Well‐Controlled Mucosal Exudation of Undiluted Plasma Proteins Serves Innate and Adaptive Immunity

ABSTRACT

Distinct from the pulmonary circulation, the human respiratory mucosa is supplied by highly responsive, superficial, systemic microcirculations. In the early symptomatic phase of mucosal infections, circulating peptides‐proteins of all sizes are released just beneath the epithelium and will soon appear on the mucosal surface. The traditional view is that mucosal injury must be involved in this plasma exudation process. However, well‐controlled human in vivo observations demonstrate that the inflammatory plasma exudation response reflects non‐injurious physiologic microvascular‐epithelial cooperation. Crucially, although plasma exudation brings unfiltered plasma solutes without size restriction to the mucosal surface this occurs without reducing the protective epithelial barrier against inhaled molecules. Plasma exudation starts early and increases until viral or bacterial infections resolve. Plasma exudation therefore has the potential to slow down, or even prevent, progression to pneumonia and beyond. Plasma exudation would boost efficacy of a mature adaptive immunity by delivering circulating pathogen‐neutralising antibodies undiluted to infection spots in the upper airways. Early mucosal infections would thus be dampened and development of lower airway infections prevented. Inferentially, this explains how treatment with vaccines still allows upper airway infections but prevent severe respiratory disease with alveolar and pulmonary circulation injury. Plasma exudation may also contribute to real‐life protection against severe influenza/Covid‐19 in airway mucosal diseases that exhibit plasma exudation hyperresponsiveness. Such hyperresponsiveness is inducible indicating feasibility of finding future treatments that increase the mucosal innate and adaptive immunity. Altogether, the present synthesis of literature suggests that plasma exudation is an important component of human respiratory mucosal antimicrobial immunity.

1. Introduction

Human nasal and bronchial mucosae are supplied by superficial systemic microcirculations (Figure 1) carrying significant levels of cathelicidins, complement proteins, fibrinogen, fibronectin, macroglobulins, mannose‐binding lectin, natural and specific antibodies, pentraxins and more. Thus peptides‐proteins of major interest in defence and repair are ready to be released just beneath the basal aspect of infected epithelium.

FIGURE 1.

(Left) Different end‐organs regulate size of the free lumen in human nasal and tracheobronchial airways: Filling of venous sinusoids and smooth muscle constriction, respectively. However, throughout the human airways, profuse, highly responsive, systemic microcirculations are juxtaposed with pseudostratified epithelial linings. This proximity is a prerequisite for the efficient delivery of circulating immune cells and, even more so (this article) for the physiologic microvascular‐epithelial interaction that results in plasma exudation at points of mucosal infection. (Right) In this cross‐section of a mid‐size bronchus from human asthmatic lung (stained by ‘Triacid’), Jezierski (1906) [1] illustrates tightly packed mucosal micro‐vessels and describes them as a “palisade‐like wall” (‘pallissadenartigen Wall’) encircling the bronchus just beneath a well‐preserved epithelial lining (blue). (a) blood vessel; (b) red blood cell; (c) lymphocytes. Small rodents including mice lack a human‐like bronchial circulation [2].

Since long it is established that even the largest plasma proteins occur in airway surface samples in association with human respiratory mucosal infections, both viral and bacterial [3, 4, 5, 6, 7]. A traditional view prevails [8] maintaining that abnormal presence of plasma macromolecules in nasal and bronchial surface liquids reflects mucosal injury involving epithelial barrier defects. Increased plasma proteins in nasal lavage fluids and sputum samples are thus commonly reported merely as vascular leakage, spilling, spill‐over, and transudation [3, 4, 6, 7, 9].

A mucosal response that involves loss of the protective epithelial barrier cannot obviously be viewed as a proper defence. However, exploratory studies in vivo in human respiratory mucosa in health and disease have demonstrated that the entire solute armamentarium of the blood circulation is brought to the respiratory mucosal surface by non‐injurious plasma exudation mechanisms [8, 9, 10]. This understanding would redefine plasma exudation responses to respiratory mucosal infections into a first line defence opportunity. I will argue in this review that plasma exudation is an underestimated, yet powerful, part of mucosal in vivo immunity, particularly in human airways (Table 1).

