‘Bedside’ observations challenge aspects of the ‘epithelial barrier hypothesis’

Early humoral defense under the radar: microvascular-epithelial cooperation at airways infection in asthma and health

“…One consequence is a lack of attention to roles of biologically active, plasma-derived molecules in early mucosal defense. Yet, in environmentally challenged airways, perhaps particularly in asthmatic bronchi ( 5 ), swift microvascular-epithelial transmission of nonsieved plasma peptides/proteins contributes prompt antimicrobial opportunities ( 6 , 7 ).…”

“…At the primary site of respiratory infections, the human conducting airways ( 8 ), nonsieved plasma-derived macromolecules are transmitted across an intact epithelial lining without impeding the normal airway barrier against cenvironmental challenges ( 5 – 7 ). This direction-dependent asymmetry is a crucial, but overlooked ( 7 ), operational feature of the airway pseudostratified epithelial lining. Bedside and in vivo data suggest that exudation of plasma-derived peptides/proteins at the airway level has capacity to reduce progression of COVID-19 into severe pulmonary stages and beyond.…”

“…As a significant pathogenic component of severe COVID-19, the pulmonary circulation leaks fluid and protein across injured endothelial and alveolar linings ( 3 , 6 ). This acute respiratory distress syndrome (ARDS)-like lung plasma leak condition is entirely distinct from the plasma exudation responses that operate at airways defense ( 5 – 7 , 9 ). Hence, extravasation of plasma from the systemic subepithelial microcirculation of human conducting airways must not be confused with poorly reversible, pathogenic leak of plasma from the low-pressure pulmonary microcirculation.…”

“…Depending on type and level of environmental challenge, the venules will leak plasma and the overlying epithelium promptly transmits extravasated plasma, for brief, biphasic, or quite prolonged but still well-controlled lengths of time ( 5 , 6 ). Experimental data indicate that the extravasated plasma itself, by slightly increasing the hydrostatic pressure that impacts on basolateral epithelial aspects, opens valve-like paracellular pathways for its own transmission across the pseudostratified epithelial lining ( 5 , 7 ). Actively regulated, venular endothelial gap formation thus caters for localized occurrence and tightly controlled duration of plasma exudation responses in conducting airways ( 6 ).…”

“…Swift epithelial transmission of bulk plasma molecules, in human and guinea pig airways, occurs without injury and without compromising the epithelial absorption barrier ( 5 – 7 , 11 , 13 – 16 ). Consistent with such dramatic, unidirectional penetrability of the pseudostratified epithelial lining, operating when approached from beneath, lymphatic protein transport may not increase ( 10 ) and edema has not been induced at mucosal challenge-induced plasma exudation ( 5 ).…”