Airways exudation of plasma macromolecules: Innate defense, epithelial regeneration, and asthma

Abstract

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.

Comment on review article by Kristina Johansson and Henry McSorley

“…Bodies constituted of epithelial cells clumped together and occurring in airway lumen material have been named Creola bodies by Naylor who demonstrated numerous Creola bodies in association with exacerbations of asthma. However, Creola bodies, as a sign of widespread, small patches of epithelial denudation, may also be a prominent feature of RSV infection. Indeed, in RSV‐infected infants Creola bodies in aspirates may be a prerequisite for the infection to be followed by development of asthma.…”

“…Effects of epithelial loss in vivo have been rarely investigated partly since the common mouse models of asthma lack this feature . With guinea pigs, it is different.…”

“…With guinea pigs, it is different. Allergen challenge of sensitized animals causes epithelial loss at distinct tracheobronchial patches, which are hot spots of inflammation and epithelial regeneration . Further, experimental removal, in vivo, of airway epithelial cells, without bleeding and leaving an intact basement membrane (as occurs in asthma), results in local asthma‐like features, which include sustained plasma exudation (establishing a provisional fibrinous barrier and a biologically highly active defence and cell regeneration milieu), mucus hyper‐secretion, recruitment and activation of granulocytes, proliferation of epithelial and smooth muscle cells, and thickened reticular basement membrane …”

“…Beyond participation of all plasma protein systems, molecular pathways involved in the pure epithelial regeneration‐induced effects listed above have not been determined. However, it is expected that IL‐33 as well as TSLP (thymic stromal lymphopoietin) would be released from such stressed epithelium.…”

“…Yet epithelial integrity may be well maintained in airways exuding proteins. Indeed, in its basic shape increased airways exudation of bulk plasma proteins is a first‐line innate defence mechanism—it does not derange the epithelial lining, and the barrier towards inhaled molecules remains intact . Hence, the numerous failures to support the popular idea of increased permeability to allergens, etc, in vivo in human asthma are well compatible with the occurrence of plasma exudation in this disease …”