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• Can airways endothelial-epithelial cooperation stop Covid-19’s march to the lung?
  Carl Persson
  Published on: 9 June 2022

• Published on: 9 June 2022

  Can airways endothelial-epithelial cooperation stop Covid-19’s march to the lung?

  • Carl Persson, emeritus professor Laboratory Medicine University Hospital of Lund, Lund, Sweden

  The state-of-the-art-review by Bridges et al. (1) entitled “Respiratory epithelial responses to SARS-CoV-2 in COVID-19” admirably updates current concepts ranging from bedside observations to cell signaling. The authors emphasize epithelial interferon/cytokine defense in upper airways, where infection starts. Advanced Covid-19 is then depicted involving alveolar and capillary injury with uncontrolled leakage of plasma from the pulmonary microcirculation (1).

  The subepithelial microcirculations that carry oxygenized blood to nasal, tracheal, and bronchial mucosae are not mentioned. Yet, infection of these conducting airways causes exudation of plasma proteins with well-known antimicrobial defense capacities. Furthermore, contrasting protein leak at lung injury (1), the airways exudative response reflects well-controlled physiological microvascular-epithelial cooperation (2).

  Minimal size-selectivity at exudation of plasma across endothelial-epithelial barriers.
  Observations in infected airways, allergic disease and mediator challenge demonstrate unfiltered and well-controlled plasma exudation responses in human airways. Lack of size-selectivity means that potent cascade systems (complement, kinin/kallikrein, coagulation) and natural antibodies (IgG,IgM) emerge locally, along with albumin, on engaged airway epithelial sites (3-13). Even cathelicidine, representing antimicrobial peptides, arrives on the affected airway surface exclusively as component of...

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  The state-of-the-art-review by Bridges et al. (1) entitled “Respiratory epithelial responses to SARS-CoV-2 in COVID-19” admirably updates current concepts ranging from bedside observations to cell signaling. The authors emphasize epithelial interferon/cytokine defense in upper airways, where infection starts. Advanced Covid-19 is then depicted involving alveolar and capillary injury with uncontrolled leakage of plasma from the pulmonary microcirculation (1).

  The subepithelial microcirculations that carry oxygenized blood to nasal, tracheal, and bronchial mucosae are not mentioned. Yet, infection of these conducting airways causes exudation of plasma proteins with well-known antimicrobial defense capacities. Furthermore, contrasting protein leak at lung injury (1), the airways exudative response reflects well-controlled physiological microvascular-epithelial cooperation (2).

  Minimal size-selectivity at exudation of plasma across endothelial-epithelial barriers.
  Observations in infected airways, allergic disease and mediator challenge demonstrate unfiltered and well-controlled plasma exudation responses in human airways. Lack of size-selectivity means that potent cascade systems (complement, kinin/kallikrein, coagulation) and natural antibodies (IgG,IgM) emerge locally, along with albumin, on engaged airway epithelial sites (3-13). Even cathelicidine, representing antimicrobial peptides, arrives on the affected airway surface exclusively as component of exuded plasma (14). Intriguingly, as demonstrated with Coronavirus229E and rhinoviruses (3,4,6,13), the plasma exudation response lasts until resolution.

  Epithelial barrier asymmetry: exuded plasma operates on an intact airway mucosa.
  Subepithelial extravasation of plasma is controlled by active, fully reversible formation of gaps between postcapillary, venular endothelial cells. The subsequent epithelial transmission of plasma reflects a direction-specific elasticity of cell junctions in pseudostratified epithelium. Thus, when approached from beneath by minimally increased basolateral hydrostatic pressure, plasma macromolecules pass outwardly by epithelial mechanisms not available to molecules deposited on the mucosal surface (2). Most important, plasma exudation proceeds without affecting the normal barrier function of the epithelial lining. In accord, inflammatory airways diseases exhibit plasma exudation without sign of increased penetration of molecules deposited on the airway mucosal surface (9,13,14). The conspicuous asymmetry of the pseudostratified epithelium of human airways makes the plasma exudation response, with its omnipotent content, a first line innate respiratory defense response (15).

  Plasma exudation building barrier and biological milieu at sites of epithelial regeneration.
  To the extent that Covid-19 causes airways epithelial injury and shedding (1), plasma exudation would again be vitally involved (13,15-17). As in asthma, infection-induced loss of pseudostratified epithelium apparently emerges as a patchy, non-sanguineous event without damage to the basement membrane. In experimental in vivo studies, such asthma-like denudation, almost independent of cause, promptly induces local plasma exudation that covers the naked membrane with a fibrin/fibronectin gel. Further, this provisional barrier-gel is continuously supplied by exuded plasma proteins creating a biological milieu suited for prompt start and speedy progress of repair. In vivo, all types of epithelial cells bordering a denuded patch dedifferentiate into fast-migrating regeneration cells. As soon as a cellular barrier is established exudation stops and the gel is shed (15-17). At vulnerable airway denudation patches, local plasma exudation would contribute both a barrier and a biologically active milieu promoting antimicrobial defense and epithelial regeneration.

