Substance P is generated in vivo following nasal challenge of allergic individuals with bradykinin

Background Bradykinin, a potent inflammatory mediator, is released during allergic and non-allergic rhinitis and asthma in man. Nasal bradykinin challenge induces a dose-dependent plasma leakage into the nasal cavity and relevant symptoms of rhinitis. Objective We now report on substance P generation during nasal bradykinin challenge in vivo. Methods The effect ot locally applied bradykinin on substance P generation was studied in nine individuals, allergic to grass pollen and six non-allergic controls. In the allergies TAME-esterase activity, histamine and substance P concentrations were measured in nasal lavages and correlated to the clinical symptoms. Results Substance P concentrations in nasal lavages increased in a dose-dependent fashion during nasal bradykinin challenge in both groups. In the allergic group Substance P-increases correlated with the production of TAME-esterase activity (r= 0.9. P < 0.05) whereas these allergic individuals did not produce any histamine increases. The generation of substance P and the increase of TAME-esterase activity was associated with the onset of clinical symptoms. Correlation of oedema and hypersecretion to substance P were signiticant by linear regression analysis (r = 0.88, P < 0.005 and r= 0.89. P < 0.02, respectively). Bradykinin induced irritations like burning and itching were shortterm and rare. Serial dilutions of nasal washes produced Substance P-RIA displacement curves that paralleled the standard curve and recovery of standard substance P that was added to nasal washes was 76 ± 4% (mean ± sem), n= 8. Conclusion Bradykinin induces in vivo a dose-dependent plasma leakage into the nasal cavity without affecting mast cells, but stimulates nerve endings resulting in the release of the neuropeptide substance P.     

Relationship between nasal hyperreactivity, mediators and eosinophils in patients with perennial allergic rhinitis and controls

Background In perennial allergic rhinitis, patients are almost daily exposed to aeroallergens. This ongoing allergic reaction results in increased sensitivity to allergens and non-specific stimuli. It is generally known that inflammatory cells and mediators are involved in the pathogenesis of the allergic reaction. Objectives To study the relationship between nasal hyperreactivity and nasal inflammation during natural allergen exposure. Methods In 48 patients with perennial allergic rhinitis and in 11 volunteers a nasal brush, a nasal lavage and a histamine challenge were performed. Nasal inflammation was estimated by the number of eosinophils, levels of albumin, tryptase, prostaglandin D₂ (PGD₂), eosinophil cationic protein (ECP) and leukotriene C₄/D₄/E₄ (LTC₄/D₄/E₄). Results In contrast to PGD₂ and tryptase, eosinophils (1.9 vs 0%, P = 0.0023), LTC₄/ D₄/E₄ (17.51 vs 1.43pg/mL, P= 0.0001) and albumin (8.61 vs 2.37mg/mL, P= 0.0008) were significantly increased in rhinitis patients as compared with controls. Patients also showed increased responses to nasal histamine challenge assessed using a composite symptom score (21.5 vs 4 points, P=0.0001). The nasal response to histamine was weakly correlated with the total number of eosinophils in the cytospin (correlation coefficient r=0.38, P= 0.009). Conclusion Nasal hyperreactivity is correlated with the percentage of eosinophils in patients with perennial rhinitis. The patients' mediator profiles suggest that eosinophils are important in the ongoing allergic reaction and nasal hyperreactivity.     

