Complement activation on the nasal mucosal surface--a feature of the immediate allergic reaction in the nose.

Complement is a system of functionally linked serum proteins that interact to exert biologic effects in inflammatory and immunologic processes. As part of a larger study with a potential topical antiallergic drug, we measured C3a des Arg and C5a des Arg in 13 patients with seasonal allergic rhinitis and in five nonatopic controls after placebo treatment. After 1 week of placebo treatment, a nasal allergen challenge with increasing doses of pollens was performed in both allergic subjects and controls. A symptom score method was used, and in returned nasal lavage fluid, the activity of C3a des Arg and C5a des Arg was measured. We found that allergen challenge in the allergic subjects induced nasal symptoms concomitantly with increased levels of C3a des Arg and C5a des Arg (P < 0.05). No increases either in symptoms or in the very low base-line levels of C3a des Arg and C5a des Arg were observed in the nonallergic controls. We conclude that the activation of the complement cascade is one part of the vasculature exudative response during the immediate allergic reaction in the upper airways. Because of their biologic potency, these proteins may be an essential part of the exudative response which perpetuates the ongoing inflammatory reaction.

Glucocorticoid-induced attenuation of mucosal exudation of fibrinogen and bradykinins in seasonal allergic rhinitis.

The mucosal plasma exudate with its proteins, enzymes, derived peptides, and matrix molecules is an important factor in inflammatory airway diseases. This study investigated whether topical glucocorticosteroid treatment influences mucosal exudation of bulk plasma (fibrinogen) and the generation of plasma-derived mediators (bradykinins) in seasonal allergic rhinitis. Twenty-two patients with birch-pollen-induced allergic rhinitis participated in a double-blind, randomized, placebo-controlled study during the birch pollen season in 1989. After a 2-week run-in period, the participants received treatment with budesonide (200 micrograms per nasal cavity and day) or placebo. The patients kept a diary to record their daily nasal symptoms (itching, sneezing, nasal blockage, and secretion). The amount of birch pollen in the air was determined with the aid of a Burkhard pollen trap. A nasal lavage was performed once a week, and the levels of bradykinins and fibrinogen were determined in the lavage fluid samples. The birch pollen season was very mild, resulting in only minor nasal symptoms. In spite of the low pollen exposure, treatment with budesonide reduced the lavage fluid levels of both bradykinins and fibrinogen. The present results show that topical glucocorticosteroid treatment attenuates plasma exudation and the generation of plasma-derived mediators in seasonal allergic rhinitis. This action may not result from simple vascular antipermeability effects of the drug but may rather reflect the anti-inflammatory efficacy of topical glucocorticoids in the airway mucosa.

Histamine-induced airway mucosal exudation of bulk plasma and plasma-derived mediators is not inhibited by intravenous bronchodilators.

Experimental data suggest the possibility that common bronchodilators, such as the xanthines and beta 2-adrenoceptor agonists, may produce microvascular anti-permeability effects in the subepithelial microcirculation of the airways. In this study, we have examined the effect of bronchodilators given intravenously on exudation of different-sized plasma proteins (albumin and fibrinogen) and the generation of plasma-derived peptides (bradykinins) in human nasal airways challenged with histamine. In a double-blind, crossover, placebo-controlled and randomised trial, 12 normal volunteers were given i.v.infusions of terbutaline sulphate, theophylline and enprofylline to produce therapeutic drug levels. The effect of topical nasal provocation with histamine was closely followed by frequently nasal lavage with saline. The lavage fluid levels of albumin, fibrinogen and bradykinins increased significantly after each histamine provocation. The ratio of albumin-to-fibrinogen in plasma and the lavage fluid was 24 and 56, respectively, indicating that topical histamine provocation induced a largely non-sieved flux of macromolecules across the endothelial-epithelial barriers. The systemically administered drugs did not affect the nasal symptoms (sneezing, secretion and blockage), nor did they significantly reduce the levels of plasma proteins and plasma-derived mediators in the nasal lavage fluids. The present data suggest that systemic xanthines and beta 2-adrenoceptor agonists, at clinically employed plasma levels, may not affect the microvascular (and epithelial) exudative permeability and the bradykinin forming capacity of human airways.

