COMPARTMENTALIZED EXPRESSION OF RANTES IN A MURINE MODEL OF ENDOTOXEMIA

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.