We postulated that the seleno-organic compound
ebselen would attenuate neutrophil recruitment and activation after aerosolized challenge with
endotoxin (LPS) through its effect as an
antioxidant and inhibitor of gene activation. Rats were given
ebselen (1-100 mg/kg i.p.) followed by aerosolized LPS exposure (0.3 mg/ml for 30 min). Airway inflammatory indices were measured 4 h postchallenge. Bronchoalveolar lavage (BAL) fluid cellularity and
myeloperoxidase activity were used as a measure of neutrophil recruitment and activation. RT-PCR analysis was performed in lung tissue to assess gene expression of
TNF-alpha,
cytokine-induced neutrophil chemoattractant-1 (CINC-1), macrophage-inflammatory protein-2 (MIP-2),
ICAM-1,
IL-10, and inducible
NO synthase.
Protein levels in lung and BAL were also determined by ELISA.
Ebselen pretreatment inhibited neutrophil influx and activation as assessed by BAL fluid cellularity and
myeloperoxidase activity in cell-free BAL and BAL cell homogenates. This protective effect was accompanied by a significant reduction in lung and BAL fluid
TNF-alpha and
IL-1 beta protein and/or
mRNA levels.
Ebselen pretreatment also prevented lung
ICAM-1 mRNA up-regulation in response to airway challenge with LPS. This was not a global effect of
ebselen on LPS-induced gene expression, because the rise in lung and BAL CINC-1 and MIP-2
protein levels were unaffected as were lung
mRNA expressions for CINC-1, MIP-2,
IL-10, and inducible
NO synthase. These data suggest that the anti-inflammatory properties of
ebselen are achieved through an inhibition of lung
ICAM-1 expression possibly through an inhibition of
TNF-alpha and
IL-1 beta, which are potent neutrophil recruiting mediators and effective inducers of
ICAM-1 expression.