Mast cells and mediators in the nasal mucosa after allergen challenge. Effects of four weeks' treatment with topical glucocorticoid.

The study focuses on the relationship between the tissue density of mast cells, the tissue histamine levels and the levels of markers of mast cell activation after an allergen challenge of the nasal mucosa of allergic patients. The effect of 4 weeks' treatment with a topical glucocorticoid, fluticasone propionate, was studied in a double-blind, placebo-controlled study of 25 hay fever patients. Nasal biopsies were obtained before and after the treatment period for the evaluation of mast cell density and tissue histamine levels. Nasal challenges were performed at 2-week intervals for 8 weeks using a standardized nasal lavage model. TAME-esterase was analysed in the returned lavage fluid from all the challenges (weeks 0-8), while the levels of histamine and tryptase were analysed in lavage fluids from challenges performed before and after the treatment period (weeks 0 and 4). The symptoms of nasal allergy were assessed after each challenge. Treatment with fluticasone propionate did not influence mast cell density, the tissue histamine concentration, the lavage histamine levels or the TAME-esterase activity, while a reduction in nasal symptoms and tryptase in nasal lavage fluid was revealed. Our present study again emphasizes the fact that the mast cell is an important trigger cell in the immediate nasal allergic response. The study also demonstrates the usefulness of the measurements of tryptase as an indicator of both mast cell activation and the efficacy of topical steroid treatment.

Effects of nicotine on the human nasal mucosa.

BACKGROUND: Topical application of nicotine and stimulation of tachykinin containing sensory nerves have been shown to produce mucosal exudation of plasma and derangement of the epithelial lining in guinea pig and rat airways. If this occurred in man these effects might contribute to the pathogenesis of airway disease. This study, performed in healthy volunteers without atopy, examined whether nicotine affects the plasma exudation response and the mucosal absorption permeability of the human nasal airway. METHODS: The acute effects of increasing topical doses of nicotine (0.08-2.0 mg) were examined (n = 8) on nasal symptoms (pain), mucosal exudation of plasma (albumin), mucosal secretion of mucin (fucose), and mucosal exudative responsiveness (histamine induced mucosal exudation of albumin). A separate placebo controlled study was carried out to determine whether frequent applications of the high dose of nicotine (2.0 mg given eight times daily for nine days) had any deleterious effects on the airway mucosa detectable as altered responses to histamine challenge. Both mucosal exudation of plasma (n = 12) and mucosal absorption of chromium-51 labelled EDTA (n = 8) were thus examined in nasal airways exposed to both nicotine and histamine. RESULTS: Nicotine caused nasal pain and produced dose dependent mucosal secretion of fucose but failed to produce any mucosal exudation of albumin. The exudative responsiveness to histamine was, indeed, decreased when the challenge was performed immediately after administration of acute doses of nicotine, whereas the responsiveness was unaffected when histamine challenges were carried out during prolonged treatment with nicotine. The nasal mucosal absorption of 51Cr-EDTA in the presence of histamine did not differ between subjects receiving either placebo or nicotine treatment for nine days. CONCLUSIONS: The results indicate that nicotine applied to the human airway mucosa produces pain and secretion of mucin, but inflammatory changes such as mucosal exudation of plasma and epithelial disruption may not be produced. Neurogenic inflammatory responses, which are so readily produced in guinea pig and rat airways, may not occur in human airways.

Dry powder inhalation of budesonide in allergic rhinitis.

