The effect of a selective 5-lipoxygenase inhibitor, AA-861 on airway hyperresponsiveness induced by ozone exposure in dogs

To determine whether 5-lipoxygenase products are involved in hyperresponsiveness induced by ozone exposure, we studied the effect of a selective 5-lipoxygenase inhibitor, AA-861 on ozone-induced airway hyperresponsiveness in six dogs. Airway responsiveness to methacholine was measured by modified Astograph (7 Hz oscillation method) before and after ozone exposure, and TxB2 in plasma and in BALF, 6-keto-PGF1 alpha in BALF, numbers of neutrophils in the peripheral blood and differential cell counts in BALF were measured before and after ozone exposure. Ozone exposure was carried out for 2 hr at an ozone level of 3.04 +/- 0.01 ppm (mean +/- SE). There was a significant increase in airway responsiveness to methacholine after ozone exposure in the six dogs (p less than 0.01), and the numbers of neutrophils in the peripheral blood and the neutrophil counts in BALF increased significantly after ozone exposure (P less than 0.01). A selective 5-lipoxygenase inhibitor, AA-861 significantly inhibited the increase of airway responsiveness to methacholine induced by ozone exposure (p less than 0.05), and furthermore, the increase in the numbers of neutrophils in the peripheral blood and the neutrophil counts in BALF after ozone exposure were significantly inhibited by pretreatment with AA-861 (p less than 0.05). There was no significant change in the levels of TxB2 in plasma or in BALF, and also no apparent change in the levels of histamine was observed in BALF after ozone exposure. The levels of 6-keto-PGF1 alpha in BALF decreased after ozone exposure, but the decrease was not significant. These results suggest that 5-lipoxygenase products play an important role in the development of airway hyperresponsiveness and in the infiltration of neutrophils into the airway after ozone exposure in dogs.     

Effect of AA-2414, a thromboxane A2 receptor antagonist, on airway inflammation in subjects with asthma.

BACKGROUND: Asthma is a chronic inflammatory disease of the airways. The chemokines are potent chemoattractants for eosinophils and other types of cells associated with allergic inflammation. AA-2414, a new thromboxane A2 receptor antagonist, reduces bronchial hyperresponsiveness in asthmatic subjects, but its mechanism of action is unclear. OBJECTIVE: We tested the hypothesis that the beneficial effects of AA-2414 in asthma result from reduction in the number of inflammatory cells infiltrating the airway associated with inhibition of chemokine release. METHODS: We studied bronchial biopsy specimens from 31 asthmatic subjects before and after oral treatment with AA-2414 (80 mg/day) or matched placebo for 4 months in a double-blind manner. Biopsy specimens were examined by immunohistochemistry. Each subject recorded symptom score and peak expiratory flow (PEF). Lung function and bronchial responsiveness to methacholine were measured before and after treatment. RESULTS: After treatment, significant improvements in symptom score (P <.05), PEF (P <.01), diurnal variation of PEF (P <.01), and bronchial responsiveness (P <.01) were observed in the AA-2414 group compared with the placebo group. These improvements were accompanied by a significant decrease in the number of submucosal EG2(+) eosinophils (P <.05). There was also a reduction in the number of cells expressing RANTES (P <.05) and macrophage inflammatory protein (MIP)-1alpha (P <.05) in the epithelium and of cells expressing monocyte chemotactic protein-3 (P <.01), RANTES (P <.05), MIP-1alpha (P <.01), and eotaxin (P <.01) in the submucosa in the AA-2414 treatment group. A significant correlation was found between the number of EG2(+) eosinophils and numbers of monocyte chemotactic protein-3(+) (rs = 0.52, P <.005), MIP-1alpha+ (rs = 0.34, P <.05), and eotaxin+ cells (r s = 0.47, P <.01) in the submucosa. There was a significant negative correlation between the increase in bronchial responsiveness and the change in number of submucosal EG2(+) cells (rs = -0.65, P <.001). CONCLUSIONS: These findings suggest that AA-2414 treatment of patients with asthma may inhibit activated eosinophil infiltration in part by modulating the expression of chemokines in bronchial tissues.     