TABLE 1.

Physiological plasma exudation in vivo in human airways.

The following features define how mucosal exudation of unfiltered plasma proteins occurs as primarily a physiological first line respiratory mucosal innate immune defence response in vivo in human nasal‐bronchial airways [8, 9, 10]: Plasma exudation is a prompt in vivo response to airway mucosal inflammatory challenges Challenge with histamine‐type autacoids actively separate venular endothelial cells belonging to the systemic subepithelial microcirculation. Through the induced transient venular gaps portions of bulk plasma, not cells, extravasates [11] The epithelial barrier yields to minimal increases in basolateral hydrostatic pressure such as would be produced by small portions of extravasated bulk plasma The microvascular‐epithelial cooperation results in paracellular outward transmission of unfiltered plasma solutes without size restriction, yet the protective epithelial barrier function is not reduced The direction‐selective barrier of human pseudostratified epithelium in vivo is evidenced by occurrence of plasma exudation without increased penetration of inhaled molecules. This epithelial barrier asymmetry is also demonstrated in plasma exudation diseases including asthma, allergic rhinitis, and Corona virus 229E infection Plasma exudation responses proceed without being associated with overt mucosal oedema As demonstrated with autacoid challenges in human nasal airways, plasma exudation is fully reversible, repeatable, and dose‐dependent Precision of plasma exudation: unidirectional epithelial penetrability, restricted location, and well‐controlled magnitude and duration Total volume of exuded plasma in infected airways seems negligible. Thus, inhibition of plasma exudation in nasal airways has not reduced rhinovirus infection‐induced rhinorrhea [12] Neurogenic challenges increase mucus secretion without inducing plasma exudation Mucosal blood flow may be halved by nasal decongestants without reducing plasma exudation responses Inhaled corticosteroids may not inhibit acute challenge‐induced plasma exudation. However, systemic corticosteroid treatment inhibits rhinovirus infection‐induced plasma exudation [12]

2. The Traditional Notion of Plasma Exudation as a Sign and Cause of Injury and Epithelial Derangement Is Challenged

2.1. Physiology of Extravasation (Release) of Plasma Proteins and Epithelial Barrier Asymmetry

As discussed elsewhere in some detail [8, 9], human airway in vivo‐studies demonstrate that mucosal exudation of portions of bulk plasma primarily reflects physiologic non‐injurious microvascular‐epithelial cooperation mechanisms. Briefly summarised: Plasma exudation is a prompt in vivo response to airway mucosal inflammatory challenges ranging from simple histamine‐type inhalations to symptomatic mucosal infections. The challenges cause active separation of venular endothelial cells belonging to the systemic subepithelial microcirculation. Through the induced transient venular gaps, portions of bulk plasma are released into the subepithelial lamina propria [11]. Mucosal oedema is not induced indicating that the extravasated plasma solutes are not diluted. The extravasated plasma would nevertheless exert a slight hydrostatic pressure on basolateral aspects of adjacent epithelial cells sufficient to create outwardly directed paracellular epithelial pathways [9]. This mode of microvascular‐epithelial cooperation results in local mucosal transmission of portions of unfiltered plasma solutes without size restriction = plasma exudation. Yet, the protective epithelial barrier function is not reduced [9]. The peptides‐proteins that appear on the mucosal surface at points of challenge include the entire antimicrobial armamentarium of circulating plasma. Inferentially, the systemic titers of specific antibodies in mature adaptive immunity will be exported to the respiratory mucosal surface. Primarily an innate immune response, plasma exudation would also play a role in mucosal adaptive immunity by exporting specific immunoglobulins to the mucosal sites where most infections start [10].

