Abstract

To understand the basis for the refractory nature of acute respiratory distress syndrome (ARDS) to glucocorticoids, the effects of dexamethasone pretreatment (DEX, 2 mg/kg, intraperitoneally) on the kinetics of airway tumor necrosis factor-alpha (TNF alpha) and macrophage inflammatory protein 2 (MIP-2) production, and polymorphonuclear leukocyte (PMN) influx after intratracheal lipopolysaccharide (LPS) (1 mg/kg) in rats were investigated. In the absence of exogenous glucocorticoids, TNF 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, exudative PMN had 4-fold greater CD11b expression, no change in CD11a, and loss of L-selectin immunoreactivity 5 h after LPS challenge. The upregulation 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 management of ARDS.