Effect of AA-2414, a thromboxane A2 receptor antagonist, on airway inflammation in subjects with asthma

Background: Asthma is a chronic inflammatory disease of the airways. The chemokines are potent chemoattractants for eosinophils and other types of cells associated with allergic inflammation. AA-2414, a new thromboxane A₂ receptor antagonist, reduces bronchial hyperresponsiveness in asthmatic subjects, but its mechanism of action is unclear. Objective: We tested the hypothesis that the beneficial effects of AA-2414 in asthma result from reduction in the number of inflammatory cells infiltrating the airway associated with inhibition of chemokine release. Methods: We studied bronchial biopsy specimens from 31 asthmatic subjects before and after oral treatment with AA-2414 (80 mg/day) or matched placebo for 4 months in a double-blind manner. Biopsy specimens were examined by immunohistochemistry. Each subject recorded symptom score and peak expiratory flow (PEF). Lung function and bronchial responsiveness to methacholine were measured before and after treatment. Results: After treatment, significant improvements in symptom score (P < .05), PEF (P < .01), diurnal variation of PEF (P < .01), and bronchial responsiveness (P < .01) were observed in the AA-2414 group compared with the placebo group. These improvements were accompanied by a significant decrease in the number of submucosal EG2⁺ eosinophils (P < .05). There was also a reduction in the number of cells expressing RANTES (P < .05) and macrophage inflammatory protein (MIP)-1α (P < .05) in the epithelium and of cells expressing monocyte chemotactic protein-3 (P < .01), RANTES (P < .05), MIP-1α (P < .01), and eotaxin (P < .01) in the submucosa in the AA-2414 treatment group. A significant correlation was found between the number of EG2⁺ eosinophils and numbers of monocyte chemotactic protein-3⁺ (r_s = 0.52, P < .005), MIP-1α⁺ (r_s = 0.34, P < .05), and eotaxin⁺ cells (r_s = 0.47, P < .01) in the submucosa. There was a significant negative correlation between the increase in bronchial responsiveness and the change in number of submucosal EG2⁺ cells (r_s = –0.65, P < .001). Conclusions: These findings suggest that AA-2414 treatment of patients with asthma may inhibit activated eosinophil infiltration in part by modulating the expression of chemokines in bronchial tissues. (J Allergy Clin Immunol 1999;103:1054-61.)     

The effect of AH 21-132 on airway hyperresponsiveness induced by ozone exposure

We examined the effect of AH 21-132, which has been reported to relax airway smooth muscle and inhibit platelet activating factor (PAF)-induced airway hyperreactivity, on ozone-induced airway hyperresponsiveness (AHR) with airway inflammation in dogs. Airway responsiveness (AR) to methacholine was measured by modified Astograph (7 Hz oscillation method) before and after ozone exposure, and the numbers of neutrophils in the peripheral blood and total cell counts, differential cell counts and TXB2 in BALF were measured before and after ozone exposure. Ozone exposure was carried out for 2 hr at an ozone level of 3.46 +/- 0.10 ppm (mean +/- SE). There was a significant increase in AR to methacholine after ozone exposure (p less than 0.01), and the numbers of neutrophils in the peripheral blood and the total cell and neutrophil counts in BALF increased significantly (p less than 0.05). Pretreatment with AH 21-132 at an oral dose of 20 mg/kg significantly prevented the ozone-induced AHR to methacholine (p less than 0.01), and also inhibited the increase of neutrophil counts in the peripheral blood, and the total cell counts and the neutrophil counts in BALF after ozone exposure. There was no significant change in the levels of TXB2 in BALF before and after ozone exposure. In dogs not exposed to ozone, AR to methacholine and respiratory resistance to methacholine significantly decreased after administration of AH 21-132 at an oral dose of 20 mg/kg (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of thromboxane A2 and prostaglandin I2 in the increase of airway responsiveness in dogs after ozone exposure]

To investigate the role of thromboxane (Tx) A2 and prostaglandin (PG) I2 in the development of airway responsiveness after ozone exposure, we measured the airway responsiveness to inhaled methacholine (Mch), TxB2 and 6-keto-PGF1 alpha levels in bronchoalveolar lavage fluid (BALF) in 18 dogs after ozone exposure. Airway responsiveness to Mch was determined by Astograph (7 Hz oscillation method), and ozone exposure was carried out for 2 hr at an ozone level of 3.01 +/- 0.05 ppm (mean +/- SEM). Airway responsiveness to Mch increased significantly after ozone exposure (p less than 0.001). TxB2 levels in BALF were not affected by ozone exposure, but the levels of 6-keto-PGF1 alpha decreased significantly after ozone exposure (p less than 0.001). The ratio of TxB2/6-keto-PGF1 alpha increased significantly after ozone exposure, and the change in this ratio correlated significantly with the change of airway responsiveness to Mch (p less than 0.01, r = 0.654). These results suggest that airway hyperresponsiveness after ozone exposure is induced by the relative increase of TxA2 due to the decrease of PGI2.     

