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.     

Intranasal capsaicin is efficacious in non-allergic, non-infectious perennial rhinitis. A placebo-controlled study

Background Several authors described capsaicin, the pungent substance in red pepper, as an efficacious therapy for non-allergic non-infectious perennial rhinitis (NANIPER). Repeated capsaicin application induces peptide depletion and specific degeneration of the unmyelinated sensory C-fibres in the nasal mucosa. Methods We performed a placebo-controlled (NaCl 0.9%) study with 25 NANIPER patients. Daily record charts and visual analogue scales (VAS) were used for clinical evaluation. Nasal lavages were obtained before, during, and after treatment. Results There was a significant and long-term reduction in the VAS scores in the capsaicin group. No significant difference was found between the placebo and capsaicin treated groups for the mean group concentrations of leukotriene (LT) C₄/D₄/E₄, prostaglandin D₂ (PGD₂). and tryptase. The levels of mast cell mediators, tryptase and PGD₂. and leukotrienes, mediators derived from a variety of inflammatory cells, were low at baseline and comparable with levels observed in nasal lavages obtained from normals. Conclusion As involvement of inflammation could not be demonstrated, it is not surprising that capsaicin has no effect on inflammatory mediators. This suggests that inflammatory cells do not play a major part in the pathogenesis of NANIPER.     

Loratadine and desethoxylcarbonyl-loratadine inhibit the immunological release of mediators from human FcɛRI+cells

Background Loratadine, a novel histamine H₁-receptor antagonist, is effective in the treatment of patients with seasonal and perennial rhinitis and some allergic skin disorders. Histamine and other chemical mediators are synthesized and immunologically released by human peripheral blood basophils and tissue mast cells (Fc?RI⁺ cells). Objective To evaluate the effects of loratadine and its main metabolite, desethoxylcarbonyl-loratadine (des-loratadine), on the immunological release of preformed (histamine and tryptase) and de novo synthesized mediators (leukotriene C₄: LTC₄ and prostaglandin D₂: PGD₂) from human Fc?RI⁺ cells. Methods Human Fc?RI⁺ cells purified from peripheral blood and from skin (HSMC) and lung tissue (HLMC) were preincubated with loratadine and des-loratadine before immunological challenge with Der p 1 antigen or anti-Fc?RI. The release of preformed mediators (histamine and tryptase) and de novo synthesized eicosanoids was evaluated in the supernatants of human FcRI⁺ cells. Results Preincubation (15m in, 37°C) of purified (36–74%) basophils with loratadine (3 × 10^–6–10^–4M) and des-loratadine before Der p 1 antigen or anti-Fc?RI challenge concentration-dependency (5–40%) inhibited the release of histamine and LTC₄. Loratadine (3 × 10^–6–l0^–4M) and des-loratadine also inhibited (10–40%) histamine, LTC₄, and PGD₂ release from purified HLMC (16–68%) activated by anti-Fc?RI. Loratadine (3 × 10^–6–10^–4M) and des-loratadine caused concentration-dependent inhibition (10–40%) of histamine, tryptase. LTC₄, and PGD₂ release from purified HSMC (24– 72%) immunologically challenged with anti-Fc?RI. Conclusion These results indicate that loratadine and its main metabolite have anti- inflammatory activity by inhibiting the release of preformed and de novo synthesized mediators from human Fc?RI⁺ cells.     

Nasal mucosal expression of the leukotriene and prostanoid pathways in seasonal and perennial allergic rhinitis

