A new look at the pathogenesis of asthma.
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 in general 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 made that 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 to disease 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 more targeted 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.
Holgate
Stephen T
ST
University of Southampton, Southampton General Hospital, UK. sth@soton.ac.uk
Arshad
Hasan S
HS
Roberts
Graham C
GC
Howarth
Peter H
PH
Thurner
Philipp
P
Davies
Donna E
DE
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000485:Allergens / Q000009:adverse effects; D001249:Asthma / Q000209:etiology* / Q000276:immunology; D002648:Child; D002908:Chronic Disease; D018450:Disease Progression; D006801:Humans; D007113:Immunity, Innate; D012141:Respiratory Tract Infections / Q000150:complications; D055815:Young Adult
D000485:Allergens