Well-controlled mucosal exudation of plasma proteins in airways with intact and regenerating epithelium

Abstract

Superficial, systemic microcirculations, distinct from the pulmonary circulation, supply the mucosae of human nasal and conducting airways. Non-injurious, inflammatory challenges of the airway mucosa cause extravasation without overt mucosal oedema. Instead, likely reflecting minimal increases in basolateral hydrostatic pressure, circulating proteins/peptides of all sizes are transmitted paracellularly across the juxtaposed epithelial barrier. Thus, small volumes of extravasated, unfiltered bulk plasma appear on the mucosal surface at nasal and bronchial sites of challenge. Importantly, the plasma-exuding mucosa maintains barrier integrity against penetrability of inhaled molecules. Thus, one-way epithelial penetrability, strict localization, and well-controlled magnitude and duration are basic characteristics of the plasma exudation response in human intact airways. In vivo experiments in human-like airways demonstrate that local plasma exudation is also induced by non-sanguineous removal of epithelium over an intact basement membrane. This humoral response results in a protective, repair-promoting barrier kept together by a fibrin-fibronectin net. Plasma exudation stops once the provisional barrier is substituted by a new cellular cover consisting of speedily migrating repair cells, which may emanate from all types of epithelial cells bordering the denuded patch. Exuded plasma on the surface of human airways reflects physiological microvascular-epithelial cooperation in first line mucosal defense at sites of intact and regenerating epithelium.

Keywords: epithelial regeneration; first line defense; human airway mucosa; maintained epithelial barrier; microvascular‐epithelial cooperation; plasma exudation.

FIGURE 1

Throughout the human nasal and tracheobronchial airways, profuse, highly responsive, systemic microcirculations are juxtaposed with pseudostratified epithelial linings. As illustrated, the “Epithelium” and the “Subepithelial plexus of blood vessels” of the conducting airways (“Tracheobronchial mucosa”) are similarly organized in the “Nasal mucosa.” However, filling of “Venous sinusoids” and constriction of circular “Smooth muscle,” respectively, regulate size of the free lumen in human nasal and tracheobronchial airways. (Previously published, Persson, Svensson, et al., 1992). The guinea‐pig trachea is equipped with a similar subepithelial microcirculation positioned just beneath a pseudostratified epithelial lining (Erjefält et al. 1994, 1996).

FIGURE 2

Schematic illustration of the pathway for microvascular‐epithelial exudation of bulk plasma (broken arrow lines) that agrees with observations in vivo in guinea‐pig trachea and human airways. The intact pseudostratified epithelium is represented by six ciliated cells, two secretory cells, and three basal cells. Mucosal challenges by toxins and infections cause extravasation of bulk plasma through actively regulated inter‐endothelial gaps. The extravasated bulk plasma enters the lamina propria and apparently needs to increase the epithelial basolateral hydrostatic pressure by only 5 cm H₂O or less to drive an unfiltered proteinaceous exudate across the pseudostratified epithelial lining through paracellular pathways. The epithelial passage occurs without overt distention of lateral intercellular spaces and without injury. In vivo, plasma‐derived macromolecular tracers move all‐around epithelial cells up to tight junctions in the area of interest. However, the crucial pathways through the tight junctional belt with all its grooves and ridges remain to be defined and understood to comply with the passage of bulk plasma exudates without altering the mucosal barrier function against penetration of inhaled molecules. Since plasma proteins/peptides are exudated without size restriction, the listed wide range of circulating antimicrobial molecules will also appear on the mucosal surface at the site of challenge. This figure is a slight modification of a previously published version (Persson, 2019b).

FIGURE 3

Non‐sieved plasma exudation (arrow lines) at patchy sites of epithelial loss caused by inflammatory challenges or merely by mechanical removal of epithelium, both interventions being without injury to the basement membrane and without bleeding. The denuded patches are promptly covered and by a neutrophil‐rich plasma exudate gel kept together by a fibrin‐fibronectin net. The gel‐cover is maintained by exuded plasma that provides a molecular milieu in which apparently all epithelial cell types bordering the denuded patch promptly dedifferentiate into rapidly migrating repair cells. Ciliated cells, secretory cells, and basal cells are illustrated. Epithelial repair also induces inflammatory and remodeling effects. The figure is a slight modification of a previously published version (Persson, 2019b). DCC, Dedifferentiating ciliated cell internalizing or shedding its cilia, flattening, and migrating; DRC, dedifferentiated mesenchymal‐like regeneration cells migrating speedily; DSC, dedifferentiating secretory cell releasing its secretory granules, flattening, and migrating; E, eosinophils undergoing primary cytolysis liberating its protein‐releasing granules; IEG, venular inter‐endothelial gaps through which non‐sieved plasma proteins extravasate; N, neutrophils; PFSM, proliferating fibrocytes/smooth muscle cells; TRBM, thickened reticular basement membrane.