EC O'Leary and SH Zuckerman
Cardiovascular Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.

In an intratracheal endotoxin lipopolysaccharide (LPS) challenge model of acute lung injury, we recently reported that while dexamethasone (DEX) at 2 to 4 mg/kg reduced neutrophil (PMN) emigration into the airways, bronchoalveolar lavage (BAL) fluid contained substantial amounts of immunoreactive macrophage inflammatory protein-2 (MIP-2). In the present study, DEX in quantities up to 30 mg/kg further reduced PMN influx, but MIP-2 levels were unaffected 3 h following LPS challenge. MIP-2 in 3-h BAL samples from DEX- or vehicle-pretreated animals was bioactive and approximately 75% of the ex vivo chemotactic activity was neutralized by polyclonal antirat MIP-2. In contrast to the in vivo studies, DEX significantly suppressed MIP-2 synthesis from LPS- stimulated rat alveolar macrophages in vitro. Ex vivo chemotactic activity was comparable between BAL samples from DEX- and vehicle- pretreated rats. Chemotaxis of rat PMN to recombinant MIP-2 exhibited a bell-shaped concentration-response profile in vitro with optimal activity at 17.6 ng/ml and this was shifted 16-fold to the right by antirat MIP-2. Three-hour BAL MIP-2 (10.73 +/- 0.45 ng/ml) correlated with the ascending limb of the recombinant rat MIP-2 concentration- response profile. In addition to inhibiting chemotaxis, antirat MIP-2 also reduced the chemokinetic response to 3-h BAL fluid by 84%. The present study demonstrates that in vivo MIP-2 is bioactive, and because its synthesis within the rat lung is resistant to DEX it is likely to play a significant role in glucocorticoid refractory PMN influx within the airways during acute lung injury.

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