Critical role for T cells in Sephadex-induced airway inflammation: pharmacological and immunological characterization and molecular biomarker identification.
Intratracheal instillation of Sephadex particles is a convenient model for assessing the impact of potential anti-inflammatory compounds on lung eosinophilia thought to be a key feature in asthma pathophysiology. However, the underlying cellular and molecular mechanisms involved are poorly understood. We have studied the time course of Sephadex-induced lung eosinophilia, changes in pulmonary T cell numbers, and gene and protein expression as well as the immunological and pharmacological modulation of these inflammatory indices in the Sprague Dawley rat. Sephadex increased T cell numbers (including CD4(+) T cells) and evoked a pulmonary eosinophilia that was associated with an increase in gene/protein expression of the Th2-type cytokines IL-4, IL-5, and IL-13 and eotaxin in lung tissue. Sephadex instillation also induced airway hyperreactivity to acetylcholine and bradykinin. A neutralizing Ab (R73) against the alphabeta-TCR caused 54% depletion of total (CD2(+)) pulmonary T cells accompanied by a significant inhibition of IL-4, IL-13 and eotaxin gene expression together with suppression (65% inhibition) of eosinophils in lung tissue 24 h after Sephadex treatment. Sephadex-induced eosinophilia and Th2 cytokine gene and/or protein expression were sensitive to cyclosporin A and budesonide, compounds that inhibit T cell function, suggesting a pivotal role for T cells in orchestrating Sephadex-induced inflammation in this model.
Haddad
El-Bdaoui
el-B
Pharmacology Department, Dagenham, United Kingdom. Respiratory and RA Disease Group, Aventis Pharma, Bridgewater, NJ 08807, USA.
Underwood
Stephen L
SL
Dabrowski
Dominika
D
Birrell
Mark A
MA
McCluskie
Kerryn
K
Battram
Cliff H
CH
Pecoraro
Michaela
M
Foster
Martyn L
ML
Belvisi
Maria G
MG
D000109:Acetylcholine / Q000008:administration & dosage; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015415:Biomarkers / Q000032:analysis; D001920:Bradykinin / Q000008:administration & dosage; D016535:Bronchial Hyperreactivity / Q000139:chemically induced; D019819:Budesonide / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016572:Cyclosporine / Q000627:therapeutic use; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003911:Dextrans / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008212:Lymphocyte Depletion; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D016207:Cytokines; D003911:Dextrans; D007376:Interleukin-2; D019819:Budesonide; D016572:Cyclosporine; C025614:sephadex; D000109:Acetylcholine; D001920:Bradykinin