Systemic exposure to LPS initiates a complex sequence of events culmin
ating in organ-specific leukocyte recruitment and end organ injury. We
hypothesized that RANTES, a C-C chemokine with potent M phi (mononucl
ear phagocyte) chemotactic activity, is expressed in vivo in response
to endotoxemia, and that this protein may play an important role in th
e recruitment of M phi to the lung. CD-1 mice were challenged with LPS
(200 mu g), resulting in a maximal fourfold increase in polymorphonuc
lear leukocyte (neutrophils) at 6 h post LPS, and a 2.4-fold increase
in numbers of M phi within lung minces at 24 h. A time-dependent incre
ase in RANTES mRNA was detected in lung after LPS treatment, whereas m
inimal quantities of RANTES mRNA were detected in blood buffy coats an
d liver. Furthermore, treatment with LPS resulted in time-dependent in
crease in RANTES protein within lung homogenates, with immunolocalizat
ion to alveolar epithelial cells. The pretreatment of mice with goat a
nti-RANTES Ab significantly inhibited the influx of lung M phi, but no
t polymorphonuclear leukocyte and lymphocytes, at 24 h post-LPS challe
nge. Lastly, the pretreatment of animals with soluble TNF receptor: Ig
construct 2 h before LPS resulted in a 60% reduction in steady state
levels of RANTES mRNA within lung homogenates at 4 h post-LPS. Our obs
ervations suggest that RANTES represents an important mediator of lung
M phi recruitment in the setting of endotoxemia, and that the express
ion of RANTES in vivo is dependent upon the endogenous production of T
NF.