- The role of the epithelium in asthma
- The link between the epithelium, inflammation and remodeling
- Mechanisms of the asthma exacerbation
- Rethinking the cause and pathophysiology of asthma
The Pathophysiology of asthma across the lifecourse
The role of the epithelium in asthma. My research has focused on the causes of human asthma and its treatment. After establishing the key role that mast cells and other key effector cells play in triggering the acute allergic inflammatory response in asthma, I have focused my attention upon the mechanisms of disease chronicity and variability across the lifecourse. Using airway biopsies and primary cell cultures, we have established that asthma is primarily a disease of the lung epithelium that originates during fetal lung development. The disordered epithelium increases susceptibility to injury and altered repair after birth. This new concept was captured by describing sustained activation of the epithelial mesenchymal trophic unit (EMTU) in asthma. There is a dynamic communication between the epithelium and underlying mesenchyme that is established during the development of the fetal lung. We describe how varied activation of the EMTU connects the origins of asthma to its progression over time. This involves increased epithelial susceptibility to oxidant injury, impaired barrier function and reduced innate immunity. It also embraces altered mesenchymal susceptibility to promote airway remodelling such as the enhanced secretion of the metalloprotease enzyme, ADAM33, and a tendency for mesenchymal progenitor cells to adopt a contractile muscle-type phenotype.
The link between the epithelium, inflammation and remodeling. A key question that has arisen from this work is whether the “set point” for a chronic wound response by the asthmatic epithelium upon environmental injury is fundamentally altered. We have now shown that gene transcription factors involved in the differentiation of airway and alveolar epithelium in fetal lung (e.g. TTF-1, spdef, Foxa2) are also involved in asthma where their differential expression strongly promoted a mucus-secreting phenotype as functionally confirmed in the airways of mice by conditional expression or deletion of the TTF-1 gene. Moreover, the reduced epithelial TTF-1 expression in asthma not only increased mucus secretion, but also the capacity of the airways to express allergic-type inflammatory and tissue remodelling profiles in response to allergen exposure. These experiments provide strong additional support for the view that, through the EMTU, the airway epithelium plays a crucial role in orchestrating multiple cellular events of asthma.
While remodelling of the airways in asthma could occur secondary to chronic inflammation, anti-inflammatory drugs (such as corticosteroids) have limited effect on this component. We now propose that distortion of a hypersensitive and chronically damaged epithelium by repeated bronchoconstriction is also capable of driving remodelling, possibly as an initial protective response. We found that the the early asthmatic response provoked by inhaled allergen (inflammatory stimulus) or methacholine (non-inflammatory stimulus) produced similar increases in airway remodelling. As predicted, only allergen triggered eosinophil influx into the airways in association with the inflammatory response of the late asthmatic response. Prevention of methacholine-induced bronchoconstriction by prior administration of the inhaled2-agonist (salbutamol) completely inhibited the indices of remodelling. This indicates that repeated narrowing of asthmatic airways per se provides a sufficient stimulus for inducing “mechanotransductive” airway remodelling.
Mechanisms of the asthma exacerbation. A major cause of asthma morbidity and death is the exacerbation in which deterioration in disease control occurs over several days. Although allergen exposure is one cause of disease exacerbation, in real life this accounts for only a small proportion of events. On the basis of clinical anecdote many asthma exacerbations appeared to be precipitated by respiratory viral infections. To obtain concrete evidence for this, we first established novel PCR-based methods for the detection of common cold human rhinoviruses (RV). Viral detection was then applied to longitudinal cohort studies to reveal that detection of respiratory viruses in nasopharyngeal secretions was closely linked to asthma exacerbation and its seasonal variation both in children (>85%) and adults (>65%), with RV dominating.
We were the first to establish causality by controlled nasal infection of asthmatics with RV16 precipitating clinical and physiological features of exacerbation driven by mixed eosinophilic and lymphocyte inflammation of the lower airways. A key question was why asthmatic airways are so susceptible to usually innocuous common cold viruses? Controlled nasal infection with RV16 to revealed preferential infection of the asthmatic lower airway epithelium. In order to determine if viral responses of the asthmatic epithelium differed from that of normals, epithelial cell cultures infected with RV16 were developed. While epithelial cells from normal subjects could effectively inhibit viral replication and eliminate remaining virus through activation of programmed cell death (apoptosis), those derived from asthmatic airways not only enabled the virus to survive, but also facilitated viral replication leading to cytotoxic cell death, inflammatory mediator release and enhanced virus shedding. We have shown that this asthma-related defect was due to impaired signalling by the microsomal danger recognition receptor, toll-like receptor 3 (TLR3), following interaction with viral double stranded RNA. The consequence of this was reduced (IFN)- mediated anti-viral defense. This defect in IFN production could in large part explained by enhanced epithelial production of TGF-β and represents yet a further consequence of EMTU activation in asthma. Of great significance was our finding that full anti-viral defense could be restored to the asthmatic epithelium by adding back a low concentration of IFNwhereas under natural conditions of virus infection, the defective local IFN induction was compensated by a large systemic innate TLR/IFN immune response and a weaker adaptive immune response.
In order to translate these findings into the clinic we first showed that inhaled IFN-1a could activate the airway anti-viral pathways in asthma. We have now completed a successful Phase 2 clinical trial showing that inhaled recombinant human IFN-1a given at the start of a common cold in patients with severe asthma could fully restore protection against viral-related exacerbations as well as reduce viral shedding (http://www.synairgen.com/).
Rethinking the cause and pathophysiology of asthma. These observations are leading to a fundamental re-evaluation of asthma pathogenesis. Rather than allergic inflammation being the prime abnormality, our work places the airway epithelium at the centre of disease pathogenesis by, serving as the orchestrator of inflammatory and remodelling responses over the lifecourse. The engagement of different causative molecular pathways leads to disease heterogeneity which is reflected in the variable response to therapeutics in accordance with the relative contribution of that pathway to the overall disease manifestation. This forms the basis for a more stratified or personalized approach to treatment which is especially important for the highly targeted new biologics.