Topical steroids are known to be effective in allergic inflammatory airway diseases. However, progress in the treatment of these diseases has also called for the use of unadulterated drugs, without lubricants and preservatives. Rhinocort Turbuhaler, a multi-dose inhaler containing budesonide as a pure powder, is a newly developed device without any carrier gas, preservatives or lubricants. The efficacy and tolerance of this product were evaluated in 60 patients with birch pollen rhinitis. After a run-in period of 1 week the patients received once daily for 4 weeks either budesonide pure powder (400 micrograms) or placebo in a double-blind randomized fashion. Assessment of efficacy was made by comparing scores for different nasal and eye symptoms. The additional use of antihistamine tablets was assessed. In 22 of the patients nasal peak inspiratory flow rate was measured before and after 1 week of treatment. Budesonide was significantly more effective than placebo in controlling the nasal symptoms (P-values ranging from 0.011-0.045). The use of antihistamine tablets was significantly lower in the budesonide group (P = 0.012). The nasal inspiratory flow rate was increased after 1 week of treatment in the budesonide treated group of patients as compared with placebo (P = 0.007). No differences were observed between the groups with regard to eye symptoms or adverse effects. The results show that budesonide delivered from a dry powder inhaler is an effective and well tolerated treatment of seasonal allergic rhinitis.

Mast cells and eosinophils in the allergic mucosal response to allergen challenge: changes in distribution and signs of activation in relation to symptoms.

An allergen challenge was performed in 10 asymptomatic patients with strictly seasonal allergic rhinitis. For comparison; seven nonallergic subjects were challenged with allergen, and seven allergic patients were challenged with diluent. Cell samples, obtained with use of a brush technique to recover cells from within the epithelium and nasal lavage to collect cells from the epithelial surface, and symptom scores were taken before challenge and at 2-hour intervals during 12 hours. The cell suspensions were cytocentrifuged onto object slides for light microscopy. Histamine was determined in the cell pellets. In brush samples from the allergic patients challenged with allergen, eosinophils, expressed as a percentage of the total granulocytes, increased from 4.3% +/- 2.7% (mean +/- SEM) to 10.3% +/- 3.8% (p < 0.05) 4 hours after challenge. This level was maintained for up to 12 hours. A similar increase was noted in the lavage specimens 2, 6, and 8 hours after the challenge. In the brush samples the proportion of eosinophils containing two or more cytoplasmic vacuoles, taken as a sign of activation, increased from 20% to 72% (p < 0.05) 8 hours after provocation. In brush samples from the allergic patients challenged with allergen, the numbers of metachromatic cells increased to a maximum of eightfold at 10 hours. In the lavage specimens, no metachromatic cells were observed before provocation, but they progressively increased in number 2 to 12 hours after provocation. Cell pellet histamine content decreased temporarily 2 to 4 hours after challenge (p < 0.05) in brush samples from allergen-challenged allergic patients. The local metachromatic cell density before challenge, as reflected in the brush specimens, correlated with nasal congestion, sneezing, and the degree of eosinophilia.

Topical vasoconstrictor (oxymetazoline) does not affect histamine-induced mucosal exudation of plasma in human nasal airways.

Mucosal exudation of almost unfiltered plasma proteins, plasma-derived mediators and fluid has recently been advanced as a major respiratory defence mechanism. Oxymetazoline chloride is a commonly used decongestant agent. By reducing blood flow it may reduce mucosal exudation and thus compromise the mucosal defence capacity. This study examines the effect of topically applied oxymetazoline on histamine-induced plasma exudation into human nasal airways. Twelve normal volunteers participated in a double-blind, randomized, cross-over and placebo-controlled study with pretreatment with a single dose oxymetazoline chloride (5 micrograms or 50 micrograms; a dose previously known to reduce nasal mucosal blood flow by almost 50%) prior to the histamine challenge sequence. Nasal lavages were performed every 10 min for 140 min, and three histamine challenges were performed at 30-min intervals during this period. The concentrations of two exudative indices, N-alpha-tosyl-L-arginine methyl ester (TAME)-esterase activity and albumin, were measured in the nasal lavage fluids. Nasal symptoms (sneezing, nasal secretion and blockage) were assessed by a scoring technique. Histamine induced all three symptoms with correlatively raised levels of the biochemical markers for plasma exudation. Oxymetazoline chloride caused a significant decrease in nasal stuffiness, but did not influence the other nasal symptoms or the histamine-induced plasma exudation. It is concluded that histamine-induced plasma exudation is not influenced by topical oxymetazoline. Thus, an important airway defence reaction such as plasma exudation may be little affected by topical alpha-adrenoreceptor-mediated vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Eosinophils, secretory responsiveness and glucocorticoid-induced effects on the nasal mucosa during a weak pollen season.