Background Leukotrienes (LTs) and prostanoids are potent pro‐inflammatory and vasoactive lipid mediators implicated in airway disease, but their cellular sources in the nasal airway in naturally occurring allergic rhinitis (AR) are unclear. Objective To quantify cellular expression of enzymes of the 5‐lipoxygenase (5‐LO) and cyclooxygenase (COX) pathways by immunohistochemistry in nasal biopsies from patients with symptomatic perennial AR (PAR, n=13) and seasonal AR (SAR, n=14) and from normal subjects (n=12). Methods Enzymes of the 5‐LO pathway (5‐LO, FLAP, LT A₄ hydrolase, LTC₄ synthase) and the COX pathway (COX‐1, COX‐2, prostaglandin D₂ synthase) were immunostained in glycol methacrylate resin‐embedded inferior turbinate biopsy specimens, quantified in the lamina propria and epithelium, and co‐localized to leucocyte markers by camera lucida. Results In the lamina propria of PAR biopsies, median counts of cells expressing FLAP were fourfold higher than in normal biopsies (Mann–Whitney, P=0.014), and also tended to be higher than in SAR biopsies (P=0.06), which were not different from normal. PAR biopsies showed threefold more cells immunostaining for LTC₄ synthase compared with SAR biopsies (P=0.011) but this was not significant compared with normal biopsies (P=0.2). These changes were associated with ninefold more eosinophils (P=0.0005) with no differences in other leucocytes. There were no significant differences in the lamina propria in immunostaining for 5‐LO, LTA₄ hydrolase, COX‐1, COX‐2 or PGD₂ synthase. Within the epithelium, increased expression of COX‐1 was evident in PAR biopsies (P=0.014) and SAR biopsies (P=0.037), associated with more intra‐epithelial mast cells in both rhinitic groups (P<0.02). Conclusions In the nasal biopsies of PAR subjects, increased expression of regulatory enzymes of the cysteinyl‐LT biosynthetic pathway was associated with lamina propria infiltration by eosinophils. Seasonal rhinitis biopsies shared only some of these changes, consistent with transient disease. Increased intra‐epithelial mast cells and epithelial COX‐1 expression in both rhinitic groups may generate modulatory prostanoids.     

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.)     

TNF α is localized to nasal mucosal mast cells and is released in acute allergic rhinitis

Allergic mucosal inflammation is characterized by tissue infiltration with eosinophils, and associated activation of mast cells and T lymphocytes. Tumour necrosis factor (TNF) alpha/cachectin is a candidate cytokine relevant to the pathogenesis of these events through its capacity to upregulate the expression of endothelial cell adhesion molecules, mediate granulocyte chemoattraction, and activate eosinophils, mast cells and T cells. To investigate the presence and localization of TNF α in the nasal mucosa in allergic rhinitis, nasal biopsies from perennial rhinitic (n=13) and non-rhinitic volunteers (n=11) were embedded in glycol methacrylate and immunostained with a monoclonal antibody directed against TNF α, and adjacent 2μm sections stained for tryptase, CD3 and eosinophil cationic protein. This identified positive immunostaining for TNF α in the submucosa of both the rhinitic and normal subjects (median cell counts 13 and 23 cells/mm² respectively, P=0.24) with cellular localization to mast cells but not to T-lymphocytes or eosinophils. In a subsequent study of seven atopic subjects, nasal allergen challenge produced increases in lavage levels of histamine and albumin, which was associated with significant release of TNF α as early as 2 min post-allergen when compared with the saline control day (P=0.5). This difference was also apparent when studying the area under the curve both at 30 and 60 min post-challenge t-test (P=0.015 and 0.02 respectively). These findings which both locate immunoreactive TNF α to nasal mast cells and identify its release following in vivo exposure to allergen, provide evidence for mast cells as an important source of this cytokine in patients with allergic rhinitis.     

In vitro diagnosis of chronic nasal inflammation

BACKGROUND: Differential diagnosis of chronic nasal inflammation is insufficient when based solely on clinical examination and radiography of paranasal sinuses. Patients complain about more or less similar symptoms. Activation of mast cells and eosinophils is pivotal in nasal inflammation. OBJECTIVE: To compare tryptase and eosinophilic cationic protein (ECP) in nasal secretions in different forms of chronic nasal inflammation and to establish norm values. METHODS: The study included 1710 patients presenting with nasal complaints. Nasal secretions were gained by the cotton wool method and analysed for tryptase, as a marker of mast cell activation, and for ECP, as a marker of tissue eosinophilia and activation. Patients were grouped according to their diagnosis: chronic, non-allergic rhinosinusitis (sinusitis, n=194), non-allergic nasal polyposis (polyposis, n=138), non-allergic rhinitis with eosinophilia syndrome (NARES, n=198), isolated perennial allergic rhinitis (AR) (n=126), isolated seasonal AR (n=132), and patients allergic to both, seasonal and perennial allergens (n=193). Seven hundred and twenty-nine patients with nasal complaints due to a deviated septum and without any nasal inflammation served as controls. RESULTS: Nasal tryptase was highly significantly (P<0.001) elevated in polyposis, NARES, and in AR. ECP was highly significantly (P<0.001) elevated in all groups of patients suffering from chronic nasal inflammation. Based on our data and method we established norm values (95% confidence interval of mean value) for nasal tryptase in healthy adults, ranging from 12.0 to 18.7 ng/mL and for ECP ranging from 84.4 to 102.6 ng/mL. CONCLUSION: Mast cells and eosinophils are involved in non-allergic and allergic forms of chronic nasal inflammation. We established an in vitro assay for tryptase and ECP in nasal secretions and defined norm values based on our data and method. In vitro measurement of biological markers in nasal secretions provides important information for differential diagnosis and therapeutic strategies of chronic nasal inflammation.     

