Differential effects of ebselen on neutrophil recruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation.
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.
Haddad
El-Bdaoui
el-B
Department of Pharmacology, Aventis Pharma, Bridgewater, NJ, 08807-0800, USA. el-bdaoui.haddad@aventis.com
McCluskie
Kerryn
K
Birrell
Mark A
MA
Dabrowski
Dominika
D
Pecoraro
Michela
M
Underwood
Steve
S
Chen
Bei
B
De Sanctis
George T
GT
Webber
Steve E
SE
Foster
Martyn L
ML
Belvisi
Maria G
MG
D000336:Aerosols; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001393:Azoles / Q000008:administration & dosage* / Q000627:therapeutic use; D001980:Bronchi / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000502:physiology; D002630:Chemotactic Factors / Q000096:biosynthesis; D004195:Disease Models, Animal; D006133:Growth Substances / Q000096:biosynthesis; D007249:Inflammation / Q000276:immunology; D007274:Injections, Intraperitoneal; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D054833:Isoindoles; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D008297:Male; D015846:Monokines / Q000096:biosynthesis; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000276:immunology*; D016566:Organoselenium Compounds / Q000008:administration & dosage* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000336:Aerosols; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001393:Azoles; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513297:Cxcl1 protein, rat; C513296:Cxcl2 protein, rat; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D054833:Isoindoles; D008070:Lipopolysaccharides; D015846:Monokines; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C042986:ebselen