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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.

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.

The "vasoconstrictor" effect of dermally applicated steroids is a widely used parameter when determining the potency of glucocorticoids. A similar effect on the nasal mucosa has been suggested as providing an explanation for the clinical effect of topically administered glucocorticoids in the treatment of nasal disorders such as allergic and vasomotor rhinitis. The recently described 133Xe wash-out method was used for the purpose of blood flow determination in 11 healthy subjects. In a randomized double-blind cross-over study, the effect of topically administered budesonide, a non-halogenated glucocorticoid, for 1 week was compared with that of placebo. No difference was found to occur in the mucosal blood flow after the administration of budesonide, as compared with placebo. It seems likely that a more complex activity than vasoconstriction is responsible for the clinical effect in the treatment of nasal disorders, and further research is required in order to clarify this issue.

In a nasal allergen challenge test, the effect of the glucocorticosteroid, Budesonide, on the pollen allergic type I reaction has been investigated. Placebo and two different dosages of budesonide were administered intranasally for 1 week before the challenge was performed. The study was designed as a double-blind cross-over trial. One week of treatment with the active steroid significantly reduced the nasal secretion compared to placebo as measured with the aid of a symptom score, and significantly reduced the induced nasal blockage measured objectively by means of rhinomanometry. No difference was found between the two dosages of budesonide, 400 micrograms and 100 micrograms daily, used in the study.

Symptomatic seasonal allergic rhinitis has previously been found to be associated with a redistribution of mast cells from the subepithelial stroma to the epithelial lining and the surface of the nasal mucosa. The present study was designed in order to elucidate the interaction between topical glucocorticosteroids, effective in the treatment of allergic rhinitis, and the migration of mast cells described earlier. Six patients treated prophylactically in the nose with budesonide were studied. Imprints and biopsies from the nasal mucosa were taken 2–3 weeks before and 2–3 weeks into the birch pollen season. The biopsies were used for light microscopy and tissue histamine determination. The morphologic studies showed, also in the actively treated patients, an increased number of metachromatically stained cells on the nasal mucosal surface of the same order of magnitude as previously reported for untreated patients. We did, however, find a decrease in the histamine content of the nasal mucosa, which was not associated with a decrease in the number of mast cells. Together with similar previous findings in the unstimulated allergic nasal mucosa these results suggest that glucocorticosteroids induce a decrease in the mast cell histamine pool, possibly due to an inhibition of the intracellular synthesis of histamine. This effect might contribute to the clinically beneficial effect of topical glucocorticosteroids in the treatment of hay fever.

In order to determine the effect of PAF-acether on the vascular bed in the human nose, 11 healthy volunteers were studied. Rhinomanometry was performed to determine the effect on the capacitance vessels, and the 133Xe wash-out method enabled determination of the mucosal blood flow, regulated mainly by the resistance vessels. These measurements were made before and after topical administration of PAF-acether in three different doses; 0.26 micrograms, 2.6 micrograms and 26 micrograms per nostril. The results indicate that PAF-acether induces a dose-dependent vasoconstriction of the capacitance vessels and a reduction in mucosal blood flow. That PAF-acether should be a principal mediator in the allergic reaction in the human nose is not supported by these findings.

Insight into the pathogenesis of human allergic and inflammatory disorders has been obtained through a combination of in vitro and in vivo studies. These investigations have demonstrated that human basophils and mast cells release mediators after nonimmunologic as well as immunologic activation in vitro and in vivo: nonimmunologic triggers include changes in osmolarity. Although these cells share many properties, including the presence of high-affinity receptors for IgE on their cell surface, the presence of histamine in granules, the ability to generate and release large quantities of leukotriene C4 (LTC4) after activation, and the ability of several pharmacologic agents including phospholipase inhibitors, acetylene analogues of arachidonic acid (ETYA, ETI), methylxanthines, prostaglandin E2 (PGE2) beta-agonists, and cyclic AMP to inhibit mediator release, they also display notable differences. Human lung mast cells generate and release large quantities of prostaglandin D2 (PGD2) after activation; basophils generate no known cyclooxygenase product. Indomethacin, arachidonic acid, and 5-hydroperoxyeicosatetraenoic acid (5-HPETE) all enhance histamine and LTC4 release from human basophils; no effect is seen with human lung mast cells. Overnight incubation of basophils with glucocorticoids produces a marked inhibition of mediator release; this treatment does not affect the release of mast cell mediators. These in vitro observations are consistent with our in vivo observations and our hypotheses concerning the importance of these cells in allergic disease.(ABSTRACT TRUNCATED AT 250 WORDS)

The possible mode of action of the lately demonstrated steroid effect on the immediate type allergic reaction was investigated. The influence of a topical steroid, budesonide, on the effects that released mediators have on the nasal mucosa was also studied. A nasal histamine challenge study was performed in a double-blind, cross-over fashion, a 1-week pretreatment with budesonide or placebo preceding the challenge. Symptoms were recorded by means of symptom score as well as objectively via rhinomanometry. In contrast to a previous allergen challenge study, the steroid was found to have minimal effect on the histamine-induced nasal symptoms. It is therefore concluded that other modes of steroid action must also be involved in the steroid effect on the immediate type allergic reaction.

