GLUCOCORTICOID EFFECTS IN AN ENDOTOXIN-INDUCED RAT PULMONARY INFLAMMATION MODEL - DIFFERENTIAL-EFFECTS ON NEUTROPHIL INFLUX, INTEGRIN EXPRESSION, AND INFLAMMATORY MEDIATORS

To understand the basis for the refractory nature of acute respiratory distress syndrome (ARDS) to glucocorticoids, the effects of dexametha sone pretreatment (DEX, 2 mg/kg, intraperitoneally) on the kinetics of airway tumor necrosis factor-alpha (TNF alpha) and macrophage inflamm atory protein 2 (MIP-2) production, and polymorphonuclear leukocyte (P MN) influx after intratracheal lipopolysaccharide (LPS) (1 mg/kg) in r ats were investigated. In the absence of exogenous glucocorticoids, TN F alpha and MIP-2 levels in bronchoalveolar lavage (BAL) fluid peaked at 21 and 300 ng, respectively, by 3 h. DEX pretreatment resulted in a 74% reduction in BAL TNF alpha, yet MIP-2 accumulation was unchanged. In addition, DEX reduced PMN influx at 5 h by 58.4% to 4.1 +/- 0.7 x 10(6) PMN (n = 5). DEX, however, did not mitigate the 3-fold increase in total BAL protein observed at 5 h, attributable to albumin influx. The effects of subacute DEX treatment (3.8 mg/kg per day, for 3 days) on cell-surface expression of the adhesion molecules CD11a, CD11b, and L-selectin were determined by flow cytometric analysis of peripheral blood and autologous BAL PMN. Compared with peripheral blood PMN, exud ative PMN had 4-fold greater CD11b expression, no change in CD11a, and loss of L-selectin immunoreactivity 5 h after LPS challenge. The upre gulation of CD11b on exudative PMN was insensitive to DEX pretreatment , which, together with a failure to suppress MIP-2 levels, provides a possible explanation for the lack of efficacy of steroids in the manag ement of ARDS.