Laser high performance liquid chromatography determination of prostaglandins in nasal lavage fluid in allergic rhinitis

This study was designed to analyse prostaglandins (PGs) in human nasal lavage- fluid using the combination of microcolumn high performance liquid chromatography and a He/Cd laser induced fluorescence detection system. Forty-seven patients with allergic rhinitis and 12 healthy volunteers were investigated. Four species of PG. i.e. PGD₂, PGE₂, PGF_2x and 6-keto-PGF₁, were detected in the nasal lavage fluid. Concentrations of PGD₂; (1.33 ± 0.17 nmol/ml) and PGE₂ (0.87 ± 0.11 nmol/ml) in nasal lavage fluid from patients with allergic rhinitis (the allergy group) were significantly increased compared with those of volunteers (the control group, 0.23 ± 0.16 nmol/ml, 0.29 ±0.19 nmol/ml, respectively). On the other hand, no significant differences were observed in concentrations of cither PGF_2x, or 6-keto-PGF^1x between the control group and the allergy group. Histamine concentration in nasal lavage fluid was significantly increased in the allergy group (53 ± 7.6 nmol/l) compared with the control group (3.4 ± 1.0 nmol/1). No significant correlation was observed between PGD₂ and histamine concentration (r= 0.24), or between PGE₂ and histamine concentration (r= 0.08) in nasal lavage fluid from patients with allergic rhinitis. Treatment with oxatomide, an anti-histamine and anti-allergic drug, significantly improved symptom scores, but did not alleviate them completely. Concentrations of each PG detected in nasal lavage fluid did not change significantly after oxatomide treatment. It is concluded that, not only histamine but also PGs, particularly PGD₂ and PGE₂, might be involved in the genesis of allergic rhinitis.     

Effect of continuous allergen challenge on clinical symptoms and mediator release in dust-mite-allergic patients

This study investigated the early, prolonged immediate, and late-phase reactions of dust-mite-sensitive subjects undergoing long-term challenge in the Vienna challenge chamber (VCC) in terms of clinical symptoms and inflammatory mediator level patterns in nasal lavage fluids. A concentration of 70 ng Der p 1/m³ of air (feces of Dermatopliagoides) was maintained over 8 h in the VCC. To show the clinical impact of this challenge model, the effect of a histamine H₁-receptor antagonist that also has some antiallergic properties (loratadine) was also investigated. The study followed a doubleblind, placebo-controlled, crossover design. Medication was given orally over 7 days before the provocation at a dose of 10 mg once daily. All 12 patients, whose dust-mite sensitivity was confirmed by disease history, skin prick test, and RAST, completed the challenge session. The documentation of the chosen parameters was performed every 30 min. Subjective nasal and ocular symptoms were assessed via a visual analog scale of 100 mm. nasal flow was recorded by active anterior rhinomanometry, and mediator release was evaluated with nasal lavages. Clinical aspect: the whole sample population showed a rise of nasal and ocular symptom severity and a nasal flow reduction, which were perceptibly, but not significantly attenuated by active drug treatment. Mediator pattern: in each patient, prostaglandin (PG)D₂ and leukotriene (LT)C₄ levels peaked within the first 2 h of provocation, PGD₂ then moving toward baseline levels, and LTC₄ then again rising continuously. Eosinophil cationic protein (ECP) exhibited a constant level increase over the whole provocation period, and tryptase levels did not change significantly. Whereas the area under the curve values of tryptase and ECP were higher in drug-treated patients than the placebo group, the early PGD, peak occurring during the first two challenge hours seemed to be mitigated by loratadine. These results reveal that there is no link between the clinical symptoms, the drug efficacy, and the released mediators (LTC₄, PGD₂, ECP and tryptase).     