Inhibitory effect of prostaglandin I2 on the increase of airway responsiveness induced by inhaled thromboxane A2 mimetic U-46619 in dogs

To investigate the effect of prostaglandin I2 (PGI2) on the increase of airway responsiveness induced by inhaled thromboxane A2 (TxA2), we measured the airway responsiveness to inhaled methacholine (Mch) after inhalation of TxA2 mimetic U-46619 alone and after inhalation of U-46619 in combination with PGI2 (U-46619/PGI2) in six dogs. Airway responsiveness to Mch was determined by Astograph (7Hz oscillation method). Inhalation of U-46619 was carried out for five minutes at a half of minimum threshold concentration, and the concentration of PGI2 was double that of U-46619. Inhaled U-46619 significantly increased airway responsiveness to Mch (p less than 0.01). However the airway responsiveness to Mch did not increase following inhalation of U-46619/PGI2, and the increase of airway responsiveness to Mch induced by inhaled U-46619 was inhibited significantly by PGI2 (p less than 0.01). PGI2 inhalation alone did not affect the basal airway responsiveness to Mch. These results indicate that PGI2 protects the hyperresponsiveness induced by TxA2 inhalation in dogs.     

Bronchial hyperresponsiveness and airway neutrophil accumulation induced by interleukin-8 and the effect of the thromboxane A2 antagonist S-1452 in guinea-pigs

Interleukin-8 (IL-8) has been shown to be a chemotactic factor for neutrophils, T-lymphocytes and eosinophils, but it is unknown whether the IL-8-induced inflammatory cell accumulation into the airways can cause the bronchial hyperresponsiveness (BHR) characteristic of asthma. IL-8 at a dose of 0.5 or 5μg/kg was administered intranasally to guinea-pigs twice a week for 3 weeks. One day after the last administration, animals were anesthetized and artificially ventilated through tracheal cannula and lateral pressure at the cannula (Pao) was measured as an overall index of airway responses to increasing concentrations of inhaled histamine (25, 50, 100, and 200 μg/ml). The IL-8 treatment significantly enhanced bronchial responsiveness to histamine in a dose-dependent manner (ANOVA P < 0.01). The provocative concentration of histamine causing a 100% increase in Pao (PC100) at a dose of 0.5 and 5μg/kg of IL-8 was 68.1 (Gsem 1.12) and 35.6 (Gsem 1.25) μg/ml, respectively. The latter was significantly (P < 0.01) lower than that in control animals treated with PBS (93.3 [Gsem , 1.14] μg/ml)- The IL-8 treatment also induced a significant influx of neutrophils, but not eosinophils, in bronchoalveolar lavage (BAL) fluid (18.3 ± 8.8 and 30.6 ± 8.3% in animals treated with 0.5 and 5 μg/kg, respectively, of IL-8 vs 3.6 ± 0.7% in phosphate buffered saline-(PBS)-treated animals). Furthermore, we examined the effect of the thromboxane receptor antagonist S-1452 (0.01 or 0.1 mg/kg, i.p. 24 and 1 h before anesthesia) on this IL-8 induced BHR. S-1452 significantly inhibited the BHR dose-dependently (ANOVA P < 0.001). PC100 was 94.0 (Gsem 1.19), 137.4 (Gsem 1.17) and 43.0 (Gsem 1.24) μg/ml with S-1452 at doses of 0.01 and 0.1mg/ml and saline, respectively. We conclude that IL-8 causes BHR and airway neutrophil inflammation, and that thromboxane A₂ is important in the development of BHR induced by IL-8.     

Effect of Y-20811, a long-lasting thromboxane A2 synthetase inhibitor, on antigen-induced airway hyperresponsiveness in guinea pigs.