This study examined the seasonal effects on eosinophils and secretory responsiveness of the nasal mucosa in 22 patients with allergic rhinitis due to birch pollen (11 patients received placebo and 11 budesonide, 200 micrograms once daily in each nostril). The pollen counts during the study season were too low to produce a significant symptomatology. Hence, our findings demonstrate threshold alterations of the airway mucosa in allergic rhinitis and their inhibition by anti-inflammatory drug intervention. The patients were monitored for 8 weeks with daily recordings of pollen counts and symptom scores. Once every week a series of laboratory tests was carried out: the local eosinophil influx was determined using a Rhinobrush technique; the levels of eosinophil cationic protein (ECP) were analysed in nasal lavage fluids; and the secretory response to intranasal methacholine was measured. Treatments started after a 2-week run-in period. The proportion of eosinophils increased markedly in the placebo group and was elevated also during the last two study weeks when the pollen counts were practically nil. The secretory responsiveness to methacholine increased during the pollen season and returned to baseline towards the end of the study period. The topical glucocorticoid treatment reduced the proportion of eosinophils, the ECP levels, and the secretory response to methacholine compared to placebo. We conclude that the increased traffic and activity of eosinophils and less conspicuously the increased secretory responsiveness are expressions of the mucosal inflammation that precede the development of symptoms in seasonal allergic rhinitis.

Effects of histamine, ethanol, and a detergent on exudation and absorption across guinea pig airway mucosa in vivo.

This study examined effects of three substances that cause mucosal provocation (histamine, ethanol, and the detergent dioctylsodium sulphosuccinate (DOSS] on the flux of solutes across airway vascular mucosal barriers in anaesthetised guinea pigs. The inward flux was assessed as absorption of iodine-131 labelled albumin (MW 69,000) from the tracheobronchial surface into the circulation and the outward flux as the exudation of two intravenously administered plasma tracers--125I albumin (MW 69,000) and fluorescein isothiocyanate conjugated (FITC) dextran (MW 70,000)--into the airway. The absorption of technetium-99m labelled DTPA (MW 492) from the tracheobronchial airways was determined in separate experiments. Histamine (5.0 nmol) dissolved in 40 microliters saline and superfused on the tracheobronchial mucosal surface caused significant and similar entry of 125I albumin and FITC dextran into the airway lumen. This dose of histamine did not, however, alter the absorption of small (99mTc DTPA) or large (131I albumin) solutes across the airway mucosa. Ethanol (0.17 mumol), superfused in the same way, also caused significant exudation of the plasma tracers into the airway lumen. In addition, ethanol increased the absorption of 131I albumin without causing change in the disappearance rate of 99mTc DTPA. The detergent, DOSS (0.28 nmol), dissolved in ethanol (0.17 mumol), caused a pronounced increase in exudation and much increased absorption of small and large tracer solutes. Thus three patterns of change in airway mucosal barriers were found. The agents that are toxic to membranes, ethanol and DOSS, caused a bidirectional increase in permeability across the mucosa, whereas histamine caused only an outward exudative flux. The results obtained with histamine are similar to those seen previously with bradykinin, capsaicin, and allergen, suggesting that endogenous inflammatory mediators have a role in mucosal defence, producing entry of plasma exudates into the airway lumen without increasing the mucosal absorption of luminal material.

