Age-dependent vulnerability to experimental acute pancreatitis is associated with increased systemic inflammation and thrombosis.
The severity and mortality rates of acute pancreatitis (AP) are significantly elevated in the elderly population. However, due to a lack of appropriate animal models, the underlying mechanisms for this age-dependent vulnerability remain largely unknown. The purpose of this study was to characterize a murine model of AP, which displays age-associated severity, and to use this model to identify pathophysiologies that are distinctive of the aged with AP. AP was induced in young (4-5 months), middle-aged (12-13 months), and aged (23-25 months) C57BL/6 mice by repeated injection of caerulein, a homologue of the gastrointestinal hormone cholecystokinin. Approximately 10% of aged mice died during AP, while young and middle-aged mice showed no mortality. Although both young and aged mice exhibited early signs of edema and inflammation in the pancreas, kidney, and lung, young mice showed signs of recovery within 24 h, while aged mice exhibited increasingly severe tissue damage and cell death. There was a significant age-dependent increase in pancreatic neutrophil activation and systemic inflammation as assessed by pancreatic myeloperoxidase and plasma interleukin-6 (IL-6) concentration, respectively. Importantly, aged but not young mice with AP showed significantly elevated thrombosis in the lung and kidney as well as a marked increase in plasma concentration of plasminogen activator inhibitor-1 (PAI-1), a primary inhibitor of the fibrinolytic system. These results demonstrate that aging is associated with increased severity of AP characterized by augmented and prolonged pancreatic inflammation and the presence of multiple extra-pancreatic sequelae including thrombosis.
Department of Surgery, Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0298, USA.
Daiki
D
Okamura
Marlene E
ME
Starr
Eun Y
EY
Lee
Arnold J
AJ
Stromberg
B Mark
BM
Evers
Hiroshi
H
Saito
D000208:Acute Disease; D000375:Aging / Q000097:blood* / Q000276:immunology* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010195:Pancreatitis / Q000097:blood / Q000473:pathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D013927:Thrombosis / Q000097:blood / Q000473:pathology*
D005338:Fibrin Fibrinogen Degradation Products; D017395:Plasminogen Activator Inhibitor 1; C036309:fibrin fragment D