We investigated the role of
platelet-activating factor (PAF) as a priming signal for
cytokine-induced neutrophil
chemoattractant (CINC) expression by bronchoalveolar macrophages in
acute pancreatitis.
Pancreatitis was induced by four
intramuscular injections of
cerulein (50 micrograms/kg at 1-h intervals) in Wistar rats. The animals were injected intraperitoneally with 10 micrograms/kg of
lipopolysaccharide (LPS) as a septic challenge.
Pancreatitis rats were treated with a bolus
intravenous injection of
TCV-309 (3 or 30 micrograms/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 septic 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 macrophages obtained from
pancreatitis rats 6 h after the first
cerulein injection, immediately before septic challenge, was enhanced but was significantly reduced in a TCV-309-sensitive manner. LPS-stimulated in vitro CINC production by naive bronchoalveolar macrophages was significantly enhanced by pretreatment with PAF.
TMB-8 (an inhibitor of
calcium release from endoplasmic reticulum) or
W7 (
calmodulin antagonist) completely abrogated the
chemoattractant production by bronchoalveolar macrophages pretreated with PAF after LPS stimulation. Altered intracellular
calcium, due to Ca2+ efflux from intracellular stores, may be involved in the "priming" of bronchoalveolar macrophages to release CINC after triggering with LPS during acute
cerulein-induced
pancreatitis. The PAF antagonist
TCV-309 effectively prevented hyperactivity of bronchoalveolar macrophages and
pancreatitis-associated
lung injury after the septic challenge.