Differential effects of ebselen on neutrophil recruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation. Journal of immunology (Baltimore, Md. : 1950) [J Immunol] Journal article | | Title | Differential effects of ebselen on neutrophil recruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation. | | Author(s) | Haddad el-B, McCluskie K, Birrell MA, Dabrowski D, Pecoraro M, Underwood S, Chen B, De Sanctis GT, Webber SE, Foster ML, Belvisi MG | | Institution | Department of Pharmacology, Aventis Pharma, Bridgewater, NJ, 08807-0800, USA. el-bdaoui.haddad@aventis.com | | Source | J Immunol 2002 Jul 15; 169(2):974-82. | | MeSH | Aerosols
Animals
Anti-Inflammatory Agents, Non-Steroidal
Azoles
Bronchi
Bronchoalveolar Lavage Fluid
Chemokines, CXC
Chemotactic Factors
Comparative Study
Disease Models, Animal
Growth Substances
Inflammation
Injections, Intraperitoneal
Intercellular Adhesion Molecule-1
Intercellular Signaling Peptides and Proteins
Interleukin-1
Lipopolysaccharides
Lung
Male
Monokines
Neutrophil Infiltration
Organoselenium Compounds
RNA, Messenger
Rats
Tumor Necrosis Factor-alpha
Up-Regulation
| | Abstract | 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. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 12097404 |
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