Suppressive effect of loratadine on allergen-induced histamine release in the nose.

It has been speculated whether the recently developed non-sedating antihistamines may possess other properties than merely being antagonists at the H1-receptors. To investigate this suggestion 12 patients with strictly seasonal allergic rhinitis participated in a double-blind placebo controlled randomized cross-over study outside the pollen season. At steady state levels of 10 mg loratadine, a new non-sedating antihistamine, the patients were challenged with methacholine. This was followed by a nasal challenge with increasing doses of allergen. 24 h later the patients were rechallenged nasally with the same methacholine dose as the day before. The volume of the methacholine-induced nasal secretion was measured and the response to allergen was determined by scoring technique. In returned nasal lavage fluid the levels of histamine and TAME-esterase activity were measured. It was found that loratadine significantly reduced the immediate allergic nasal symptoms compared with placebo (P less than 0.01). Loratadine also reduced the allergen-induced release of histamine into the nasal cavity after the strongest allergen dose, from 9.6 +/- 1.5 (mean +/- SEM) to 6.4 +/- 1.4 ng/ml (P less than 0.05). A similar decrease in the TAME-esterase activity after treatment with loratadine was observed. The TAME-esterase activity decreased from 11.6 *10(3) +/- 2.47 *10(3) to 5.60 *10(3) +/- 1.45 *10(3) CMP (P less than 0.05). There were no significant changes between the active and placebo treatments regarding the methacholine-induced secretory response. This was true for the initial methacholine challenge as well as the secretory response 24 h later.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption of 51Cr EDTA across the human nasal airway barriers in the presence of topical histamine.

Whether histamine, a mediator that causes exudation, affects the airway absorption of luminal solutes has been examined in a study of eight healthy volunteers. Fluid containing the absorption tracer chromium-51 labelled EDTA was instilled into one nasal cavity for 15 minutes, with a nasal pool-device (total volume 14 ml). The airway absorption of 51Cr EDTA determined by urinary recovery of radioactivity corresponded to 0.095 (SE 0.023) ml of the instillate in the absence of histamine. When histamine was added to the nasal instillate at a concentration of 2.0 mg/ml, which is known to produce substantial exudation of plasma into the airway lumen, the absorption of 51Cr EDTA was unchanged (0.093 (0.025) ml of the instillate). Separate experiments excluded the possibility that any swallowed portion of 51Cr EDTA could have contributed significantly to the amount absorbed. The present data agree with previous observations in guinea pig tracheobronchial airways, where histamine and other exudative agents did not increase the mucosal absorption of solutes from the airway lumen. These data suggest that the potent protein systems of blood plasma can transverse the endothelial-epithelial linings and operate on the surface of the airway mucosa without compromising its integrity as a barrier to luminal material.

Tryptase in nasal lavage fluid after local allergen challenge. Relationship to histamine levels and TAME-esterase activity.

The activation of mast cells is generally considered to be an important trigger mechanism in the immediate allergic response. This study focused on the determination of three markers of mast cell activation after an allergen challenge. Nasal allergen challenges were performed in 25 subjects with seasonal allergic rhinitis using three allergen doses increasing in 10-fold steps in a standardised nasal lavage model for the subsequent recovery of the markers of mast cell activation. The levels of histamine and tryptase in the nasal lavage fluid were determined using radioimmunoassays, while the TAME-esterase activity was determined using a radiochemical technique. The nasal symptoms obtained on challenge were assessed using a scoring technique. The allergen challenge resulted in significant increases in the levels of all three markers, tryptase, histamine and TAME-esterase. In the individual measurements after the challenges there was a highly significant correlation between the TAME-esterase levels and the tryptase levels (r = 0.71; P less than 0.001), while the generation of histamine and tryptase was not significantly correlated. When comparing the cumulative generation of the three markers, significant correlations were found between all three. Allergen challenges in six non-allergic controls using the same technique did not result in any increase in tryptase levels. The findings suggest that the determination of tryptase in nasal lavage fluid may be a valuable indicator of mast cell activation in the upper airways.