The direction‐selective barrier of human pseudostratified epithelium in vivo is evidenced by the occurrence of plasma exudation without increased penetration of inhaled molecules. Such asymmetry of the epithelial barrier is also demonstrated in plasma exudation diseases including common cold, allergic rhinitis, and asthma. Beside unidirectional epithelial penetrability, the precision of plasma exudation responses is defined by restricted location and well‐controlled magnitude and duration [8, 9, 10].

2.2. Further Physiologic/Pharmacologic Aspects of Interest for Roles in Mucosal Defence

• Neurogenic challenges increase mucus secretion without inducing plasma exudation

• Mucosal blood flow may be halved by nasal decongestants without reducing plasma exudation responses.

• Inhaled corticosteroids may attenuate acute challenge‐induced plasma exudation

• Systemic corticosteroid treatment may inhibit infection‐induced plasma exudation.

In summary, the in vivo physiology‐pharmacology of human airway plasma exudation [9, 10] provides a novel framework for the present interpretation of plasma‐derived peptides/proteins in airway surface liquids at respiratory mucosal infections.

3. Expansion of the Antimicrobial Opportunities Provided by Mucosal Plasma Exudation

A previous article on plasma exudation in this journal [13] contains a schematic illustration of microvascular‐epithelial exudation of unfiltered plasma in intact airway mucosa; additionally, plasma exudation occurring at spots of epithelial denudation in vivo is highlighted and its role in early phase epithelial regeneration discussed. The article speculates on a defence role of plasma exudation in SARS‐CoV‐2infection [13]. Specific data on early plasma exudation responses in Covid‐19 like those demonstrated at nasal infection with Coronavirus‐229E [5] are lacking. However, circumstantial evidence has emerged that supports a role of plasma exudation in defence against severe influenza and Covid‐19. Real‐world epidemiologic studies thus show that respiratory disease conditions such as asthma and allergic rhinitis, which exhibit increased plasma exudation responsiveness, may protect against the severe viral diseases [10, 14, 15, 16]. The present synthesis of the literature expands the antimicrobial plasma exudation theme and is discussed below under the following subheadings:

• Scattered infection points and strictly localised exudative responses suggest that antimicrobial defence can be exerted with minimal plasma exudate volumes

• Major immune defence molecules, even those considered to be produced by local airway cells, emanate as components of plasma exudates in vivo in human challenged airways

• Plasma exudation intriguingly associates with the resolution of human respiratory mucosal viral and bacterial infections.

• Plasma exudation provides barrier and immune defence at mucosal denudation spots

• Plasma exudation in asthma and allergic rhinitis may protect against severe influenza and Covid‐19

• Training humoral innate immunity: Plasma exudation hyperresponsiveness can be induced within days

• Plasma exudation may decide the efficacy of a mature adaptive antimicrobial immunity.

• Respiratory mucosal plasma exudation may explain how antiviral vaccines protect against severe respiratory infections without protecting against initial airway mucosal infections

4. Scattered Infection Points and Strictly Localised Exudative Responses Suggest That Antimicrobial Defence Can Be Exerted With Minimal Plasma Exudate Volumes

In vivo studies involving nasal rhinovirus spray inoculations have demonstrated that only a small, spotty fraction of epithelial cells, mostly ciliated cells, becomes infected [17, 18]. Despite the nasal viral deposition, the infection spreads to the bronchial epithelium, still with a similar spotty pattern of distribution of infected cells. Surrounded by uninfected epithelium, singular cells or small islets of adjacent cells are infected [18]. At such sites, local mucosal inflammatory responses start by binding of virus to specific epithelial cell receptors, followed by activation of pattern recognition receptors, in turn inducing cells to produce and release cytokines, interferons, and traditional mediators/autacoids. Discrete points of infection would thus be hot spots endowed with a wide variety of biologically active molecules known to be involved in early host cellular inflammatory and innate immune responses.

Several of the molecules released locally by viral infection potentially contribute to extravasation of plasma from the human subepithelial microcirculations. However, it is not known which released molecules cause the increased vascular permeability that leads to mucosal exudation of plasma in human airways in vivo at viral or bacterial infections.