Effects of bβ‐endorphin on nasal allergic inflammation

Background πβ‐endorphin is a derivative of pro‐opiomelanocortin. Cells of the immune system can also synthesize and secrete β‐endorphin. Its concentration is increased during the allergic reaction and during stress. Increased reactivity during psychological stress of allergic subjects is also well known. Objective Is β‐endorphin one physiological link between stress and an exacerbation of the allergic reaction? Methods First, intranasal β‐endorphin challenges with subsequent lavages to determine histamine and albumin levels and measurements of nasal flow and resistance in dose‐response and time course experiments were performed. Secondly, we examined whether β‐endorphin pre‐treatment increased the antigen‐induced release of histamine and albumin in nasal lavages and the clinical symptoms. Results Exogenous β‐endorphin (100 pM?10 µM/mL) induced a dose‐dependent increase in nasal symptoms in asymptomatic allergic subjects with rhinitis (n = 14) as well as in non‐allergic controls (n = 10), but did not release any mediators into nasal secretion. However, comparing the antigen‐evoked release of mediators into nasal secretions with that of a β‐endorphin pre‐treated antigen challenge we could note a significant enhancement of human serum albumin influx (P < 0.05) and histamine liberation (P < 0.05) 10 min after antigen challenge compared with the allergen challenge alone, with also a correlation with the more pronounced decrease in nasal flow (P < 0.05). Conclusion These results suggest that β‐endorphin‐induced increase in nasal congestion is mediated through direct neuroendocrine receptor activation independent of mast cell activation and that during the allergic reaction there is a β‐endorphin/mast cell interaction that enhances the mediator response to nasal allergen challenge.     

Selective recruitment of eosinophils by substance P after repeated allergen exposure in allergic rhinitis

We have investigated the nasal response to substance P after pollen exposure in seasonal allergic rhinitic patients. Seven patients with strictly seasonal allergic rhinitis were studied during the pollen season, 24 h after nasal challenge with pollen. They received increasing doses of nebulized substance P (0 to 80 nmol) in each nostril. Responses were assessed by measurement of nasal airway resistance by posterior rhinomanometry and quantification of albumin, histamine, and inflammatory cells in the nasal lavage fluid. Nasal airway resistance increased in a dose-dependent manner after substance P challenge. Protein and albumin in nasal lavage fluids increased after administration of substance P: from 2.6 ± 0.3 to 6.8 ± 1.1 mg for protein (P≤0.01) and from 0.2 ± 0.1 to 3.1 ± 0.6 mg for albumin (P≤0.02). Expressed as a percentage of total protein, albumin increased from 10.5 ± 3.6% to 39.9 ± 3.5% (P≤0.02), suggesting occurrence of plasma leakage. No histamine release was observed after challenge with substance P. Total cell counts significantly increased from 11.4 ± 2.4 to 41.8 ± 17.3 × 10³ cells/ml after substance P (P≤0.05). Eosinophils were already numerous before substance P challenge (2.1 ± 0.7 × 10³ cells/ml), and the number of eosinophils markedly increased in all patients after substance P (for the whole group, 25.8 ± 13.3 cells/ml, P≤0.05). In contrast, the number of neutrophils only slightly increased in five patients, and changes did not reach significance for the group as a whole. Our results show that substance P induces nasal obstruction and albumin extrusion in allergic rhinitic patients after repeated pollen exposure. These vascular phenomena are associated with recruitment of eosinophils. Since substance P is known to be released after nasal allergen challenge, our data suggest a role for substance P in the chronic eosinophilic inflammation of the nasal mucosa observed in symptomatic allergic rhinitis.     

Mucosal blood flow in the human nose following local challenge with histamine

Nasal blood flow was measured using the 133Xe wash-out method in 10 non-allergic subjects and 13 asymptomatic hay fever patients. Determinations were made before and 15 min after challenge with diluent, 0.13 mg, 1.3 mg and 13 mg of histamine/nasal cavity. Nasal symptom scores were recorded. The nasal inspiratory peak flow was determined simultaneously in the hay fever patients. No differences in blood flow or symptom score recordings were found between the normal subjects and allergic patients under basal conditions or after histamine challenge. The nasal blood flow increased after challenge with the highest histamine dose. The increase was 34% (P less than 0.05) from baseline in normals and 47% (P less than 0.05) in allergics. There was a dose-dependent increase in nasal symptom scores following histamine challenge, again with no difference between normal and allergic subjects. The nasal peak flow decreased in a similar manner with a maximum decrease of 74% (P less than 0.001). The present study gives further support to the notion that histamine is not the only mediator involved in vascular reactions during allergic rhinitis.     

