Pancreas recovery following cerulein-induced pancreatitis is impaired in plasminogen-deficient mice.
OBJECTIVE
The plasminogen (plg) system participates in tissue repair in several organs, but its role in pancreas repair remains poorly characterized. To understand better the role of plg in pancreas recovery following injury, we examined the course of cerulein-induced pancreatitis in plg-deficient and -sufficient mice.


METHODS
Pancreatitis was induced by cerulein administration (50 microg/kg, 7 intraperitoneal injections). Mice were killed either at the acute phase (7 hours after the first cerulein injection) or during recovery (at 2, 4, and 7 days). In pancreatic sections, we examined pancreatic morphology, trypsin activation, inflammatory cell infiltration, acinar cell death, cell proliferation, extracellular matrix deposition, activation of stellate cells (PSCs), and components of the plg and metalloproteinase systems.


RESULTS
In plg-sufficient mice, pancreatic plg levels and plasmin activity increased during the acute phase and remained elevated during recovery. Pancreatitis resolved in plg-sufficient mice within 7 days. Pancreas recovery involved reorganization of the parenchyma structure, removal of necrotic debris, cell proliferation, transient activation of PSCs, and moderate deposition of extracellular matrix proteins. Acute pancreatitis (7 hours) was indistinguishable between plg-deficient and -sufficient mice. In contrast, pancreas recovery was impaired in plg-deficient mice. Plg deficiency led to disorganized parenchyma, extensive acinar cell loss, poor removal of necrotic debris, reduced cell proliferation, and fibrosis. Fibrosis was characterized by deposition of collagens and fibronectin, persistent activation of PSCs, and up-regulation of pancreatic transforming growth factor beta1.


CONCLUSIONS
Plg/plasmin deficiency leads to features similar to those found in chronic pancreatitis such as parenchymal atrophy and fibrosis.
Lugea
Aurelia
A
USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California 90073, USA. alugea@ucla.edu
Nan
Li
L
French
Samuel W
SW
Bezerra
Jorge A
JA
Gukovskaya
Anna S
AS
Pandol
Stephen J
SJ
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002108:Ceruletide / Q000633:toxicity; D004195:Disease Models, Animal; D005341:Fibrinolysin / Q000378:metabolism; D005500:Follow-Up Studies; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010958:Plasminogen / Q000172:deficiency*; D020127:Recovery of Function / Q000502:physiology*; D012720:Severity of Illness Index; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014357:Trypsin / Q000378:metabolism
C508961:Tgfb1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D002108:Ceruletide; D010958:Plasminogen; D014357:Trypsin; D005341:Fibrinolysin