Immune-compromised state in the rat pancreas after chronic alcohol exposure: the role of peroxisome proliferator-activated receptor gamma.
Alcohol exposure is known to sensitize acinar cells to various insults but the pathophysiological mechanisms of alcoholic pancreatitis remain unknown. Alcohol abuse has been shown to mediate an anti-inflammatory response and periods of immune suppression seem to be associated with organ injury and mortality. The purpose of this study was to determine the mechanisms by which alcohol exerts transcriptional activities in the rat pancreas and how alcohol alters the inflammatory response. Using the Lieber-DeCarli alcohol/control diet, rats that were fed with alcohol over 14 weeks demonstrated a decrease of inflammatory cells in pancreatic tissue compared to controls. The anti-inflammatory effects of alcohol were confirmed by decreased expression of pro-inflammatory cytokines including TNFalpha, IL-1beta, IL-18, TGFbeta, and MCP-1. In addition, alcohol significantly increased the activity of PPARgamma, which is a known anti-inflammatory transcription factor, while pro-inflammatory factors including AP-2 and EGR-1 were significantly suppressed. NFkappaB binding showed a tendency towards a reduction. Electron microscopy studies revealed enlarged and injured mitochondria and lysosomes, accompanied by peri-cellular fibrosis. Furthermore, alcohol exposure increased the activities of trypsin and cathepsin B, both known to be critical in initiating acinar cell injury and pancreatitis. Despite the known alcohol-mediated acinar cell and mitochondrial injury, the mitochondrial-mediated apoptotic pathway was attenuated. These data demonstrate that the pancreas exposed to alcohol maintains an anti-inflammatory state by activating PPARgamma. Intracellular mitochondrial and lysosomal damage after chronic alcohol exposure induces premature activation of digestive enzymes and establishment of peri-cellular fibrosis in the absence of inflammation.
Fortunato
F
F
Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Germany. Franco.Fortunato@med.uni-heidelberg.de
Berger
I
I
Gross
M-L
ML
Rieger
P
P
Buechler
M W
MW
Werner
J
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002401:Cathepsin B / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D000431:Ethanol / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects*; D018836:Inflammation Mediators / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000187:drug effects / Q000648:ultrastructure; D047495:PPAR gamma / Q000187:drug effects / Q000502:physiology*; D010179:Pancreas / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D019512:Pancreatitis, Alcoholic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014357:Trypsin / Q000378:metabolism
D016207:Cytokines; D018836:Inflammation Mediators; D047495:PPAR gamma; D012333:RNA, Messenger; D000431:Ethanol; D009195:Peroxidase; D014357:Trypsin; D002401:Cathepsin B