Glucocorticoid effects in an endotoxin-induced rat pulmonary inflammation model: differential effects on neutrophil influx, integrin expression, and inflammatory mediators.

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.

Differential Effects of Ebselen on Neutrophil Recruitment, Chemokine, and Inflammatory Mediator Expression in a Rat Model of Lipopolysaccharide-Induced Pulmonary Inflammation

“…Exposure to aerosolized or endotracheally administered rTNF-␣ has been associated with chemokine release in bronchoalveolar lining fluid (59), up-regulation of ICAM-1 on pulmonary vascular endothelium (23), margination of leukocytes in the pulmonary vasculature (60), and neutrophilic infiltration of the interstitium or alveolar septae (60). In agreement with published data, we found that LPS challenge induces TNF-␣ protein and/or mRNA expression in lung tissue and BAL fluid, suggesting an important role of this pleiotropic cytokine in this model (12,44,61). Furthermore, ebselen and dexamethasone were able to inhibit protein and mRNA expression for TNF-␣.…”

“…In rats, modest glucocorticoid effects on LPS-induced lung expression of CINC and MIP-2 have been reported (42,43). The observed effect of dexamethasone on CXC chemokine BAL fluid protein level expression is largely in agreement with published data in which airway CINC-1 and/or MIP-2 expression were unaffected by glucocorticoids (36,44,45). Stimulusspecific differences in glucocorticoid sensitivity may account for the more potent effect of dexamethasone on lung CINC and MIP-2 expression observed in ozone-exposed brown Norway rats (31, 32).…”

The murine neutrophil-chemoattractant chemokines LIX, KC, and MIP-2 have distinct induction kinetics, tissue distributions, and tissue-specific sensitivities to glucocorticoid regulation in endotoxemia

“…In rats, modest glucocorticoid effects on LPS-induced lung expression of KC and MIP-2 have been reported in some studies [52,53]. However, our results for MIP-2 are consistent with recent reports by O'Leary et al, who found no effect of dexamethasone on MIP-2 protein levels in the rat lung in an intratracheal LPS administration model [49,54]. The possible role of endogenous glucocorticoids was not evaluated by O'Leary et al If we assume that MIP-2 is regulated similarly in rats and mice, our results extend those of O'Leary et al by showing that the lack of effect of dexamethasone on MIP-2 lung expression is not due to masking by the effects of the endogenous glucocorticoid response (as is the case for LIX).…”

β2-Adrenergic receptor-dependent sexual dimorphism for murine leukocyte migration

“…Stress can affect inflammatory diseases (see Black, 2002(Black, 2002a for review), in part mediated by the effect of stress hormones on leukocyte function (Bierhaus et al, 2006;Bilbo et al, 2002;Dhabhar, 2002;Landmann et al, 1984;O'Leary et al, 1996;Shephard, 2003), and catecholamines mediate interactions between the sympathetic and the immune systems, to alter immune cell activity (Benschop et al, 1997;Downing and Miyan, 2000;Elenkov et al, 2000;Oberbeck, 2006;Straub et al, 1998). Norepinephrine, released from sympathetic nerve terminals, and epinephrine, released from the adrenal medulla (Elenkov et al, 2000), act primarily on α 2 and β 2 adrenergic receptors expressed on most resting and activated immune cells (Barnes, 1995;Barnes, 1999;Kin and Sanders, 2006;Maestroni, 2006;Wahle et al, 2005).…”