Platelet-activating factor antagonist (TCV-309) attenuates the priming effects of bronchoalveolar macrophages in cerulein-induced pancreatitis rats

We investigated the role of platelet-activating factor (PAF) as a priming s ignal for cytokine-induced neutrophil chemoattractant (CINC) expression by bronchoalveolar macrophages in acute pancreatitis. Pancreatitis was induced by four intramuscular injections of cerulein (50 mu g/kg at l-h intervals) in Wistar rats. The animals were injected intraperitoneally with 10 mu g/k g of lipopolysaccharide (LPS) as a septic challenge. Pancreatitis rats were treated with a bolus intravenous injection of TCV-309 (3 or 30 mu g/kg) 30 min before the septic challenge. Intense mononuclear cell infiltration and lung hemorrhage occurred in pancreatitis rats complicated with sepsis but were not seen in pancreatitis rats receiving a bolus TCV-309. Pancreatitis rats treated with TCV-309 had lower serum concentrations of CINC after sept ic challenge and lower levels of CINC messenger RNA (mRNA) in the lung, as well as fewer pulmonary infiltrates immunoreactive for CINC or Mac-1 (CD11b /CD18). in vitro CINC production in response to LPS by bronchoalveolar macr ophages obtained from pancreatitis rats 6 h after the first cerulein inject ion, immediately before septic challenge, was enhanced but was significantl y reduced in a TCV-309-sensitive manner. LPS-stimulated in vitro CINC produ ction by naive bronchoalveolar macrophages was significantly enhanced by pr etreatment with PAF. TMB-8 (an inhibitor of calcium release from endoplasmi c reticulum) or W7 (calmodulin antagonist) completely abrogated the chemoat tractant production by bronchoalveolar macrophages pretreated with PAF afte r LPS stimulation. Altered intracellular calcium, due to Ca2+ efflux from i ntracellular stores, may be involved in the "priming" of bronchoalveolar ma crophages to release CINC after triggering with LPS during acute cerulein-i nduced pancreatitis. The PAF antagonist TCV-309 effectively prevented hyper activity of bronchoalveolar macrophages and pancreatitis-associated lung in jury after the septic challenge.