The pancreatitis-associated protein induces lung inflammation in the rat through activation of TNFα expression in hepatocytes

Abstract

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 μg/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 TNFα, 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 TNFα level was increased and TNFα mRNA was strongly overexpressed in liver, with concomitant activation of NF-κB; in situ hybridization revealed that TNFα overexpression was mainly located to hepatocytes. Lung inflammation induced by PAP could be prevented by injection of anti-TNFα antibodies. It was concluded that, during pancreatitis, PAP released by the pancreas could mediate lung inflammation through induction of hepatic TNFα expression and subsequent increase in circulating TNFα. Copyright © 2003 John Wiley & Sons, Ltd.This work was supported by 2001FR0005 (CSIC-INSERM); E. Folch was supported by a grant from IDIBAPSPeer reviewe