title: Glucocorticoid-mediated inhibition of neutrophil emigration in an endotoxin-induced rat pulmonary inflammation model occurs without an effect on airways MIP-2 levels.
abstract: 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.
authors.affiliation: Cardiovascular Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: O'Leary
authors.forename: S H
authors.initials: SH
authors.lastname: Zuckerman
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D054426:Chemokine CXCL2; D002630:Chemotactic Factors / Q000096:biosynthesis* / Q000494:pharmacology / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D015846:Monokines / Q000096:biosynthesis* / Q000494:pharmacology / Q000502:physiology; D009504:Neutrophils / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000276:immunology
chemical_list: D054426:Chemokine CXCL2; D002630:Chemotactic Factors; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D015846:Monokines; D003907:Dexamethasone