Variations in histamine concentration in nasal secretion in patients with allergic rhinitis

The histamine concentration and content in nasal secretion and the volume of nasal secretion in nasal washing samples were measured under different conditions in 28 patients with allergic rhinitis sensitive to birch pollen. The mean histamine concentration was significantly lower after intranasal birch pollen challenge (2.08 micrograms/ml) than in prechallenge samples (6.96 micrograms/ml), and was also significantly lower in untreated patients during the birch pollen season (2.30 micrograms/ml) than off-season (7.18 micrograms/ml). The same relationship was found between the histamine content of the secretion samples obtained on these occasions. The mean secretion volume was greater after than before challenge, but not significantly higher during the season than off-season. A partial reversion of the changes in histamine concentration and content that occurred during the season was observed during intranasal corticosteroid therapy. The concentration and content of histamine in nasal secretion from symptomatic patients after intranasal histamine challenge did not differ significantly from those in asymptomatic subjects before challenge. It was concluded that although the histamine level in nasal secretion can be used as a marker of changes in the severity of allergic rhinitis, it is not ideal for this purpose.     

Study of the effects of paf-acether on human nasal airways

In 6 normal subjects and 6 patients with allergic rhinitis, nasal response to insufflation of paf-acether (paf, platelet-activating factor), lyso-paf and histamine was evaluated. Nasal challenge with paf, at doses of 300 and 600 nM, induced nasal obstruction, associated with an increase in nasal airway resistances, measured by anterior passive rhinomanometry. Maximum increase in nasal airway resistance was observed at 30 min after challenge (mean percent change + 481 with 600 nM paf; P less than 0.05). Other symptoms induced by paf insufflation were rhinorrhea (6 out of 12 subjects), itching (8 out of 12), sneezing (4 out of 12) and a burning sensation (6 out of 12). No differences were observed between normal and rhinitic subjects, concerning nasal sensitivity to paf. Neither nasal symptoms nor changes in nasal airway resistance were observed after nasal challenge with lyso-paf (300 and 600 nM); by contrast, histamine (100 nM) induced sneezing, nasal obstruction, itching and rhinorrhea in all the studied subjects, associated with an increase in nasal airway resistance (maximum 5 min after challenge; percent change + 358; P less than 0.02). Nasal effects of paf were not mediated by histamine, since no increase in histamine levels was observed in nasal washings following paf insufflation. We conclude that paf may have pathogenetic relevance in allergic rhinitis.     

Substance P induced histamine release from nasal mucosa of subjects with and without allergic rhinitis

OBJECTIVE AND DESIGN: There is evidence that substance P (SP) is involved in events related to allergic and nonallergic rhinitis. Furthermore, some effects of SP seem to be greater in subjects suffering from allergic rhinitis than in nonallergic subjects. To investigate if these effects may be partly mediated by histamine release (HR) we studied the influence of SP on HR from nasal mucosa of subjects with and without allergic rhinitis using an in vitro organ culture system. SUBJECTS: Nasal mucosa of the inferior turbinate was obtained from ten patients suffering from allergic rhinitis and eighteen non-allergic subjects receiving surgical therapy for nasal obstruction. METHODS: Tissue samples of nasal mucosa were stimulated with 10(-5) M SP or with 10(-5) M Ca-ionophore A23187 for 120 minutes, and the histamine content was determined in the culture supernatant. RESULTS: Both SP and Ca-ionophore A23187, caused a significantly higher HR from the samples of the non-allergic group (p < 0.01) compared to baseline controls (spontaneous release). The same effect was seen in the allergic group (p < 0.01 and p = 0.036). Comparing the increase in HR from allergic and non-allergic mucosa, in allergics the HR stimulated by SP was significantly higher (p = 0.031), whereas Ca-ionophore A23187 did not show this effect. CONCLUSION: These findings suggest a role of SP in inducing release of histamine from human nasal mucosa, thereby influencing physiologic and pathophysiologic nasal conditions, especially in allergic inflammatory processes.     

