The purpose of this study was to investigate whether
pituitary adenylate cyclase-activating polypeptide (
PACAP) prevents mortality due to
sepsis in mice. Mice were given
PACAP at designated time points before or after cecal
ligation and
puncture (CLP), and organ injury and mortality were investigated. Serum inflammatory and anti-inflammatory
cytokine levels were assessed after CLP. Plasma
corticosterone and
adrenocorticotropic hormone levels were also measured. Isolated tissue macrophages (Mfs) were incubated with or without
PACAP, and production of
cytokines was measured. Activation of NF-κB was investigated in tissue Mfs isolated from CLP animal in the presence and absence
PACAP in vitro.
PACAP treatment significantly prevented
acute lung injury and mortality after CLP. Plasma
endotoxin levels and bacterial load were not different between
PACAP-treated and nontreated groups. Increased serum TNF-α and
HMGB1 levels in animals treated with vehicle were significantly blunted in
PACAP-treated animals after CLP. Furthermore, serum
IL-10 levels were significantly greater in the
PACAP-treated group compared with the vehicle group. Production of
HMGB1 and TNF-α by isolated hepatic Mfs was significantly inhibited in the presence of
PACAP, whereas production of
IL-10 by isolated hepatic Mfs and interstitial lung Mfs was significantly increased. Plasma
corticosterone and
adrenocorticotropic hormone levels were significantly greater in the animals treated with
PACAP compared with vehicle after CLP. Activation of NF-κB was significantly inhibited by
PACAP in the hepatic Mfs compared with other tissue Mfs.
PACAP prevents mortality due to septic
peritonitis by inhibiting
inflammation via NF-κB activation and possible effects on the brain.