  Summarizing: The above humoral aspect of mucosal defense in human airways with intact or regenerating epithelial lining is overlooked in currently leading notions (1). As listed elsewhere (2), numerous factors may contribute to this oversight. A major factor is unappreciation of the asymmetry of human airways epithelial barriers (15). Another concerns specificity. However, precision of airways plasma exudation resides not in molecular specificity but in its highly localized distribution along with strict control of its duration (2). A further shortcoming of the present complementary concepts concerns the fact that they are underpinned by classical observational medical research, which was outdated already in 1990s (18). Word count 595

  References

  1. Bridges JP, Vladar EK, Huang H, Mason RJ. Respiratory epithelial cell responses to SARS-CoV-2 in COVID-19. Thorax 2022;77:203-209.
  2. Persson C. Early humoral defense under the radar: microvascular-epithelial cooperation at airways infection in asthma and health. Am J Physiol Lung Cell Mol Physiol 2022;322:L503-L506. Doi:10.1152ajplung.00470.2021.
  3. Proud D, Naclerio RM, Gwaltney JM, Hendley JO. Kinins are generated in nasal secretions during natural rhinovirus colds. J Infect Dis. 1990;161:120-123.
  4. Åkerlund A, Greiff L, Andersson M, Bende M, Alkner U, Persson C. Mucosal exudation of fibrinogen in coronavirus-induced common colds. Acta Otolaryngol. 1993;113:642-648.
  5. Pizzichini MMM, Pizzicini E, Efthimiadis A, et al. Asthma and natural colds. Inflammatory indices in induced sputum: a feasibility study. Am J Respir Crit Care Med. 1998;158:1178-1184.
  6. Winther B, Gwaltney JM Jr, Humphries JE, Hendley JO. Cross- linked fibrin in the nasal fluid of patients with common cold. Clin Infect Dis. 2002;34:708-710.
  7. Stockley RA, Mistry M, Bradwell AR, Burnett D. A study of plasma proteins in the sol phase of sputum from patients with chronic bronchitis. Thorax. 1979;34:777-782
  8. Van Vyve T, Chanez P, Bernard A, et al. Protein content in bronchoalveolar lavage fluid of patients with asthma and control subjects. J Allergy Clin Immunol. 1995;95:60-68.
  9. Greiff L, Andersson M, Åkerlund A, et al. Microvascular exudative hyperresponsiveness in human coronavirus-induced common cold. Thorax. 1994;49:121-127.
  10. Greiff L, Andersson M, Erjefalt JS, Svensson C, Persson CG. Loss of size- selectivity at histamine-induced exudation of plasma proteins in atopic nasal airways. Clin Physiol Funct Imaging. 2002;22:28-31.
  11. Andersson M, Michel L, Llull JB, Pipkorn U. Complement activation on the nasal mucosal surface – a feature of the immediate allergic reaction in the nose. Allergy. 1994;49:242-245.
  12. Svensson C, Baumgarten CR, Pipkorn U, Alkner U, Persson C. Reversibility and reproducibility of histamine-induced plasma leakage in nasal airways. Thorax. 1989;44:13-18.
  13. Persson C. Humoral first-line mucosal innate defence in vivo. J Innate Immun. 2020;2020(12):373-386.
  14. Liu MC, Xiao HQ, Brown AJ, Ritter CS, Schroeder J. Association of vitamin D and antimicrobial peptide production during late-phase allergic responses in the lung. Clin Exp Allergy. 2012;42:383-391.
  15. Persson C. ‘Bedside’ observations challenge aspects of the ‘Epithelial barrier hypothesis’. Nat Rev Immunol 2021;21:829. https://doi.org/ 10.1038/s41577-021- 00650-8.
  16. Persson CGA, Erjefält JS. Airway epithelial restitution following shedding and denudation. In: Crystal RG, West JB, Weibel ER, Barnes PJ, eds. The Lung: Scientific Foundations, 2nd edn. New York: Raven; 1997:2611-2627.
  17. Persson C. Airways exudation of plasma macromolecules: innate defense, epithelial regeneration, and asthma. J Allergy Clin Immunol. 2019;143:1271–1286.
  18. Persson C. Clinical research, or classical clinical research? Nat Med. 1999;5(7):714-715.

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  Conflict of Interest:
  None declared.

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