Department of Medical History

Contennial notions of asthma as an eosinophilic, desquamative, exudative, and steroid-sensitive disease

This review discusses in vivo airway aspects of plasma exudation in relation to current views on epithelial permeability and epithelial regeneration in health and disease. Microvascular-epithelial exudation of bulk plasma proteins characteristically occurs in asthmatic patients, being especially pronounced in those with severe and exacerbating asthma. Healthy human and guinea pig airways challenged by noninjurious histamine-leukotriene–type autacoids also respond through prompt mucosal exudation of nonsieved plasma macromolecules. Contrary to current beliefs, epithelial permeability in the opposite direction (ie, absorption of inhaled molecules) has not been increased in patients with asthma and allergic rhinitis or in acutely exuding healthy airways. A slightly increased subepithelial hydrostatic pressure produces such unidirectional outward perviousness to macromolecules. Lack of increased absorption permeability in asthmatic patients can further be reconciled with occurrence of epithelial shedding, leaving small patches of denuded basement membrane. Counteracting escalating barrier breaks, plasma exudation promptly covers the denuded patches. Here it creates and sustains a biologically active barrier involving a neutrophil-rich, fibrin-fibronectin net. Furthermore, in the plasma-derived milieu, all epithelial cell types bordering the denuded patch dedifferentiate and migrate from all sides to cover the denuded basement membrane. However, this speedy epithelial regeneration can come at a cost. Guinea pig in vivo studies demonstrate that patches of epithelial denudation regeneration are exudation hot spots evoking asthma-like features, including recruitment/activation of granulocytes, proliferation of fibrocytes/smooth muscle cells, and basement membrane thickening. In conclusion, nonsieved plasma macromolecules can operate on the intact airway mucosa as potent components of first-line innate immunity responses. Exuded plasma also takes center stage in epithelial regeneration. When exaggerated, epithelial regeneration can contribute to the inception and development of asthma.

Glucocorticoids are widely used to treat various inflammatory lung diseases. Acting via the glucocorticoid receptor (GR), they exert clinical effects predominantly by modulating gene transcription. This may be to either induce (transactivate) or repress (transrepress) gene transcription. However, certain individuals, including those who smoke, have certain asthma phenotypes, chronic obstructive pulmonary disease (COPD) or some interstitial diseases may respond poorly to the beneficial effects of glucocorticoids. In these cases, high dose, often oral or parental, glucocorticoids are typically prescribed. This generally leads to adverse effects that compromise clinical utility. There is, therefore, a need to enhance the clinical efficacy of glucocorticoids while minimizing adverse effects. In this context, a long-acting β₂-adrenoceptor agonist (LABA) can enhance the clinical efficacy of an inhaled corticosteroid (ICS) in asthma and COPD. Furthermore, LABAs can augment glucocorticoid-dependent gene expression and this action may account for some of the benefits of LABA/ICS combination therapies when compared to ICS given as a monotherapy. In addition to metabolic genes and other adverse effects that are induced by glucocorticoids, there are many other glucocorticoid-inducible genes that have significant anti-inflammatory potential. We therefore advocate a move away from the search for ligands of GR that dissociate transactivation from transrepression. Instead, we submit that ligands should be functionally screened by virtue of their ability to induce or repress biologically-relevant genes in target tissues. In this review, we discuss pharmacological methods by which selective GR modulators and “add-on” therapies may be exploited to improve the clinical efficacy of glucocorticoids while reducing potential adverse effects.

The current exclusive focus on airway inflammation and remodelling in asthma and chronic obstructive pulmonary disease has dwarfed the interest in simple relaxation of the bronchi. This commentary highlights the particular importance of reducing smooth muscle constriction of human small airways in these obstructive diseases. Furthermore, the need of novel drugs in this area is underscored by in vitro and in vivo data demonstrating limited small airway relaxant efficacy of currently available bronchodilators.

Pathogenic granulocytes (eosinophils and neutrophils) infiltrate airway tissues in asthma and chronic obstructive pulmonary disease. Granulocytes release tissue-toxic and inflammatory mediators, making their removal an important pharmacological goal. Removal is thought to be accomplished through apoptosis followed by engulfment by macrophages. Thus, the molecular mechanisms of granulocyte apoptosis have been unravelled and pro-apoptotic actions that target granulocytes have been proposed as desirable features of future airway drugs. However, observations in vitro and in airway lumen that support this role of granulocyte apoptosis translate poorly to airway tissues in vivo. Either apoptosis cannot be demonstrated, even at the resolution of airway inflammation, or, when significant granulocyte apoptosis is induced in airway tissues in vivo, there is insufficient engulfment of apoptotic granulocytes. Therefore, apoptotic eosinophils and neutrophils in airway tissues undergo secondary necrosis, causing inflammation. As an alternative or complement to the apoptosis hypothesis, in vivo work indicates that egression to the airway lumen can produce swift non-injurious removal of tissue granulocytes. Once in the airway lumen, granulocytes can undergo apoptosis and engulfment, be trapped by secretions and plasma exudates and be removed by mucociliary escalator mechanisms. In this article, we propose that egression into the airway lumen is an effective mode of inflammatory cell disposal that connotes novel drug opportunities.