Facial thermography during nasal provocation tests with histamine and allergen

Changes of skin temperature (T°) of the nose area during nasal provocation tests with histamine and allergen were followed by means of an infrared thermography camera. By a colimator system in which temperatures measured on a given surface can be integrated and averaged, thermography allows the continuous and quantitative recording of the temperature during the whole procedure in a completely noninvasive way. In 10 normal subjects, increasing doses of histamine induced a dose-dependent rise of the nose external temperature. No significant change was observed with the vehicle solution. In six subjects allergic to grass pollen, the nebulization of increasing concentrations of a pollen extract induced a dose-dependent rise in T°. The T° rise observed after histamine or allergen corresponded to a marked nasal obstruction. The nebulization of the highest dose of the pollen extract did not induce any T° rise in six nonallergic subjects. The continuous recording of the skin temperature by a noninvasive method might yield additional information on the vascular changes rapidly occurring during nasal challenges.     

Exudative hyperresponsiveness of the airway microcirculation in seasonal allergic rhinitis

Background Mucosal exudation of plasma is a non-injurious, physiological response of the airway microcirculation to different inflammatory processes. The exudative response is similar in the nose and bronchi and exudation occurs in both allergic asthma and rhinitis. The educative response is a specific end-organ function of the mucosal microcirculation that may be altered in airway diseases. Objective This study examines the hypothesis of altered responsiveness of the superficial airway microcirculation to vascular permeability-increasing challenges in sustained allergic inflammation. Methods Fourteen patients with birch-pollen induced allergic rhinitis were studied for 7 weeks during a Swedish birch-pollen season. Nasal symptoms (itching, sneezing. blockage, and discharge) were recorded and the occurrence of pollen was determined. The plasma exudation response was examined by topical histamine challenges at the end (May) and well out of (December) the season. Challenge and lavage were carried out concomitantly using a‘nasal pool’ -device. The unilateral nasal cavity was filled for consecutive 10 minute periods with saline and two concentrations of histamine (80μg/ mL and 400μg/mL). The lavage fluid levels of different-sized plasma proteins (albumin-66 000 D. fibrinogen-340000 D, and α₂-macroglobulin-725000D) were determined. Results The pollen season was mild resulting in only minor nasal symptoms. Histamine produced exudation of all plasma proteins across the microvascular epithelial barriers with particularly strong correlation between the levels of albumin and α₂-macroglobulin (r =0.98; P< 0.001). The exudative response to histamine was concentration-dependent (P<0.05) and, furthermore, it was significantly greater late into the season compared with outside the pollen season (albumin: P < 0.05. tibrinogen: P<0.05. α₂-macroglobulin: P<0.01). Conclusion We conclude that histamine produced concentration-dependent nasal airway exudation of bulk plasma in subjects with seasonal rhinitis and that this response is abnormally great during the pollen season. Whether angiogenesis or increased responsiveness of the mierovascular endothelium may explain this phenomenon now remains unknown. We suggest that a mierovascular exudative hyperresponsiveness may characterize allergic airway disease.     

Histamine concentrations in nasal secretion and secretory activity in allergic rhinitis

The prerequisites for using the assayed histamine concentration in nasal secretion as an objective measure of disease activity in allergic rhinitis were investigated. It was demonstrated that in histamine determination procedures the presence of quenching substances in the nasal secretion could lead to underestimation of the histamine concentration. This bias was eliminated in a modified spectrofluorometric assay. Only an insignificant fraction of the histamine in samples collected by nasal spray washing was bound to unfiltrable particles or cells. The mean histamine concentration in nasal secretions from 15 healthy subjects was 11.2 micrograms/ml and in a group of nine patients with allergic rhinitis out of season 3.36 micrograms/ml. The histamine concentration in the latter group decreased during the pollen season and after positive allergen challenge. It is suggested that this decrease is caused by the increase in volume of the secretion during the allergic response. The use of lithium as an exogenous marker permitted quantitation of the increase in the relative amount of nasal secretion recovered by washing in the symptomatic subjects.     

