Earlier work from our laboratory has suggested a role for the
neuropeptide substance P (SP) in inducing
lung injury in
sepsis. In that study, mice lacking the
preprotachykinin-A gene, which encodes for SP, were protected against
lung injury in
sepsis. To further substantiate the role of SP in
sepsis and to study its mechanism, we have evaluated the effect of
SR140333, a SP receptor antagonist, on
lung injury in
sepsis, which was induced in male Swiss mice by cecal
ligation and
puncture (CLP).
Sham-operated animals received the same
surgical procedure, except CLP. Vehicle or
SR140333 (1 mg/kg, s.c.) was administered to CLP mice 30 min before or 1 h after the CLP. Eight hours after surgery, lung tissue was collected and analyzed for
myeloperoxidase (MPO) activity,
chemokines,
cytokines, and adhesion molecules. The CLP procedure alone caused a significant increase in the lung levels of MIP-2, MCP-1, IL-1beta,
IL-6,
ICAM-1, E- and
P-selectin, and MPO activity when compared with
sham-operated mice.
SR140333 injected 30 min before or 1 h after CLP significantly attenuated the increased lung MPO activity and levels of MIP-2, MCP-1, IL-1beta,
IL-6,
ICAM-1, and E- and
P-selectin compared with CLP-operated mice injected with the vehicle. Histological evaluation of the lung sections further supported the beneficial effect of
SR140333 on
lung inflammation. Therefore, SP receptor antagonism can be a potential therapeutic target in polymicrobial
sepsis, and this effect is brought about via reduction in leukocyte recruitment.