Effects of airway luminal concentration of albumin on histamine-induced mucosal exudation of radio-iodine labelled albumin.

In an in vivo study of guinea-pig airway barriers we have examined the effects of the luminal concentration of albumin on exudation (outward) and absorption (inward) permeabilities to radio-iodine labelled albumin. Previously validated techniques for superfusion of solutes onto the tracheobronchial mucosal surface and for subsequent tracheal lavage were employed. [125I]albumin was administered intravenously as plasma tracer and [131I]albumin was superfused topically as absorption tracer. Histamine (5.0 nmol) was superfused onto the mucosal surface together with the absorption tracer and in the presence of different albumin concentrations (0.3, 3.0 and 30 mg ml-1). The experiment was terminated 10 minutes after the tracheal mucosal superfusion and samples of plasma and tracheal lavage fluid were collected. The mucosal exudation response was calculated from the detection of [125I]albumin in the airway lumen. The absorption ability of the mucosa was determined by the detection of [131I]albumin in circulating plasma. Histamine induced a significant mucosal exudation of [125I]albumin. This effect was unaffected by the level of albumin on the mucosal surface. There was a small but significant absorption of [131I]albumin in the presence of 0.3 and 3.0 mg ml-1 of albumin in the luminal liquid. An albumin concentration of 30 mg ml-1 markedly increased the rate of absorption of [131I]albumin. However, the absorption rate was not affected by the histamine-induced mucosal exudation process at any level of luminal albumin. The present data further demonstrates that plasma exudation and mucosal absorption are independent processes. The data are in keeping with the view that an increased subepithelial hydrostatic pressure moves the plasma exudate across the mucosa as a distinct outward process.

Dermal blood flow after local challenges with allergen, histamine, bradykinin and compound 48/80.

Blood flow was determined in weal and flare reactions and in late dermal reactions after skin-prick tests with allergen, histamine, bradykinin and compound 48/80 in pollen-allergic subjects. Local blood flow was measured with laser Doppler flowmetry intermittently for up to 48 hr at three distances from the prick centre (2 mm; weal, 15 mm; flare and 30 mm). Continuous recordings were also made in the weal area after challenge with bradykinn and compound 48/80. The size of the induced weal and flare area of all the substances and the late phase after allergen was determined using digitized planimetry. Furthermore, simultaneous determinations of local dermal temperature and blood flow in the weal and flare site were performed intermittently for 6 hr after allergen and histamine challenges. There was a dose-dependent and distance-related increase in blood flow for all the substances tested. The blood flow in the 2-mm registrations had normalized 20 min after bradykinin, 1.5-2 hr after histamine and 3 hr after compound 48/80, while allergen induced a continuous increase in blood flow for more than 24 hr. The area of the weal and flare reaction was dose related for all substances, and a similar dose-dependent increase was noted for the observed dermal late-phase reactions present after allergen. The local temperature after challenge with allergen and histamine was also increased in a distance-dependent manner. These studies suggest that laser Doppler flowmetry is a sensitive and reproducible method to quantify blood flow changes occurring after skin-prick tests. Different putative mediators or mast cell stimulating substances produce various response profiles, all of which differ from those observed after allergen. Temperature measurements after skin-prick tests seem to follow the observed changes in blood flow as measured with laser Doppler flowmetry, which may be why both techniques might reflect changes in capillary blood flow.

Macrophages on the nasal mucosal surface in provoked and naturally occurring allergic rhinitis.