Infection of only a small fraction of epithelial cells together with strictly localised plasma exudation responses tally with the notion that only a small total volume of unfiltered plasma exudates may occur in infected airways. In accord, Gustafson et al. demonstrate that inhibition of rhinovirus infection‐induced nasal plasma exudation does not reduce the induced rhinorrhea [12].

5. Major Immune Defence Molecules, Even Those Considered to Be Produced by Local Cells, May Emanate as Components of Plasma Exudates In Vivo in Human Challenged Airways

Several of the circulating peptides‐proteins evoke interest partly because they can also be produced in vitro by local airway cells. However, in vivo, airways plasma exudation may be the major source of the increased mucosal surface levels. An example is cathelicidin, an antimicrobial peptide with double‐digit antimicrobial mechanisms persistently considered a local cellular product only [19]. By contrast, the increased sputum levels of cathelicidin in human challenged bronchi in vivo are fully explained by plasma exudation [20]. Similarly, plasma exudation would deliver fibronectin, the coagulation cascade, the complement system, immunoglobulins (IgA, IgG), and more to the surface of infected nasal and bronchial mucosae [3, 10, 21, 22, 23].

6. Plasma Exudation and Resolution of Human Respiratory Mucosal Viral and Bacterial Infections

Patients with bronchial infections present with increased, individually variable bronchial exudation of plasma proteins‐peptides. Thus, sputum α₂‐macroglobulin [4], fibrinogen [6, 24], and cathelicidin [25] are increased with bronchial bacterial or viral infections. Data in a case study suggest that the resolution phase of Chlamydia pneumoniae infection begins when sputum fibrinogen levels peak. The exudation then decreases towards baseline along with return of health [6]. Following local inoculations with rhinovirus, both magnitude and time‐course of nasal plasma exudation [7, 23, 26] indicate that it is an early response along with start of symptoms. Furthermore, they agree with a role in infection resolution. Similarly, nasal mucosal levels of complement 3a and 5a increased and declined during the course of influenza A infection [27]. Early induced plasma exudation, approximately rising in magnitude until infection starts resolving, is also observed with nasal infection by coronavirus 229E [5]. In agreement with intact nasal epithelium in common cold [17], the unfiltered plasma exudation, reflected by fibrinogen levels in nasal lavage liquids [5], occurs without increasing mucosal absorption penetrability [28]. As exemplified by respiratory mucosal infections, which turn out to be non‐severe, the kinetics of induced plasma exudation strengthen the idea that this innate humoral response contributes to combatting human respiratory mucosal infections.

7. Plasma Exudation Provides Barrier and Immune Defence at Spots of Denudation

An airway model, with human‐like both epithelial barrier structure and plasma exudation responses, was used to examine in vivo events following loss of epithelial cells from an intact basement membrane. Gentle non‐sanguineous epithelial denudation alone caused prominent plasma exudation. Precision in terms of localization, onset, and duration observed in non‐injurious challenge of intact airway mucosa was also seen at the spotty sites of epithelial loss [9, 29, 30].

Plasma‐derived fibrinogen‐fibronectin gels soon covered the denuded area [30]. Such an in vivo response may partly explain a maintained barrier in desquamatory conditions such as bronchial asthma; it would also contribute a dynamic molecular soup that optimises early epithelial regeneration. High speed of repair is secured in this in vivo milieu by the demonstration that all types of epithelial cells bordering the denuded spot promptly dedifferentiate into rapidly migrating stem cells [9, 29]. Coinciding with restitution of a cell barrier, plasma exudation stops [30]. The experimental in vivo data suggest that mere loss of airway epithelium in discrete spots, as may occur in severe mucosal infections and be pronounced in severe asthma [31], evokes local plasma exudation. This response would contribute antimicrobial defence during a most vulnerable phase of epithelial regeneration [9, 10, 13].

8. Plasma Exudation in Asthma and Allergic Rhinitis May Protect Against Severe Influenza and Covid‐19

Asthma protected against severe influenza in 2009 (H1N1)‐pandemic [32]. Such real‐life protection is currently evident in asthma and allergic rhinitis as reported both with Covid‐19 [14, 15, 33, 34] and influenza [16]. Hence, the protection would reflect more general immune defence features than exclusive to SARS‐CoV‐2 infection.

