Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification

• Published in: The Journal of immunology (1950) 2002-03, Vol.168 (6), p.3004-3016
• Main Authors: Haddad, El-Bdaoui, Underwood, Stephen L, Dabrowski, Dominika, Birrell, Mark A, McCluskie, Kerryn, Battram, Cliff H, Pecoraro, Michaela, Foster, Martyn L, Belvisi, Maria G
• Format: Article
• Language: English
• Subjects: Acetylcholine - administration & dosage; Animals; Antibodies, Monoclonal - administration & dosage; Biomarkers - analysis; Bradykinin - administration & dosage; Bronchial Hyperreactivity - chemically induced; Budesonide - therapeutic use; Cell Movement - drug effects; Cell Movement - immunology; Cells, Cultured - drug effects; Cells, Cultured - immunology; Cells, Cultured - metabolism; Cyclosporine - therapeutic use; Cytokines - biosynthesis; Cytokines - genetics; Dextrans - toxicity; Gene Expression Regulation - drug effects; Gene Expression Regulation - immunology; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - immunology; Inflammation - metabolism; Interleukin-2 - biosynthesis; Intubation, Intratracheal; Lung - drug effects; Lung - immunology; Lung - metabolism; Lung - pathology; Lymphocyte Depletion; Male; Mast Cells - drug effects; Mast Cells - immunology; Pulmonary Eosinophilia - chemically induced; Pulmonary Eosinophilia - immunology; Rats; Rats, Sprague-Dawley; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Time Factors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.168.6.3004

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.