Effect of Y-20811 on airway hyperresponsiveness was studied in sensitized guinea pigs. Airway hyperresponsiveness to acetylcholine (ACh) reached maximum 7 h after antigen challenge in guinea pigs sensitized actively. Y-20811 (0.3-3 mg/kg) administered orally 3 h prior to challenge inhibited this airway hyperresponsiveness in a dose-dependent manner. Y-20811 (3 mg/kg) administered orally 4 h after antigen challenge also decreased the airway hyperresponsiveness. On the other hand, Y-20811 did not affect the bronchoconstriction induced by ACh, serotonin and histamine in nonsensitized guinea pigs. The number of eosinophils in bronchoalveolar lavage fluid in the guinea pig reached the peak 7 h after antigen challenge. Y-20811 had a tendency to decrease the number of total cells, macrophages and eosinophils in a dose-dependent manner. These results suggest that Y-20811 suppress the asthmatic mechanism which causes antigen-induced airway hyperresponsiveness.     

Clinical study on the inhibitory effect of AA-2414 on platelet function in asthmatic patients

We studied the effect of AA-2414, a TXA2 receptor antagonist, on platelet function in 12 asthmatic patients, 6 males and 6 females, whose mean age was 43.6 years. AA-2414 was orally administered to each patient at 20 mg/day for two weeks and then at 40 mg/day for the following two weeks. Platelet aggregation, plasma concentration of TXB2, and serum concentrations of AA-2414 and its metabolites were measured before and after the administration of each dose. Platelet aggregation induced by U-46619 (an analogue of PGH2), STA2 (a stable analogue of TXA2) and arachidonic acid with the administration of AA-2414 was significantly inhibited. The degree of this inhibition was proportional to the serum level of the drug. Plasma concentration of TXA2 tended to be lowered by administration of AA-2414, but it was not statistically significant. Eight (75.0%) of the 12 patients showed clinical improvement. In the cases where the drug was ineffective, the inhibition of platelet aggregation after administration of AA-2414 was less than in those cases where it was effective. We conclude that AA-2414 might exert its antiplatelet and antiasthmatic effects through antagonism of the TXA2 receptor. Investigation of the response to AA-2414 may be useful in assessing the clinical effect of this compound.     

Effect of ozone exposure on allergic sensitization and airway inflammation induced by dendritic cells

BACKGROUND: Epidemiological studies suggest that ozone exposure is related to increased asthma symptoms. Dendritic cells (DCs) are the principal antigen-presenting cells in the airways. OBJECTIVE: We have examined whether ambient doses of ozone (100 ppb for 2 h) enhance allergic sensitization and/or airway inflammation in a mouse model. METHODS: C57BL/6 mice were sensitized to inhaled ovalbumin (OVA) by intratracheal instillation of OVA-pulsed DCs on day 0. Daily exposure to OVA aerosol on days 14-20 resulted in an eosinophilic airway inflammation, as reflected in bronchoalveolar lavage fluid and lung histology. In a first experiment, mice were exposed to ozone or room air immediately prior to and following sensitization. Subsequently, we tested the effect of ozone exposure during antigen challenge in DC-sensitized mice. RESULTS: Exposure to ozone during sensitization did not influence airway inflammation after subsequent allergen challenge. In contrast, in sensitized mice, challenge with OVA together with ozone (days 14-20) resulted in enhanced airway eosinophilia and lymphocytosis, as compared with mice exposed to OVA and room air (1.91 x 106 +/- 0.46 x 106 vs. 0.16 x 106 +/- 0.06 x 106 eosinophils/mL lavage fluid; P = 0.015; 0.49 x 106 +/- 0.11 x 106 vs. 0.08 x 106 +/- 0.03 x 106 lymphocytes/mL lavage fluid; P = 0.004). Ozone exposure without subsequent OVA exposure did not cause airway inflammation. CONCLUSION: Ozone exposure does not increase allergic sensitization but enhances antigen-induced airway inflammation in mice that are sensitized via the airways.     

