Pancreatic stellate cell activation and MMP production in experimental pancreatic fibrosis.
BACKGROUND
The early events in pancreatic fibrosis are poorly understood. We examined the production of collagen and matrix metalloproteinases as well as the activation of pancreatic stellate cells in a rodent model of pancreatic fibrosis.


METHODS
Pancreatitis was induced in rats by hyperstimulation with cerulein (50 microg/kg/day ip) and concurrent pancreatic duct obstruction (SHOP model) for 96 h (n = 48). Sham animals were injected with saline and underwent laparotomy and manipulation of the pancreas with no duct obstruction (n = 28). Rats were sacrificed daily for 18 days. Serial pancreatic sections were stained with H&E [histology], trichrome [collagen], and alpha smooth muscle actin (alpha-SMA) antibodies [activated stellate cells]. Total pancreatic matrix metalloproteinase (MMP)-2 and 9 were determined by gelatin zymography. MMP-1 production was examined using Western blotting.


RESULTS
There were occasional alpha-SMA-positive cells in the pancreatic parenchyma of normal and sham animals. Within 48 h of pancreatitis induction in SHOP animals, histologic evidence of pancreatic inflammation was present, and stellate cells (alpha-SMA-positive cells) appeared surrounding pancreatic acini. The appearance of these cells was followed by collagen deposition in the same area. MMP-1 and 2 proteins increased significantly during pancreatitis while MMP-9 did not. The pancreatic architecture returned to normal by 18 days after the induction of pancreatitis.


CONCLUSIONS
Acute pancreatic inflammation results in stellate cell activation and collagen deposition in the same area. Collagen is then resorbed at a time when MMP-1 and 2 peak. The fibrosis of acute pancreatic inflammation in this model completely resolves with restoration of normal architecture.
Yokota
Tokuyasu
T
Division of Gastrointestinal and Endocrine Surgery, Department of Surgery, Northwestern University School of Medicine, Chicago, Illinois 60611, USA.
Denham
Woody
W
Murayama
Kenric
K
Pelham
Carolyn
C
Joehl
Raymond
R
Bell
Richard H
RH
D000199:Actins / Q000032:analysis; D000818:Animals; D015153:Blotting, Western; D002108:Ceruletide; D003094:Collagen / Q000032:analysis / Q000378:metabolism; D003250:Constriction; D004487:Edema; D005355:Fibrosis; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D009130:Muscle, Smooth / Q000201:enzymology; D010179:Pancreas / Q000201:enzymology* / Q000473:pathology*; D010183:Pancreatic Ducts / Q000737:chemistry / Q000473:pathology; D010195:Pancreatitis / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000199:Actins; D002108:Ceruletide; D003094:Collagen; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1