Mast cells were studied by light microscopy in mucosal imprints and in biopsies of nasal mucosa of 12 birch pollen allergic individuals before and during the pollen season, using techniques optimized for the demonstration of mucosal mast cells. We also measured the histamine content of nasal mucosa, whole blood and plasma, and counted the numbers of circulating blood basophils. Before the pollen season the nasal mucosa was found to contain many mast cells located in the mucosal connective tissue stroma, and very few cells with basophilic and metachromatic granules were found in mucosal imprints. During the pollen season there was a redistribution of mast cells into the epithelium, many such cells now being recovered in mucosal imprints. The total number of mucosal mast cells counted in tissue sections did not change significantly with the onset of the pollen season, suggesting a redistribution of mucosal mast cells by migration. Judged by morphologic appearance and naphthol-AS-D chloroacetate esterase activity, the intraepithelial mast cells found in tissue sections had rather the properties of tissue mast cells than of blod basophils, and only a few of the basophilic cells of the imprints had a morphology compatible with blood basophils. The histamine content of the mucosa, as well as histamine levels of whole blood and plasma, and circulating blood basophil numbers did not change significantly in relation to the pollen season. These findings suggest that an intraepithelial migration of mucosal mast cells is part of the allergic mucosal response. This reaction resembles the nematode response of certain rodents and may explain how contact is established between mucosal allergens and effector cells when the allergic reaction is initiated.

The correlation between allergen-induced specific and non-specific (histamine) nasal reactions was studied, especially as regards topical glucocorticosteroid effects on the non-specific reactions. Thirteen patients with strictly seasonal allergic rhinitis participated. A nasal challenge with histamine and three increasing doses of allergen was performed on the first day. The patients were rechallenged 24 h later with the same histamine dose and the lowest allergen dose from the previous day. The same 2-day challenge was also performed after pretreatment for one week with budesonide in 8 of these patients. Symptom scores were recorded. The N-alpha-tosyl-L-arginine-methyl-esterase (TAME esterase) activity in nasal lavages was determined. The nasal symptoms and the TAME-esterase activity increased at rechallenge for both histamine and allergen, compared with the initial challenge. The mean ( +/- SE) composite nasal symptom score after histamine increased from 3.5 +/- 0.49 to 4.9 +/- 0.35 (p less than 0.01) and after allergen from 1.62 +/- 0.3 to 3.2 +/- 0.5 (p less than 0.01) at rechallenge. Similar increases were recorded for the TAME-esterase activity. A close correlation between the allergen-induced increase in specific (allergen) and non-specific (histamine) reactivity was found (r = 0.7, p less than 0.01, composite nasal symptom score). Treatment with topical glucocorticosteroids abolished the allergen-induced increase in both specific (p less than 0.001) and non-specific (histamine) (p less than 0.01) nasal reactivity.

The possible mode of action of the recently demonstrated steroid effect on the immediate type allergic reaction has been studied. The influence of a topical steroid, budesonide, on the nasal mucosal histamine content and anti-IgE induced histamine release was studied in an open study. A 1-week treatment with budesonide, used locally in the nose, was administered to 22 hay fever patients who were studied out of the pollen season. There was a decrease of histamine content after steroid treatment and also a blockade of the anti-IgE mediated histamine release, as shown in an in vitro release procedure. This steroid effect may partly explain the effect of steroids on the immediate reaction, as it has been demonstrated in allergen challenge studies.

It has been previously demonstrated in nasal challenge studies that there is an increased sensitivity to allergen following an initial allergen challenge. A similar feature has been demonstrated following natural allergen exposure in patients with seasonal allergic rhinitis. To further explore the characteristics of this “priming” phenomenon and its relationship to other expressions of their allergic airway disease, 28 hay fever patients with strictly seasonal disease were studied. Skin tests with the relevant pollen allergen and histamine were performed and the size of the immediate and late phase allergic reaction was determined. An initial nasal allergen challenge was followed by a rechallenge of the nose with allergen 24 h later using a lavage technique. Determinations of TAME-esterase activity, as a biochemical marker of the allergic reaction, were made in the returned lavage fluid. The number of sneezes was counted and nasal symptoms were also assessed using a scoring technique. 19 of 28 patients (67%), displayed an increased responsiveness at rechallenge with similar findings in terms of symptom scores and TAME-esterase measurements. The increase was statistically significant for the symptoms of nasal blockage, which increased from 0.7 ± 0.1 (mean ± SEM) to 1.1 ±0.2 (P ± 0.05), and nasal secretion which rose from 1.1 ± 0.2 to 1.7 ± 0.2 (P < 0.01). A composite nasal symptom score which also took account of the number of sneezes, increased from 2.9 ± 0.4 to 4.0 ± 0.3 (P < 0.01). The TAME-esterase activity in the recovered lavage fluid following challenge with the same allergen dose increased from 11.7 ± 2.4 to 18.7 ± 2.8 CPM/103 (P < 0.01). No correlation was found between the increased responsiveness and the size of initial immediate reaction either in the nose or in the skin, or the presence or size of any late phase dermal reaction. There was, however, a correlation between the size of initial allergen response in the nose and skin (r = 0.43). As an increased responsiveness to allergen appears to be of clinical significance at natural allergen exposure, further studies of the pathophysiology of this phenomenon are called for.