Effect of intranasal administration of CV-11974, a type 1 angiotensin II receptor antagonist,on airway hyperresponsiveness and airway inflammation induced by antigen inhalation in guinea pigs

BACKGROUND: Angiotensin II is a putative mediator in asthma, but the effect of topical administration of type 1 angiotensin II (AT1) receptor antagonists on allergic airway reactions is not known. OBJECTIVE: To investigate the effect of intranasal administration of CV-11974, an AT1 receptor antagonist, and of PD123319, a type 2 angiotensin II (AT2) receptor antagonist, on antigen-induced airway reactions in guinea pigs. METHODS: Thirty minutes after intranasal topical administration of CV-11974 (0.1 or 1.0 mg/ml) or PD123319 (10 mg/ml) into the airways, the animals were given an antigen challenge. Airway hyperresponsiveness and bronchoalveolar lavage fluid were analyzed 24 h after the antigen challenge. RESULTS: Although these compounds did not inhibit antigen-induced early-phase bronchoconstriction or late-phase airway eosinophilia, intranasal administration of CV-11974 (but not PD123319) inhibited antigen-induced airway hyperresponsiveness in a dose-dependent manner 24 h after the antigen challenge. CONCLUSION: Intranasal administration of an AT1 receptor antagonist reduces antigen-induced airway hyperresponsiveness.     

Additive effect of diesel exhaust particulates and ozone on airway hyperresponsiveness and inflammation in a mouse model of asthma

Allergic airway diseases are related to exposure to atmospheric pollutants, which have been suggested to be one factor in the increasing prevalence of asthma. Little is known about the effect of ozone and diesel exhaust particulates (DEP) on the development or aggravation of asthma. We have used a mouse asthma model to determine the effect of ozone and DEP on airway hyperresponsiveness and inflammation. Methacholine enhanced pause (P(enh)) was measured. Levels of IL-4 and IFN-gamma were quantified in bronchoalveolar lavage fluids by enzyme immunoassays. The OVA-sensitized-challenged and ozone and DEP exposure group had higher P(enh) than the OVA-sensitized-challenged group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone exposure group. Levels of IFN-gamma were decreased in the OVA-sensitized-challenged and DEP exposure group and the OVA-sensitized-challenged and ozone and DEP exposure group compared to the OVA-sensitized-challenged and ozone exposure group. Levels of IL-4 were increased in the OVA-sensitized-challenged and ozone exposure group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone and DEP exposure group compared to OVA-sensitized-challenged group. Co-exposure of ozone and DEP has additive effect on airway hyperresponsiveness by modulation of IL-4 and IFN-gamma suggesting that DEP amplify Th2 immune response.     

Inhibition by thromboxane antagonists of airway hyperresponsiveness to histamine induced by 13,14-dihydro-15-keto-PGF2α in guinea-pigs

Summary. We studied the effect of intravenous administration of 13,14-dihydro-15-keto-prostaglandin (PG) F_27alpha; on airway responsiveness to histamine and airway wall thickening in guinea-pigs. Guinea-pigs were killed and the lungs were fixed in formalin. Slides from paraffin-embedded sections of the lungs were stained and the airways that were cut in transverse section were measured by tracing enlarged images using a digitizer. Moreover, airway resistance (Raw) was determined by a pulmonary mechanics analyser and we calculated two indices, an index of airway wall thickening and the one of airway hyperresponsiveness to histamine, from changes of baseline-Raw and peak-Raw following intravenous administration of histamine before and after the intravenous administration of 13,14-dihydro-l5-keto-PGF_2n. Intravenous administration of 10/μg/kg 13,14-dihydro-15-keto-PGF_2α for 1 h did not induce an increase of the relative thickness of the airway wall by the histological examination. In analysis of airway function, intravenous administration of 10μg/kg 13,14-dihydro-15-keto-PGF_2α for 1 h induced airway hyperresponsiveness to histamine without airway wall thickening. Thromboxane A₂ (TXA₂) receptor antagonists ONO-NT-126 and ONO-8809 inhibited the 13,14-dihydro-15-keto-PGF_2α-induced airway hyperresponsiveness to histamine, suggesting that the effect of 13,14-dihydro-15-keto-PGF_2α on bronchial hyperresponsiveness is likely to be mediated through TXA₂.     

The role of thromboxane A2 in the development of airway responsiveness after platelet activating factor inhalation in dogs

To determine whether thromboxane A2 (TxA2) is involved in airway hyperresponsiveness after platelet activating factor (PAF) inhalation, we studied the effect of a specific TxA2 receptor antagonist, AA-2414 on the development of airway responsiveness induced by PAF inhalation in six dogs. Airway resistance and airway responsiveness to inhaled methacholine were determined by modified Astograph (7 Hz oscillation method). PAF inhalation (1000 micrograms/ml, ten minutes) caused a significant increase of airway resistance (p less than 0.01), and the increase of airway resistance was not inhibited by pretreated AA-2414. Airway responsiveness to inhaled methacholine increased significantly 3 hr after PAF inhalation (p less than 0.01). Pretreated AA-2414 inhibited the increase of airway responsiveness significantly (p less than 0.01), but the inhibition was partial. After PAF inhalation, total cell counts, neutrophil counts, eosinophil counts and the levels of TxB2 in bronchoalveolar lavage fluid increased significantly (p less than 0.05), and these increase were not affected by pretreated AA-2414. These results suggest that TxA2 is not involved in the bronchoconstriction induced by PAF inhalation, but TxA2 plays a partial role in the development of airway responsiveness after PAF inhalation in dogs.     