Assessment of the allergic reaction in seasonal rhinitis: acoustic rhinometry is a sensitive and objective method

Background Seasonal allergic rhinitis constitutes an excellent in vivo model of an allergic mucosal inflammatory reaction. This offers the opportunity of studying the fundamentals of allergic inflammation in addition to improvement of knowledge on the basal pathophysiological mechanisms of the disease. So far, monitoring methods of disease activity and treatment efficacy have mainly been based upon subjective assessments, illustrating the impact of introducing reliable objective methods. Objective To investigate the allergic inflammatory reaction of seasonal rhinitis through different objective methods and evaluate these as indicators of disease activity and treatment efficacy. Methods Functional parameters, i.e. acoustic rhinometry and nasal metacholine challenge, and biological markers, i.e. blood eosinophil count, eosinophil cationic protein in serum (s-ECP) and nasal lavage fluid (n-ECP), were assessed before and at peak pollen season in 27 patients with grass pollen induced rhinitis. Patients were randomized to either nasal corticosteroid or placebo treatment and recorded nasal symptom scores. Results Acoustic rhinometry revealed a significant difference in favour of steroid treatment (P < 0.05) comparing nasal volumes before and during season. This difference primarily relied upon a decrease in the placebo group (P= 0.05). A reduction from baseline of s-ECP in the steroid group (P < 0.01) was obtained. N-ECP demonstrated a difference between treatment groups, although not significant. Symptom scores increased in all patients during the pollen season, although this was only significant in the placebo treated patients (P < 0.01). The remaining methods applied did not demonstrate further differences, either within or between treatment groups. Conclusion Our results demonstrate acoustic rhinometry to be a sensitive and objective method of assessment of nasal obstruction. Furthemore, acoustic rhinometry and s-ECP reflect the impact of nasal steroid therapy on seasonal allergic rhinitis.     

Reproducibility of nasal allergen challenge in evaluating the efficacy of intranasal corticosteroid treatment

Background Although nasal challenge with allergen has often been used to evaluate the efficacy of therapeutic modalities used for the treatment of allergic rhinitis, the reproducibility of this model in quantitatively evaluating efficacy has not been rigorously examined. Objective To examine the reproducibility of the suppressive effects of an intranasal corticosteroid on the clinical and biochemical outcomes of a nasal allergen challenge during two identical treatment periods using the same subjects. Methods In a single‐blind study, 25 seasonal allergic subjects with positive skin tests to grass or ragweed were studied outside of their pollen season. Subjects underwent a baseline, three‐dose allergen challenge. Beginning 1 week later, subjects received two 7‐day courses of intranasal beclomethasone (168 μg b.i.d.) separated by a 1‐month washout period. Nasal challenges with allergen were performed after each treatment period. The nasal allergic response was evaluated by counting sneezes, recording symptom scores and measuring levels of albumin (an index of vascular permeability), lysozyme (an index of serous glandular secretion) and kinins (proinflammatory peptides) in recovered nasal lavages. Results Compared with the baseline challenge, each course of beclomethasone significantly reduced sneezing, symptom scores, albumin and kinins, but not lysozyme. Reproducibility analysis of the net changes from diluent challenge in the two beclomethasone treatment periods, showed the following intraclass correlation coefficients: sneezing (0.92), lysozyme (0.82), symptom scores (0.72), albumin (0.64) and kinins (0.28). Conclusion We conclude that the nasal challenge model is a reproducible method to evaluate the efficacy of anti‐allergic medications. For nasal corticosteroid trials, sneezing, symptom scores and albumin levels are recommended as the most reproducibly suppressive outcome measures. Cite this as: D. Proud, D. K. Riker and A. Togias, Clinical & Experimental Allergy, 2010 (40) 738–744.     