Eosinophil recruitment to nasal nerves after allergen challenge in allergic rhinitis

In allergen challenged animal models, eosinophils localize to airway nerves leading to vagally-mediated hyperreactivity. We hypothesized that in allergic rhinitis eosinophils recruited to nasal nerves resulted in neural hyperreactivity. Patients with persistent allergic rhinitis (n = 12), seasonal allergic rhinitis (n = 7) and controls (n = 10) were studied. Inferior nasal turbinate biopsies were obtained before, 8 and 48 h after allergen challenge. Eight hours after allergen challenge eosinophils localized to nerves in both rhinitis groups; this was sustained through 48 h. Bradykinin challenge, with secretion collection on the contralateral side, was performed to demonstrate nasal nerve reflexes. Twenty four hours after allergen challenge, bradykinin induced a significant increase in secretions, indicating nasal hyperreactivity. Histological studies showed that nasal nerves expressed both vascular cell adhesion molecule-1 (VCAM-1) and chemokine (C-C motif) ligand 26 (CCL-26). Hence, after allergen challenge eosinophils are recruited and retained at nerves and so may be a mechanism for neural hyperreactivity.     

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.     

Lipoxin A4 generation is decreased in aspirin-sensitive patients in lysine-aspirin nasal challenge in vivo model

Background: Lipoxins represent a group of lipoxygenase derived eicosanoids which, in contrast to leukotrienes, are potent anti‐inflammatory mediators. The aim of our study was to determine lipoxin A₄ (LXA₄) and leukotriene C₄ (LTC₄) levels in nasal lavages after intranasal challenge with aspirin in aspirin intolerant (AIA) in comparison to aspirin tolerant (ATA) asthmatics and after allergen challenge in patients suffering from allergic rhinitis. Methods: Twelve AIA, 8 ATA and 20 allergic patients were challenged with placebo, 16 mg of lysine‐aspirin (Lys‐ASA) or allergen (grasses). Nasal lavages were collected and eicosanoids’ levels were determined using ELISA. Results: Clinically positive Lys‐ASA challenge in AIA resulted in influx of leukocytes (eosinophils and basophils) to nasal secretions and increase of LTC₄ to 106.82 pg/ml (P < 0.05 vs baseline (26.58 pg/ml)) on first hour after the challenge. We did not observe any differences in LTC₄ level before and after ASA challenge in ATA. In AIA group the mean level of LXA₄ was 43 ± 21.5 pg/ml after placebo and decreased in 2 h after Lys‐ASA challenge (29 ± 17 pg/ml, P = 0.015). We found an increase in LXA₄ in ATA after ASA provocation as compared to placebo (33 ± 16 pg/ml vs 52 ± 31 pg/ml, P = 0.046). In atopic patients baseline level of LXA₄ was 33.49 ± 16.95 pg/ml with no difference after the clinically positive allergen challenge (36.22 ± 13.26 pg/ml, P = 0.23). Conclusions: Results of our study confirm that AIA have diminished LXs’ biosynthesis capacities in vivo after ASA challenge. Taking into consideration anti‐inflammatory properties of lipoxins this phenomenon may be partially responsible for the development of chronic inflammation in AIA patients.     

Inflammatory and oxidative stress biomarkers in allergic rhinitis: the effect of smoking