Macrophages are the most common cell type residing in the lumen of the lower airways. However, very little is known about the presence and putative pathogenic implications of macrophages in the upper airways. Using specific immunohistochemical techniques, the presence of and changes in macrophage density were studied before and after allergen exposure in the laboratory and during natural allergen exposure of subjects with seasonal allergic rhinitis. The monoclonal antibody EBM 11 combined with the alkaline phosphatase-anti-alkaline phosphatase-technique was applied on cytospin-prepared slides. In the challenge experiment, 0.5 +/- 0.2% (mean +/- SEM; n = 10) of the total cell number were positive for the EBM 11 marker before challenge, thereby not differing from the controls (0.2 +/- 0.2%; mean +/- SEM; n = 3). Local allergen challenge induced an increase of these cells to a peak of 1.3 +/- 0.4% after 4 h (p less than 0.05). During seasonal exposure there was also a similar increase, from 0.7 +/- 0.2 to 1.3 +/- 0.3% (p less than 0.05; n = 11) in placebo-treated patients and from 0.7 +/- 0.2 to 1.6 +/- 0.4% (p less than 0.05; n = 11) in patients treated with topical glucocorticoids. There was, however, no direct relationship between nasal symptoms and number of macrophages present on the mucosal surface. The study indicates that macrophages are involved in the inflammatory processes of allergic rhinitis.

125I-albumin may not be used as a tracer of absorption across the human nasal airway barriers.

This study set out to examine the effects of histamine on airway absorption of macromolecules. By employment of a novel "nasal pool" technique instillates containing 125I-albumin, with or without histamine, were kept for 15 min on human nasal mucosa. Unaffected by the presence of histamine, the instillations produced significant levels of plasma radioactivity, increasing for 60 min. However, gel-filtration data showed that only 30% of the plasma radioactivity was still bound to albumin. Incubation experiments indicated that radioiodine did not dissociate from albumin in nasal liquids nor in the blood. Further experiments involved oral ingestion of the entire nasal instillate. Prompt gastrointestinal absorption of radioactivity occurred, giving rise to plasma levels about two orders of magnitude higher than those recorded after the nasal applications. Moreover, only 25% of the plasma radioactivity was now bound to albumin. It must be considered unavoidable that a small portion (less than 1%) of the nasal instillate is swallowed. Hence, the plasma radioactivity detected in this study may largely reflect gastrointestinal break-down of 125I-albumin and subsequent absorption of radioiodine. We conclude that 125I-albumin may not be employed in studies addressing macromolecular absorption across the human nasal mucosa and that previous work and conclusions based on nasal absorption of 125I-albumin are invalid.

Plasma exudation as a first line respiratory mucosal defence.

A great variety of provocations of the airway mucosa produce extravasation of plasma from the abundant subepithelial microvessels. A plasma exudate has important actions through its volume, its specific and unspecific binding proteins, its enzyme systems, and its potent peptides (of kinin, complement, coagulation, fibrinolysis and other systems). If allowed to operate on the surface of an intact mucosa the plasma exudate would have important roles in normal airway defence. Recent observations in guinea-pig tracheobronchial airways and in human nasal airways suggest that the mucosal exudation of plasma into the airway lumen is a non-injurious fully reversible process. Threshold exudative responses thus resulted in the appearance of an 'unfiltered' plasma exudate not only in the lamina propria but also on the surface of an undisrupted mucosa. Even after extensive luminal entry of exudate the epithelial lining was intact, as judged by light, fluorescence and electron microscopy. Hence, the epithelial barrier was reversibly permeable when approached from beneath by the plasma exudate. This was a distinct increase in outward permeability, because even during the exudation of plasma the mucosa remained a barrier to luminal solutes. It is possible that the exudate itself, by a slight compressive action on the basolateral aspect of epithelial cells, creates intercellular pathways for its entry into the lumen. Contrary to current beliefs, we propose that plasma exudation should be considered a first line respiratory defence mechanism operating together with other systems of the mucosal surface.