A rat model reproducing key pathological responses of alcoholic chronic pancreatitis.
Although alcohol abuse is the major cause of chronic pancreatitis, the pathogenesis of alcoholic chronic pancreatitis (ACP) remains obscure. A critical obstacle to understanding the mechanism of ACP is lack of animal models. Our objective was to develop one such model. Rats were pair-fed for 8 wk ethanol or control Lieber-DeCarli liquid diet. For the last 2 wk, they received cyclosporin A (CsA; 20 mg/kg once daily) or vehicle. After 1 wk on CsA, one episode of acute pancreatitis was induced by four 20 microg/kg injections of cerulein (Cer); controls received saline. Pancreas was analyzed 1 wk after the acute pancreatitis. CsA or Cer treatments alone did not result in pancreatic injury in either control (C)- or ethanol (E)-fed rats. We found, however, that alcohol dramatically aggravated pathological effect of the combined CsA+Cer treatment on pancreas, resulting in massive loss of acinar cells, persistent inflammatory infiltration, and fibrosis. Macrophages were prominent in the inflammatory infiltrate. Compared with control-fed C+CsA+Cer rats, their ethanol-fed E+CsA+Cer counterparts showed marked increases in pancreatic NF-kappaB activation and cytokine/chemokine mRNA expression, collagen and fibronectin, the expression and activities of matrix metalloproteinase-2 and -9, and activation of pancreatic stellate cells. Thus we have developed a model of alcohol-mediated postacute pancreatitis that reproduces three key responses of human ACP: loss of parenchyma, sustained inflammation, and fibrosis. The results indicate that alcohol impairs recovery from acute pancreatitis, suggesting a mechanism by which alcohol sensitizes pancreas to chronic injury.
Gukovsky
Ilya
I
UCLA/VA Greater Los Angeles Healthcare System, West Los Angeles VA Healthcare Center, Los Angeles, CA 90073, USA. igukovsk@ucla.edu
Lugea
Aurelia
A
Shahsahebi
Mohammad
M
Cheng
Jason H
JH
Hong
Peggy P
PP
Jung
Yoon J
YJ
Deng
Quing-gao
QG
French
Barbara A
BA
Lungo
William
W
French
Samuel W
SW
Tsukamoto
Hidekazu
H
Pandol
Stephen J
SJ
D000818:Animals; D016923:Cell Death; D002108:Ceruletide; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D016572:Cyclosporine; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D019512:Pancreatitis, Alcoholic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D013997:Time Factors
D018925:Chemokines; D016207:Cytokines; D005353:Fibronectins; D007328:Insulin; D016328:NF-kappa B; D012333:RNA, Messenger; D000431:Ethanol; D016572:Cyclosporine; D002108:Ceruletide; D003094:Collagen; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9