PRINCIPLES OF ASTHMA MEDICINE 36:4 177 © 2008 Elsevier Ltd. All rights reserved. Mechanisms of asthma Chris Corrigan Abstract Asthma is a syndrome of variable airflow obstruction. It is character- ized pathologically by bronchial inflammation with prominent eosinophil infiltration and remodelling changes, physiologically by bronchial hyper- responsiveness, and clinically by cough, chest tightness and wheeze. Cytokines secreted by CD4+ Th2 type T cells play a major role in co- ordinating asthmatic bronchial inflammation and remodelling, while other effector cells, particularly eosinophils and myofibroblasts, play an intermediary role in airways damage and remodelling. Although the patho- logical changes in the airways in association with asthma are now well described, there is a gap in our understanding of precisely how these changes cause clinical symptoms. A key aetiological factor for asthma is exposure to inhaled allergens, including occupational allergens, which are probably a major drive to T cell activation in asthma. Genetic factors governing the production of T cell cytokines and their actions on target cells, as well as variability in the structure and development of the mesenchymal elements of the bronchial mucosa, influence the risk of developing asthma. Many other environmental agents exacerbate asthma but the evidence that they cause disease is much less clear. Keywords asthma; atopy; cytokine; eosinophil; pathogenesis; remodelling; T cell Clinical pathology The diagnosis of asthma is made on the basis of typical symp- toms and abnormalities in lung function. The key clinical fea- tures of asthma include the following. Variable airways obstruction – airways obstruction in asthma, as measured by spirometry, may vary spontaneously from none to severe in the course of hours to minutes, and improves after suitable therapy. Obstruction, particularly of the smaller airways, in asthmatics causes shortness of breath, impaired exercise toler- ance, tightness in the chest which may be perceived as wheeze, and chest hyperinflation (small airways obstruction prevents complete emptying of the alveoli, causing gas trapping). Non-specific bronchial hyperreactivity – this refers to the tendency of asthmatic airways to constrict in response to a whole host of non-specific (that is, non-immunological) stimuli Chris Corrigan MA MSc PhD FRCP is Professor of Asthma, Allergy and Respiratory Science at King’s College London School of Medicine and the MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, and Consultant Physician at Guy’s and St Thomas’ NHS Foundation Trust, London, UK. Competing interests: none declared. (including for example strong smells, cold air, fog, smoke, exercise, aerosol sprays, dust) that would not cause clinically significant bronchoconstriction in non-asthmatics. Bronchial hyperreactivity causes excessive cough and contributes to bronchospasm, which may have different triggers in different patients. Histopathology Asthma is characterized by inflammatory changes throughout the airways, but not the alveoli or lung parenchyma. The inflam- mation is characterized by the activation of CD4+ helper T lymphocytes, 1 as well as a selective accumulation of eosinophil leukocytes in the bronchial mucosa (Figures 1 and 2), 2 although these changes do not allow a definitive diagnosis on histopatho- logical grounds. Some chronic, severe asthmatics show a paucity of mucosal eosinophils, but a more prominent neutrophil leuko- cyte infiltrate. 3 Mast cells are present in the bronchial mucosa, as they are at all mucosal surfaces, but their numbers are not par- ticularly elevated in asthmatics. It has so far not been possible to associate aetiological subdivisions of asthma with reproducible and discernible variability in histopathology. Asthma is also associated with structural changes in the air- ways collectively termed ‘airways remodelling’ (Figure 3). 4,5 These include hypertrophy and hyperplasia of airways smooth muscle cells, increased numbers of mucous goblet cells in the airways epithelium, laying down of fibrous proteins (including collagen, fibronectin and tenascin) beneath the epithelial base- ment membrane and in the submucosa, and neovascularization (proliferation of vascular capillary beds within the submucosa). Pathophysiology Asthmatic inflammation appears to be coordinated principally by activated CD4+ T lymphocytes of the Th2 type phenotype, characterized particularly by the production of the cytokines interleukin (IL)-4, IL-13 and IL-5 (Figure 2). 1 The cytokine IL-5 acts on eosinophils, while IL-4 and IL-13 up-regulate adhesion molecules in the capillary endothelium of the bronchial mucosa, Figure 1 Section of an airway from a patient who died of acute asthma stained with haematoxylin and eosin. Eosinophils (‘eosin loving’) cells stain pink because of their basic proteins. Note the intense eosinophil infiltrate in the submucosa A the bronchial epithelium B and surrounding the large mucus plug which is occluding the lumen of the bronchiole C.