Observations in allergic rhinitis are of interest because relatively much is known about physiology and pharmacology of human nasal mucosa in allergic and infected conditions. By repeated nasal allergen challenges in allergic individuals, allergic rhinitis‐like plasma exudation and plasma exudation hyperresponsiveness can be induced within a few days [35]. In such a human in vivo model, established allergic inflammation prolongs incubation time and shortens duration of the common cold induced by inoculation with rhinovirus [36]. This, and similar observations [23], was unexplained but agrees with an antimicrobial role of plasma exudation.

It emerges that allergic rhinitis, independent of age, protects against the development of severe influenza‐type disease [14, 15, 16]. Also independent of age, symptomatic seasonal allergic rhinitis associates with increased baseline plasma exudation and plasma exudation hyperresponsiveness compared to outside the season [37, 38]. Particularly intriguing, the exaggerated seasonal plasma exudation responsiveness in allergic rhinitis coincides with protection against influenza‐type diseases observed during a sequence of symptomatic pollen seasons 2016–2019 [38].

Asthmatic bronchi exhibit increased angiogenesis compared to health [2]. Individuals with asthma also respond to influenza‐induced natural cold with much higher levels of sputum fibrinogen than non‐asthmatics with similar cold symptoms [24]. A combination of increased vascular permeability responsiveness and an abnormally profuse mucosal microcirculation (cf Figure 1) may produce exaggerated plasma exudation responses in asthma. Systemic corticosteroid treatment non‐specifically inhibits plasma exudation in rhinovirus infection, an effect associated with increased viral titers [12]. Inferentially, a reduced plasma exudation defence may have contributed to an increased risk of severe Covid‐19 that is demonstrated in asthmatics receiving systemic corticosteroids [33, 34].

It is hypothesized that exaggerated plasma exudation responses, occurring without increased absorption penetrability in both asthma and allergic rhinitis [8, 21], contribute to protection against propagation of respiratory mucosal infections into pneumonia. Interestingly, the cellular antiviral defence is considered to be reduced in allergic rhinitis [39] and asthma [40].

9. Training Humoral Innate Immunity: Plasma Exudation Hyperresponsiveness Can Be Induced Within Days

A significantly increased plasma exudation response to topical nasal histamine challenges is induced six days after human nasal inoculation with coronavirus 229E [28]. Similarly, plasma exudation hyperresponsiveness, can be induced by daily nasal allergen challenges in allergic individuals in less than a week [35]. These human airway in vivo observations suggest that the respiratory mucosal defence provided by plasma exudation can readily be trained.

10. Plasma Exudation Will Promote Efficacy of a Mature Adaptive Antimicrobial Immunity

Under baseline conditions, minimal, much diluted surface levels of antibodies up to the size of IgG and IgA would reflect size‐dependent passive microvascular‐epithelial diffusion along a concentration gradient [3]. Noting that effectiveness of circulating specific antibodies may depend on “transudation to mucosal surfaces of very high titers of antibody”, Morens, Taubenberger, and Fauci recently underscored that it is still not “understood how such transudation is controlled” [41]. It seems important to distinguish between baseline passive diffusion and inflammatory plasma exudation conditions, respectively. The diffusion is a slow and distinctly size‐restricted passage of plasma proteins to the entire respiratory mucosal surface [3]. By contrast, plasma exudation is a prompt, highly localised microvascular‐epithelial transmission of a portion of bulk plasma solutes without filtration and size restriction.