Background Accumulating evidence confirms the presence of pan‐airway inflammation in allergic rhinitis patients. Smoking is known to affect the asthmatic airway inflammation. However, no study has evaluated the impact of smoking on airway inflammation of allergic rhinitis patients. Objective The aim of the present study was to evaluate the impact of smoking on inflammatory and oxidative stress biomarkers in patients with seasonal allergic rhinitis, using non‐invasive methods for sample collection. Methods Forty patients with seasonal allergic rhinitis (20 smokers and 20 non‐smokers) and 30 healthy subjects (15 smokers and 15 non‐smokers) were recruited for the study during pollen season. All subjects were submitted to measurement of the fraction of exhaled NO (FeNO), exhaled breath condensate (EBC) collection, nasal lavage collection, pre‐ and post‐ bronchodilation spirometry and metacholine bronchial challenge testing. pH, leukotriene B₄ (LTB₄) and 8‐isoprostane were determined in EBC and nasal lavage samples. Results Patients with allergic rhinitis presented higher LTB₄ and 8‐isoprostane levels in nasal lavage (P<0.0001 for both comparisons), with no significant differences between smokers and non‐smokers. Patients with allergic rhinitis also presented higher LTB₄ levels and lower pH in EBC (P<0.001 and P=0.004, respectively), with prominent differences between smokers and non‐smokers (P<0.0001 and P=0.003, for LTB₄ and pH, respectively). A significant correlation between nasal lavage and EBC LTB₄ values was observed (r_s=0.313, P=0.048). Conclusions Patients with allergic rhinitis present increased LTB₄ and 8‐isoprostane in their nasal cavity, however, with no significant differences between smokers and non‐smokers. In contrast, smokers with allergic rhinitis present higher LTB₄ levels and lower pH in EBC, suggesting that these patients may be more susceptible to the deleterious effects of smoking, compared with non‐smokers.     

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.     

Nasal histamine challenges in symptomatic allergic rhinitis

Twenty subjects (seven with perennial allergic rhinitis, seven with symptomatic seasonal allergic rhinitis, and six normal control subjects) underwent assessment of nasal sensitivity to histamine. Nasal resistance was measured by posterior rhinometry under control conditions and after log incremental doses of histamine solution pipetted into the nose (0.5 to 5000 micrograms). Allergic subjects exhibited a twofold rise of nasal resistance with doses of 0.5, 5, or 50 micrograms of histamine, whereas the nasal resistance in normal subjects remained unchanged until 500 or 5000 micrograms of histamine had been administered. Nasal reactivity to histamine was not correlated with symptoms on the day of testing but was correlated with the number of positive wheals to skin prick testing. It was concluded that nasal resistance is more sensitive to histamine in subjects with allergic rhinitis than in normal control subjects and that this difference may be used as the basis of a diagnostic test.     

Anti-allergic effects of sinomenine by inhibition of prostaglandin D2 and leukotriene C4 in mouse bone marrow-derived mast cells

Sinomenine is an alkaloid compound and a prominent anti-allergic agent found in the root of the climbing plant Sinomenium acutum. However, its effects on the bone marrow-derived mast cell (BMMC) mediated allergy and inflammation mechanism remain unknown. In this study, the biological effects of sinomenine were evaluated while focusing on its effects on the allergic mediator in PMA plus A23187-stimulated BMMCs. An investigation was also conducted to determine its effects on the production of several allergic mediators including interleukin-6 (IL-6), prostaglandin D₂ (PGD₂), leukotriene C₄ (LTC₄), β-Hexosaminidase (β-Hex), and cyclooxygenase-2 (COX-2) protein. The results revealed that sinomenine inhibited the PMA plus A23187-induced production of IL-6, PGD₂, LTC₄, β-Hex, and COX-2 protein. Taken together, these findings indicate that sinomenine has the potential for use in the treatment of allergy.     

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.     

Gomisin N has anti-allergic effect and inhibits inflammatory cytokine expression in mouse bone marrow-derived mast cells

Gomisin N is a bioactive compound and a prominent anti-allergic agent found in the fruits of tree Schizandra chinensis. However, its effects on the bone marrow-derived mast cell (BMMC)-mediated allergy and inflammation mechanism remain unknown. In this study, the biological effects of gomisin were evaluated while focusing on its effects on the allergic mediator in PMA + A23187-stimulated BMMCs. The anti-allergic effect of gomisin has shown that inhibited PMA + A23187-induced interleukin-6 (IL-6) production. An investigation was also conducted to determine its effects on the production of several allergic mediators including prostaglandin D₂ (PGD₂), leukotriene C₄ (LTC₄), β-hexosaminidase (β-Hex), and cyclooxygenase-2 (COX-2) protein. The results revealed that gomisin inhibited the PMA + A23187-induced production of IL-6, PGD₂, LTC₄, β-Hex, and COX-2 protein. Taken together, these findings indicate that gomisin N has the potential for use in the treatment of allergy.     