Nasal nitric oxide is increased in allergic rhinitis

Background Nitric oxide (NO) plays a major role in the regulation of vascular tone and in non-specific host defence. The epithelium in the paranasal sinuses was recently identified as the major site of NO production in the upper airways. Objective To investigate NO status in allergic rhinitis, we compared the NO concentration in the nasal cavities of control subjects (n= 19) and in patients with allergic rhinitis (n= 36) with symptoms (WS, n= 17) or without symptoms (WOS, n= 19) on the day of the test. Methods NO concentration was measured using a chemiluminescent analyser aspiring from each nasal cavity at a sampling flow rate of 0.7L/min, before and 10min after administration of a nasal vasoconstrictor. Results The mean NO concentration (± se) in the control was 235 ± 11 ppb and 225 ± 9 ppb in the right and left nostrils respectively, and was decreased by 14% and 12% by the nasal vasoconstrictor (P < 0.001). The NO concentration in patients with allergic rhinitis was significantly higher in the right and left nostrils (382 × 20 ppb and 396 ± 28 respectively, P < 0.0001 versus control). All WOS patients demonstrated normal or increased NO concentrations in both nostrils, whereas two WS patients showed decreased NO concentrations in the left nostril. Inhalation of a nasal vasoconstrictor increased NO concentration by 6% and 27% in the right and left nostrils respectively in WS patients. Conclusion Nasal NO concentration is increased in patients with allergic rhinitis. Interestingly, patients without symptoms on the day of the test also showed a clear-cut increase in nasal NO production, which could reflect a permanent inflammation of the sinus mucosa.     

Effect of intranasal fluticasone proprionate on the immediate and late allergic reaction and nasal hyperreactivity in patients with a house dust mite allergy

Background Patients with perennial allergic rhinitis develop nasal symptoms not only after allergen exposure, but generally also after non-specific stimuli. Objective To evaluate the effect of 2 week's treatment with fluticasone propionate aqueous nasal spray (FPANS) on the nasal clinical response, inflammatory mediators and nasal hyperreactivity. Methods Twenty-four rhinitis patients allergic to house dust mite (HDM). participated in a douhle-blind. placebo-controlled crossover study. After 2 week's treatment with placebo or 200 μg FPANS twice daily, patients were challenged with HDM extract. Symptoms were recorded and nasal lavages were collected for up to 9.5 h after challenge. Nasal hyperreaclivity was determined by histamine challenge 24 h later. Results Because of a carry-over effect for the immediate symptom score, for this variable only the data from the first treatment period were used. FPANS treatment resulted in a significant decrease of nasal symptoms with 70%. 69% and 63% after 100. 1000 and 10000 Biological Units (BU)/mL of HDM extract respectively. Active treatment resulted in a 76% decrease of the late-phase symptoms. FPANS treatment significantly reduced albumin influx after HDM 1000 BU/mL with 62% and tended to reduce tryptase release after HDM 1000 BU ml. (P 0.0629). During the late phase FPANS treatment reduced albumin influx with 67% and eosinophil cationic protein (ECP) release with 83%. No effect of FPANS was seen on histamine levels. FPANS significantly decreased histamine-induced symptom score with 34%, secretion with 32%, and sneezes with 41%. Conclusion FPANS significantly inhibits the immediate and late allergic response, and nasal hyperreactivity, probably by suppressing mast cells and eosinophils in the nasal mucosa.     

Allergic rhinitis to grass pollen: Measurement of inflammatory mediators of mast cell and eosinophils in native nasal fluid lavage and in serum out of and during pollen season

