar cells prepared from the pancreas of rats or mice (wild-type, trypsinogen 7, or cathepsin B-deleted) were stimulated with supramaximal cerulein, and the cytosolic activity of cathepsin B and trypsin was evaluated. Permeabilized acini were used to understand the differential role of cytosolic trypsin vs cytosolic cathepsin B in activation of apoptosis. Cell death was evaluated by measuring specific markers for apoptosis and necrosis.
  
  
  
  Both in vitro and in vivo studies have suggested that during AP cathepsin B leaks into the cytosol from co-localized organelles, through a mechanism dependent on active trypsin. Cytosolic cathepsin B but not trypsin activates the intrinsic pathway of apoptosis through cleavage of bid and activation of bax. Finally, excessive release of cathepsin B into the cytosol can lead to cell death through necrosis.
  
  
  
  This report defines the role of trypsin in AP and shows that cytosolic cathepsin B but not trypsin activates cell death pathways. This report also suggests that trypsin is a requisite for AP only because it causes release of cathepsin B into the cytosol.
authors: Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India.
authors: Rupjyoti
authors: R
authors: Talukdar
authors: Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
authors: Archana
authors: A
authors: Sareen
authors: Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
authors: Hongyan
authors: H
authors: Zhu
authors: Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
authors: Zuobiao
authors: Z
authors: Yuan
authors: Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida.
authors: Ajay
authors: A
authors: Dixit
authors: Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida.
authors: Hassam
authors: H
authors: Cheema
authors: Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida.
authors: John
authors: J
authors: George
authors: Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
authors: Usman
authors: U
authors: Barlass
authors: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
authors: Raghuwansh
authors: R
authors: Sah
authors: Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
authors: Sushil K
authors: SK
authors: Garg
authors: Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida.
authors: Sulagna
authors: S
authors: Banerjee
authors: Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India.
authors: Pramod
authors: P
authors: Garg
authors: Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida.
authors: Vikas
authors: V
authors: Dudeja
authors: Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida.
authors: Rajinder
authors: R
authors: Dawra
authors: Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida. Electronic address: asaluja@miami.edu.
authors: Ashok K
authors: AK
authors: Saluja
mesh_terms: D061354:Acinar Cells / Q000201:enzymology*; D000818:Animals; D002401:Cathepsin B / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D003600:Cytosol / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000166:cytology; D010195:Pancreatitis / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014357:Trypsin / Q000502:physiology
chemical_list: D014357:Trypsin; D002401:Cathepsin B
keywords: Apoptosis; Bid Cleavage; Cytosolic Cathepsin B; Necrosis