We studied the effect of alpha-fluoromethyl histidine, an irreversible histamine synthesis inhibitor, on the immediate nasal reaction to antigen challenge in a double-blind, placebo controlled, randomized, parallel study using 13 subjects. The patients received either active drug 100 mg twice daily or placebo, for 3 weeks. A nasal allergen challenge was performed before and after at weekly intervals. Symptoms at challenge were assessed and the levels of histamine, TAME-esterase activity and kinins were measured in nasal lavages before and after antigen challenge. Skin tests were also performed at weekly intervals. In addition, the urinary excretion of the main histamine metabolite, telemethylimidazole acetic acid, was measured before and after 3 weeks of treatment. The active treatment induced 60% reduction in histamine levels in the lavage fluids before and after antigen challenge, as well as a reduction in the histamine levels in the lavage fluids before and after antigen challenge, as well as a reduction in the main urinary histamine metabolite. However, no reduction was found in nasal symptoms obtained after antigen challenge. The levels of kinins and TAME-esterase activity were not significantly reduced.

By means of rhinomanometry the effects of two oral decongestants, d-pseudoephedrine and phenylpropanolamine were compared in acute infectious rhinitis. In a single-blind study involving 20 patients no difference was found between 120 mg d-pseudoephedrine and 100 mg phenylpropanolamine in relieving nasal congestion.In an open study, the effect of 100 mg phenylpropanolamine as related to body position was measured in 14 patients. No difference was found between taking medicine and remaining recumbent as compared with assuming an upright position only.

Although theoretical considerations and experimental evidence implicate the mast cells in the pathophysiology of the immediate type hypersensitivity reaction, the evidence of their active participation in human allergic disease is still fragmentary. We have therefore sought evidence of mast cell activation in allergic mucosal disease using strictly seasonal allergic rhinitis as a model. Twelve patients with birch pollen-induced hay fever were examined before and well into the birch pollen season. Allergen exposure was monitored by pollen counts and the degree of symptoms registered daily. Small surgical biopsies and mucosal imprints were obtained from each patient before and during the season. Mast cells were analysed by light and electron microscopy and mucosal histamine was measured using a sensitive HPLC assay. We found a reduction in the number of mast cells in the nasal mucosa during pollen exposure (p less than 0.05) but no significant reduction of the histamine content. There was a correlation between the nasal mucosal mast cell density and histamine content before the pollen season (r = 0.76; p less than 0.01), but no such correlation was found during the period of pollen exposure (r = 0.19; n.s.). This finding points to secretory activity by the mast cells during the pollen season and to the appearance of a non-mast cell pool of tissue histamine. Evidence for a secretory activity of the mast cells during the pollen season was also confirmed by electron microscopy. In addition, we found a strong correlation (r = 0.77; p less than 0.01) between the histamine content of the nasal mucosa during the pollen season and the degree of nasal symptoms. The number of epithelium-associated mast cells found on mucosal imprints prior to the pollen season showed a strong correlation with the symptoms experienced later during the period of pollen exposure (r = 0.83; p less than 0.01). Taken together these observations indicate that the mast cell has a pathogenetic role in continuous allergic airway disease and re-emphasizes the role of histamine in the induction of the symptoms of allergic rhinitis.

Compared to the lower airways the human nose offers an extremely accessible part of the human airways. In recent years, several methods have been devised allowing us to study different components in reactions that occur in the upper airways. By choosing the right methods for the right questions, we will be able to obtain valuable information on the pathophysiology and pharmacology of nasal disorders. This information might not only be relevant to the upper airway; it may well be applicable to other parts of the airways as well.

Glococorticoids were previously considered not to affect the immediate allergic reaction. However, in a nasal allergen challenge, an inhibitory effect on the nasal symptoms induced at the challenge has been shown to occur in patients treated with a recently developed Glucocorticoid, budesonide, for 1 week prior to the challenge. This treatment was also found to reduce tissue histamine levels in the nasal mucosa. Mast cells in the mucosa were therefore studied with a view to finding out whether this reduction could be due to a reduction of mast cells. A double-blind study was performed in 14 asymptomatic patients. Nasal biopsies were made before and after I week's treatment with either budesonide or placebo. The number of mast cells was counted in two Epon sections after the specimens has undergone specific staining with toluidine blue. No quantitative or qualitative morphological changes in the mast cells were found as a result of treatment.

A new steroid for nasal use, Budesonide, is presented. Earlier studies have shown it to be efficacious compared to placebo in the treatment of allergic rhinitis. In a blind comparison with Beclo-methasone dipropionate, where both drugs were administered in daily 400 μg doses, the effect of budesonide proved to be significantly superior in hay fever treatment. In a long-term study of vasomotor rhinitis, no adverse effect on plasma cortisol and nasal mucosa could be detected after one year of continuous treatment. In a nasal allergen challenge study, a clear effect on the type 1 reaction could be shown after a one-week pretreatment period.