Background: In allergic rhinitis, mast cells, activated by cross-linking of allergen to mast cell–bound specific IgE, release both vasoactive mediators related to the early nasal symptoms and chemotactic mediators that attract inflammatory cells, such as eosinophils, related to the late-phase response. Objective: We have analyzed, during and out of pollen season, in blood and nasal fluid from patients allergic to grass pollen, histamine and tryptase to monitor the early phase markers and eosinophil and eosinophil cationic protein (ECP) to monitor the late phase. Methods: Twenty patients were enrolled in the study. As a control, we studied 10 nonatopic subjects. Mediators and eosinophils were assessed in blood and nasal fluid. Histamine was tested only in nasal fluid. Results: During pollen season, tryptase but not histamine increased in nasal fluids from patients (2.96 vs 0.22 U/ml, p = 0.001) and correlated with symptom scores (r_s = 0.63, p = 0.003). Tryptase was not detected in serum. Eosinophils increased in nasal cytology (17.0% vs 2.0%, p = 0.001) and in the blood (26.5 vs 12.7 × 10⁶ L, p = 0.001) from patients, but they did not correlate with symptom scores. ECP increased only in the nasal lavage (16.33 vs 1.30 ng/ml, p = 0.001) and correlated with symptom scores (r_s = 0.53, p = 0.016). Conclusions: Both ECP and tryptase increase in nasal secretion in natural disease. Therefore the measurement of tryptase and ECP levels in nasal fluid might be a useful clinical test for monitoring disease activity and the effects of therapeutic agents. (J Allergy Clin Immunol 1997;100:832-7.)     

Effects of topical budesonide and levocabastine on nasal symptoms and plasma exudation responses in seasonal allergic rhinitis

This study compares the effects of two topical nasal treatments for allergic rhinitis, budesonide and levocabastine, on symptom development during seasonal pollen exposure. Additionally, the protective effects of drug treatments on allergen-challenge-induced responses (symptoms and microvascular exudation of plasma) are examined late into the pollen season. Forty-four patients with seasonal allergic rhinitis to birch pollen participated in this single-blind, randomized, and placebo-controlled study. Topical nasal treatment with either levocabastine (200 p.g b.i.d.: n = 16), budesonide (200 μg b.i.d.; n = 16), or placebo (n= 12) was instituted before the start of the pollen season and continued for 5 weeks until the end of the birch pollen season. The participants kept diaries for scores of nasal and ocular symptoms. Nasal allergen challenges with increasing doses of a birch pollen extract (10², 10³ and lC SQ-U) were carried out both before, when patients were asymptomatic and without treatment, and late into the pollen season. A nasal lavage followed each challenge, and the lavage fluid levels of albumin were measured as an index of the acute inflammatory response of the allergic mucosa. The birch pollen season was rather mild, producing only small increases in nasal symptoms. Budesonide treatment reduced the total nasal symptoms compared to placebo (P<0.01) and to levocabastine (P<0.05), while levocabastine treatment did not differ significantly from placebo. Ocular symptoms and use of rescue medication did not differ between placebo and the active treatments. At the end of the pollen season, both treatments reduced allergen-challenge-induced nasal symptoms compared to placebo (P<0.01). Only budesonide reduced allergen-challenge- induced increments of albumin levels in postchallenge nasal lavage fluids (P<0.05, in comparison with placebo). The results suggest that budesonide reduces both seasonal and allergen-challenge-induced nasal symptoms, while levocabastine is effective against allergen-challenge-induced symptoms also during the season. In addition, the topical steroid treatment, but not the antihistamine, inhibits the inflammatory exudation evoked by allergen challenge in patients with active seasonal disease.     

Albumin, bradykinins, and eosinophil cationic protein on the nasal mucosal surface in patients with hay fever during natural allergen exposure

This study examined plasma- and eosinophil-derived products in nasal lavage fluids obtained from patients with hay fever during natural allergen exposure. Nine patients with strictly seasonal allergic rhinitis and five normal, nonallergic subjects (control group) were studied. Nasal lavages were performed twice weekly, starting 1 week before the expected birch-pollen season and continuing for 6 weeks, thereby covering the entire birch-pollen season. Nasal symptoms and pollen counts were recorded daily. The lavage fluid was analyzed for it content of albumin, bradykinins, and eosinophil cationic protein (ECP). During the pollen season, each of these solutes was significantly increased in the nasal lavage fluid from the allergic patients (p less than 0.05) but not from the control subjects. Albumin, bradykinins, and ECP generally correlated better between themselves than with symptoms and pollen counts. We conclude that natural exposure to allergens induces plasma exudation and increased levels of ECP on the human nasal mucosa.     

