Asma

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Clinical Science (2010) 118, 439–450 (Printed in Great Britain) doi:10.1042/CS20090474
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A new look at the pathogenesis of asthma
Stephen T. HOLGATE∗ , Hasan S. ARSHAD∗ , Graham C. ROBERTS∗ , Peter H. HOWARTH∗ , Philipp THURNER† and Donna E. DAVIES∗


Division of Infection, Inflammation and Immunity, University of Southampton, SouthamptonGeneral Hospital, Southampton SO16 6YD, U.K., and †Bioengineering Sciences Research Group, University of Southampton, Southampton, SO17 1BJ, U.K.

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Asthma is an inflammatory disorder of the conducting airways that has strong association with allergic sensitization. The disease is characterized by a polarized Th-2 (T-helper-2)-type T-cell response, but ingeneral targeting this component of the disease with selective therapies has been disappointing and most therapy still relies on bronchodilators and corticosteroids rather than treating underlying disease mechanisms. With the disappointing outcomes of targeting individual Th-2 cytokines or manipulating T-cells, the time has come to re-evaluate the direction of research in this disease. A case is madethat asthma has its origins in the airways themselves involving defective structural and functional behaviour of the epithelium in relation to environmental insults. Specifically, a defect in barrier function and an impaired innate immune response to viral infection may provide the substrate upon which allergic sensitization takes place. Once sensitized, the repeated allergen exposure will lead todisease persistence. These mechanisms could also be used to explain airway wall remodelling and the susceptibility of the asthmatic lung to exacerbations provoked by respiratory viruses, air pollution episodes and exposure to biologically active allergens. Variable activation of this epithelial–mesenchymal trophic unit could also lead to the emergence of different asthma phenotypes and a moretargeted approach to the treatment of these. It also raises the possibility of developing treatments that increase the lung’s resistance to the inhaled environment rather than concentrating all efforts on trying to suppress inflammation once it has become established.

INTRODUCTION
Asthma is an inflammatory disorder of the conducting airways which undergo distinct structural and functional changes,leading to non-specific BHR (bronchial hyperresponsiveness) and airflow obstruction that fluctuates over time. It is among the commonest chronic conditions in Western countries affecting 1 in 7 children and 1 in 12 adults (equivalent to 5.1 million people in the U.K.), and is responsible each year for 1500 avoidable deaths, as well as 20 million lost working days. The annual U.K. healthcare cost isestimated to be £2.5

billion. A recent assessment of asthma across Europe (Brussels Declaration) has identified substantial unmet clinical need which, in the 10 % of patients with severe disease, accounts for approx. 50 % of the health costs [1]. Most, but not all, asthma is associated with atopy (the inherited predisposition to generate IgE against common environmental allergens). This has ledasthma to be regarded largely as an allergic disorder along with other atopic diseases. However, asthma prevention has not been achieved with allergen-reduction strategies, once established there is no cure and there are currently no

Key words: allergen, asthma, inflammation, remodelling, T-cell, virus infection. Abbreviations: BHR, bronchial hyper-responsiveness; CT, computed tomography; DC,dendritic cell; ADC, airway DC; EBUS, endobronchial ultrasound; EMTU, epithelial–mesenchymal trophic unit; ETS, environmental tobacco smoke; IFN, interferon; IL, interleukin; IoW, Isle of Wight; LT, leukotriene; mAb, monoclonal antibody; RV, rhinovirus; TGF-β, transforming growth factor-β; Th-2, T-helper-2; TJ, tight junction; TSLP, thymic stromal lymphopoietin. Correspondence: Professor Stephen T....
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