Plasma exudation induced by respiratory infections would not only be a component of early mucosal innate immune defence. By moving circulating specific antibodies, undiluted and without size restriction, to mucosal points of infections, plasma exudation would promote the efficacy of a mature adaptive immunity [10]. Vissers et al. [42] examined maternal RSV‐specific IgG in nasal aspirates and serum in infants at admission with acute disease. Very high mucosal surface levels of antibodies were demonstrated suggesting that “in addition to passive transudation, other mechanisms are at play during infection”. It seems likely that plasma exudation was involved. Balfour‐Lynn et al. determined nasal lavage levels of secretory and total IgA as well as total protein in infants with upper respiratory infection. Citing the early idea of a defence role of plasma exudation [43], the authors concluded “that the increase in total IgA during early infection is due to plasma exudation” [22]. However, for different reasons [9, 10] the in vivo opportunities for plasma exudation to participate in respiratory antimicrobial immune defence have dwelled under the radar for more than three decades.

11. Respiratory Mucosal Plasma Exudation May Explain How Antiviral Vaccines Protect Against Severe Respiratory Infections Without Protecting Against Initial Airway Mucosal Infections

Discussing next‐generation antiviral treatments, Morens et al. [41] note that some influenza virus and SARS‐CoV‐2 vaccines are “only preventing severe disease (e.g., requiring hospitalization)”. Such observations remain unexplained.

It has not been appreciated that plasma exudation will export pathogen‐neutralising levels of circulating antibodies to the mucosal sites of infection where inhaled pathogens are deposited, and respiratory infections start. The microvascular response to infection may be the only ‘trafficking signal’ that is needed for the specific antibodies to arrive at the scene of interest. Hence, it is conceivable that the local plasma exudation response will resolve early upper airways infections. Thus, severe respiratory disease caused by spreading of the infection to the lower airways involving the lung and beyond would be prevented as is observed [41].

12. Future Research and Treatment Opportunities

An increased understanding of antimicrobial mechanisms along with in vivo efficacy of airways plasma exudation should put this response into common pictures of respiratory immune defence. Out of numerous questions arising, a small sample of ideas for future research has been listed below:

• What antimicrobial effects are induced by the joint appearance of the entire circulating solute armamentarium on the mucosal surfaces of human airways? A now uncharted territory of immune defence research.

• Questions need to be asked concerning antimicrobial roles of extravasated plasma proteins (against invading microbes) in the lamina propria and during their outward paracellular passage all‐around epithelial cells [9].

• Human airway in vivo‐studies and basic research are warranted to validate contributions by plasma exudation to defence and repair at epithelial regeneration currently based on preclinical in vivo‐observations [21, 29, 44].

• Human infected epithelial cells release a wide variety of biologically active molecules. Those crucially involved in infection‐induced microvascular permeability responses need to be known.

• What mechanisms may explain exudative hyperresponsiveness? Can this research field generate novel interventions that will train the microvascular‐epithelial plasma exudation response and thus improve early humoral defence against respiratory mucosal infections?

13. Conclusion

Microvascular‐epithelial cooperation in human airways mucosae together with known properties (not reviewed) of the circulating peptides‐proteins frame plasma exudation as primarily a first‐line defence against respiratory mucosal infections. Human in vivo observations on time courses of infections and mucosal surface indices, respectively, tally with operational antimicrobial roles of plasma exudation in viral and bacterial airway infections. By delivering undiluted specific antibodies to upper airway points of early infection, plasma exudation would also promote mucosal efficacy of a mature adaptive immunity. Vaccines producing pathogen neutralising immunity only in the systemic circulation would thus allow early respiratory mucosal infections but prevent propagation into severe respiratory disease. The suggested roles are further congruent with less than expected development of severe influenza/Covid‐19 in diseases like allergic rhinitis and asthma both exhibiting exaggerated plasma exudation responses. Training of the present physiologic microvascular‐epithelial immune response seems feasible. Thus, the present proposal of a primary defence role of respiratory mucosal plasma exudation may be further validated and exploited as an antimicrobial treatment.

Conflicts of Interest

The author declares no conflicts of interest.

Persson C., “Well‐Controlled Mucosal Exudation of Undiluted Plasma Proteins Serves Innate and Adaptive Immunity,” Scandinavian Journal of Immunology 102, no. 1 (2025): e70041, 10.1111/sji.70041.

Data Availability Statement

Data available only in published work that is referenced.