Allergic rhinitis in children: effects of flunisolide and disodium cromoglycate on nasal eosinophil cationic protein

Background Eosinophil cationic protein (ECP) is one of the major, cytotoxic molecules produced by eosinophils, which can be used as a marker of allergic inflammation. Objective In this placebo-controlled study we measured nasal and serum ECP levels to verify their possible role in monitoring the efficacy of anti-inflammatory therapy in allergic chronic rhinitis in 38 children aged from 4 to 14 yr, allergic to house dust mites. Method Nasal ECP, by the method of direct incubation on nasal mucosa, and serum ECP were determined before and after 3 weeks of treatment with flunisolide nasal spray 50 μg twice/daily (13 cases, Group 1), disodium cromoglycate (DSCG) 10.4mg three times/day (15 cases, Group 2) and placebo (10 cases, Group 3). The effectiveness of therapy was evaluated clinically and correlated to serum and nasal ECP values. Results Before treatment no significant difference emerged in the clinical scores of the three groups of patients. Before and after treatment serum ECP levels were not statistically different from normal controls. Before treatment nasal ECP was significantly higher in all patients compared with controls (P < 0.001). Nasal ECP decreased significantly in flunisolide-treated patients (P < 0.01) (before therapy: median 111 μg/L, range from 33.6 to 200 μg/L; after therapy: median 36.8 μg/L, range from 2.6 to 196 μg/D, but not in DSCG-treated patients, (before therapy: median 66.2 μg/L, range from 32.3 to 200 μg/L; after therapy: median 60.4 μg/L, range from 7.9 to l44 μg/L). No significant variation was present in the placebo group. Clinical improvement was statistically significant after flunisolide therapy (P < 0.05), less evident after DSCG (P = 0.06). Conclusion Serum ECP in chronic allergic rhinitis has been shown to be not useful in monitoring allergic inflammation, but nasal ECP, determined by mucosal incubation, may be used to evaluate the activity of eosinophils and monitor the anti-inflammatory efficacy of therapy in chronic rhinitis.     

Nasal response to a single antigen challenge in patients with allergic rhinitis — inflammatory cell recruitment persists up to 48 hours

BACKGROUND: Allergen challenge in some patients with respiratory allergy is followed by an early and a late reaction. OBJECTIVE: To evaluate the duration of mediator release and inflammatory cell recruitment during the late antigen-induced nasal response. METHODS: Eight patients with seasonal allergic rhinitis due to grass pollen underwent local challenge with the relevant allergen, a non-relevant allergen (Parietaria judaica), and nebulized saline solution. Nasal lavages were performed at baseline and 6, 24, 48, 72 h after challenge. Eosinophil cationic protein (ECP), leukotriene C4 (LTC4), leukotriene B4 (LTB4) myeloperoxidase (MPO) and prostaglandin D2 (PGD2) levels were radioimmunoassayed and histamine concentration was measured by an automated fluorometric method. RESULTS: Nasal challenge with the relevant antigen induced a response 6 h after stimulation, which subsided within 24 h. Eosinophilia, observed in the nasal lavages collected from 6 to 24 h after this challenge, was accompanied by ECP release. Neutrophilia were found in the nasal lavages collected from 6 to 24 h after challenge. The increase in neutrophil number correlated with MPO levels and LTB4 concentrations, but not with the intensity of nasal obstruction. Antigen challenge also induced significant recruitment of mononuclear cells 48 h after provocation. The challenge significantly raised histamine, but not PGD2, levels in the nasal lavages collected 6 h after provocation. A trend towards an increase in LTC4 levels in the nasal lavages collected 6 h after specific antigen challenge was also found. Nasal challenge with a non-relevant allergen or with saline solution did not cause either inflammatory cell recruitment or mediator release. CONCLUSION: Nasal challenge with the relevant antigen can induce a late response characterized by local accumulation of eosinophils, neutrophils and mononuclear cells persisting for 48 h and accompanied by release of ECP, MPO, LTB4 and histamine. These results indicate that a single antigen challenge in patients with allergic rhinitis causes prolonged inflammatory alterations which may contribute to the development of airway hyperreactivity.