Pancreatic response to endotoxin after chronic alcohol exposure: switch from apoptosis to necrosis?
Chronic alcohol consumption is known to increase the susceptibility to acute and chronic pancreatitis, and it is likely that a cofactor is required to initiate the progression to alcoholic pancreatitis. The severity and complications of alcoholic and nonalcoholic acute pancreatitis may be influenced by a number of cofactors, including endotoxemia. To explore the effect of a possible cofactor, we used endotoxin [lipopolysaccharide (LPS)] as a tool to induce cellular injury in the alcoholic pancreas. Single, increasing doses of endotoxin were injected in rats fed an alcohol or control diet and killed 24 h after the injection. We examined the mechanism by which LPS exacerbates pancreatic injury in alcohol-fed rats and whether the injury is associated with apoptosis or necrosis. We showed that chronic alcohol exposure alone inhibits apoptosis through the intrinsic pathway and the downstream apoptosis executor caspase-3 compared with the controls. Pancreatic necrosis and inflammation increased after LPS injection in control and alcohol-fed rats in a dose-dependent fashion but with a significantly greater response in the alcohol-fed animals. Caspase activities and TdT-mediated dUTP nick-end labeling positivity were lower in the alcoholic pancreas injected with LPS, whereas the histopathology and inflammation were more severe compared with the control-fed animals. Assessment of a putative indicator of necrosis, the ratio of ADP to ATP, indicated that alcohol exposure accelerates pancreatic necrosis in response to endotoxin. These findings suggest that the pancreas exposed to alcohol is more sensitive to LPS-induced damage because of increased sensitivity to necrotic cell death rather than apoptotic cell death. Similar to the liver, the pancreas is capable of responding to LPS with a more severe response in alcohol-fed animals, favoring pancreatic necrosis rather than apoptosis. We speculate that this mechanism may occur in acute alcoholic pancreatitis patients.
University Hospital Zurich, Department of Visceral and Transplantation Surgery, Sternwartstrasse 14, CH-8091 Zurich, Switzerland. franco.fortunato@usz.ch
Franco
F
Fortunato
Xiaoying
X
Deng
Lawrence K
LK
Gates
Craig J
CJ
McClain
Daniel
D
Bimmler
Rolf
R
Graf
David C
DC
Whitcomb
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D020169:Caspases / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000633:toxicity*; D004731:Endotoxins / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000633:toxicity*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D037181:Lectins, C-Type / Q000096:biosynthesis; D051847:Lithostathine / Q000096:biosynthesis; D008297:Male; D009336:Necrosis; D010179:Pancreas / Q000187:drug effects* / Q000473:pathology*; D000073718:Pancreatitis-Associated Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D002492:Central Nervous System Depressants; D004731:Endotoxins; D037181:Lectins, C-Type; D051847:Lithostathine; D000073718:Pancreatitis-Associated Proteins; D000431:Ethanol; D000255:Adenosine Triphosphate; D051547:Heme Oxygenase-1; D020169:Caspases