The pancreatitis-associated protein induces lung inflammation in the rat through activation of TNFalpha expression in hepatocytes.
The pancreatitis-associated protein (PAP) is a pancreatic stress protein overexpressed during acute pancreatitis, a disease often accompanied by lung inflammation. We investigated whether PAP was involved in the occurrence of this remote complication of pancreatitis and whether the liver might be implicated in the process. PAP was injected into the vena cava of rats (40 or 400 micro g/kg body weight). For comparison, pancreatitis was induced in rats by intraductal administration of sodium taurocholate. Three hours later, parameters of inflammation and mRNA concentrations of TNFalpha, P-selectin, heat shock protein (HSP)-70, and extracellular superoxide dismutase (EC-SOD) were monitored in lung and liver. Significant increases in P-selectin expression, neutrophil infiltration, and oxidative stress revealed that PAP treatment induced lung inflammation in rats and exacerbated inflammation in animals with pancreatitis. Plasma TNFalpha level was increased and TNFalpha mRNA was strongly overexpressed in liver, with concomitant activation of NF-kappaB; in situ hybridization revealed that TNFalpha overexpression was mainly located to hepatocytes. Lung inflammation induced by PAP could be prevented by injection of anti-TNFalpha antibodies. It was concluded that, during pancreatitis, PAP released by the pancreas could mediate lung inflammation through induction of hepatic TNFalpha expression and subsequent increase in circulating TNFalpha.
Folch-Puy
Emma
E
Centre de Recherche INSERM, EMS 0116, Marseille, France.
García-Movtero
Andrés
A
Iovanna
Juan L
JL
Dagorn
Jean Charles
JC
Prats
Neus
N
Vaccaro
Maria Inés
MI
Closa
Daniel
D
D000818:Animals; D000951:Antigens, Neoplasm / Q000633:toxicity*; D014408:Biomarkers, Tumor / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism*; D037181:Lectins, C-Type; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D019007:P-Selectin / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced; D000073718:Pancreatitis-Associated Proteins; D011014:Pneumonia / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D016328:NF-kappa B; D019007:P-Selectin; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D012333:RNA, Messenger; C000612144:Reg3b protein, rat; D014409:Tumor Necrosis Factor-alpha