Effect of levocetirizine on nasal provocation testing with adenosine monophosphate compared with allergen challenge in allergic rhinitis

Background End‐organ hyperreactivity is an important feature of the allergic airway. There are no data directly comparing the responsiveness to treatment of different nasal provocation tests (NPT). Objective We compared the effect of levocetirizine on nasal adenosine 5′‐monophosphate (AMP) with specific allergen challenge in patients with intermittent and persistent allergic rhinitis (AR). Methods Patients with AR were randomized in double‐blind cross‐over fashion to receive single doses of levocetirizine 5 mg or identical placebo, with nasal challenge performed 12 h after dosing. Sixteen participants completed per protocol. Nasal AMP or allergen challenge was conducted on separate days with 1‐ and 2‐week washout periods in between, respectively. Measurements of peak nasal inspiratory flow (PNIF) were made over 60 min after each challenge. The primary end‐point was the provocative concentration of AMP or allergen causing a 20% drop in the PNIF (PC₂₀). Results The time‐profile for PNIF recovery [area under the 60 min time–response curve as % PNIF change (min)] were significantly attenuated for AMP challenge, as mean difference [95% confidence interval (CI)]: 11.57 (3.87, 19.25), P=0.005 and for allergen challenge: 17.82 (0.11, 35.53), P=0.04. A highly significant correlation was shown between methods for the area under the curve: (R=0.86, P<0.001). A statistically significant correlation was also seen for the PC₂₀: (R=0.94, P<0.001). PC₂₀ improvement amounted to a 1.26 (95% CI 0.16, 2.35) and 0.16 (95% CI ?0.41, 0.73) doubling‐dilution shifts for allergen and AMP challenges, respectively. Bland–Altman plots confirmed good agreement between methods. Conclusion A high correlation and statistical agreement has been demonstrated between AMP and allergen challenge for all outcome measures. In particular, the recovery profile after NPT is a sensitive and discriminatory measure of anti‐allergic treatment.     

Human nasal mucosal carboxypeptidase: Activity, location, and release

Background: Carboxypeptidases (CPs), such as carboxypeptidase N (CPN) (kininase I, E.C.3.4.17.3), may regulate peptide-mediated vasodilation and vascular permeability in respiratory mucosa by degrading proinflammatory peptides such as bradykinin, anaphylatoxins, and neuropeptides during allergic and nonallergic inflammation. The sources of CP activity in human nasal secretions were investigated. Methods: Well-characterized human nasal provocation and secretion analysis methods were used. Potential sources of CPN in human nasal mucosa were identified by immunohistochemistry. CP activity was defined as DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid inhibitable Bz-Gly-Lys degradation. CP activity was measured in nasal mucosal homogenates and nasal lavage fluids induced by methacholine, histamine, and allergen nasal provocation. Results: CPN-immunoreactive material was localized to the glycocalyx of the epithelium, some vessels, and gland ducts near the epithelial basement membrane but not to submucosal gland cells. CP activity in human nasal lavage fluid after saline nasal provocation was 0.10 ± 0.04 U/L. Histamine provoked secretion of significantly more CP activity (3.84 ± 0.99 U/L; p < 0.01 vs saline). Methacholine did not significantly increase secretion (0.54 ± 0.22 U/L). After nasal allergen challenge, CP activity was at a maximum between 11 and 20 minutes, and CP activity correlated with IgG concentration (r = 0.91, p < 0.01), a marker for proteins of plasma origin, suggesting that CP activity originated in plasma. Conclusions: These data suggest that plasma is the predominant source of CP activity secreted from human nasal mucosa and that plasma extravasation and interstitial fluid exudation across the epithelium are the primary processes regulating its appearance in nasal secretions. (J ALLERGY CLIN IMMUNOL 1995;96:924-31.)