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

El-Bdaoui Haddad^*,, Stephen L. Underwood^*,, Dominika Dabrowski^*, Mark A. Birrell, Kerryn McCluskie, Cliff H. Battram^¶, Michaela Pecoraro^*, Martyn L. Foster and Maria G. Belvisi^1,

^* Pharmacology Department, Dagenham, United Kingdom; Respiratory and RA Disease Group, Aventis Pharma, Bridgewater, NJ 08807; Respiratory Pharmacology, Cardiothoracic Surgery, Imperial College School of Medicine, National Heart and Lung Institute, London, United Kingdom; AstraZeneca, Charnwood, United Kingdom; and ^¶ Novartis, Horsham, United Kingdom

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 -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.

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				M. G. Belvisi, D. S. Bundschuh, M. Stoeck, S. Wicks, S. Underwood, C. H. Battram, E.-B. Haddad, S. E. Webber, and M. L. Foster Preclinical Profile of Ciclesonide, a Novel Corticosteroid for the Treatment of Asthma J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 568 - 574. [Abstract] [Full Text] [PDF]

				M. A. Birrell, K. McCluskie, E.-B. Haddad, C. H. Battram, S. E. Webber, M. L. Foster, M. H. Yacoub, and M. G. Belvisi Pharmacological Assessment of the Nitric-Oxide Synthase Isoform Involved in Eosinophilic Inflammation in a Rat Model of Sephadex-Induced Airway Inflammation J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 1285 - 1291. [Abstract] [Full Text] [PDF]