The role of lipid mediators in bronchial hyperresponsiveness and airway eosinophil accumulation induced by antigen challenge in guinea pigs]

The aim of this study was elucidate the role of lipid mediators in bronchial hyperresponsiveness (BHR) and airway eosinophil accumulation 24 hours after an antigen challenge in guinea pigs. Thromboxane (TX) A2 receptor antagonist, S-1452 (1, 10 mg/kg), cysteinyl leukotriene (cLT) receptor antagonist, ICI-198, 615 (0.5, 5 mg/kg), platelet activating factor (PAF) receptor antagonist, E-6123 (1, 10 micrograms/kg), and each vehicle were intraperitoneally given 1 h before and 11 h after an ovalbumin (OVA) challenge. BHR to inhaled methacholine was measured and then bronchoalveolar lavage (BAL) was performed 24 h after the OVA challenge. The three drugs significantly inhibited BHR to methacholine, dose dependently. S-1452 significantly inhibited total cell counts (TCC). ICI-198, 615 significantly reduced both TCC and eosinophil percentage, but E-6123 did not alter TCC and cell differentiation in BAL fluid. Therefore, these results clearly showed that lipid mediators were involved in antigen-induced BHR and suggested that TXA2 and cLT may contribute to the penetration of inflammatory cells through capillary wall, still more cLT is concerned eosinophil accumulation with cell specificity. PAF dose not take part in the penetration of inflammatory cells.     

The effect of a bradykinin B2 receptor antagonist, NPC-567, on allergen-induced airway responses in a porcine model

OBJECTIVE AND DESIGN: In order to assess the effect of selective blocking of the bradykinin (BK) B2 receptor in allergic airway reactions, the BK B2 receptor antagonist NPC-567 was administered to sensitized pigs before allergen challenge. MATERIAL: Fourteen specific pathogen-free pigs sensitized to Ascaris suum were used. TREATMENT: NPC-567 (2.5 mg, in 1 ml saline) was delivered as an aerosol twice to six pigs. METHODS: Ascaris antigen (in 2 ml saline) was given as an aerosol to all pigs and airway mechanics were monitored for 8 h. NPC-567 (2.5 mg) was given at t = -30 min (in 1ml saline) and mixed with the antigen at t = 0 to six pigs. RESULTS: Allergen challenge caused an acute reaction with a rapid, significant increase in airways resistance from 4.1 +/- 0.5 cm H2O/l/s to a maximum of 16.2 +/- 3.0 cm H2O/l/s in the control pigs. In the NPC-567-treated pigs, the resistance only increased from 2.9 +/- 0.3 cm H2O/l/s to 6.5 +/- 0.9 cm H2O/l/s (p<0.005 compared to controls). There was also a higher reduction in dynamic lung compliance in the controls than in the treated animals upon allergen challenge. The histamine concentration in urine in the control pigs was markedly elevated after allergen challenge peaking at 15-30 min. This release was inhibited in the NPC-567-treated pigs. CONCLUSIONS: The BK B2 receptor antagonist NPC-567 seems to be effective in inhibiting the acute response to allergen in the pig airways, possibly due to inhibition of mast cell activation via indirect mechanisms. The late obstructive response was reduced as well, probably as a consequence of the reduced mediator release in the acute reaction.     

The effect of passive smoking on asthma symptoms,atopy,and airway hyperresponsiveness in schoolchildren

Passive smoking is a major cause of respiratory morbidity, and is associated with increased bronchial responsiveness in children. To evaluate the effect of smoking by a parent on asthma symptoms, atopy, and airway hyperresponsiveness (AHR), we conducted a cross-sectional survey of 503 schoolchildren that involved questionnaires, spirometry, allergy testing, and a bronchial challenge test. If the PC20 methacholine was less than 16 mg/mL, the subject was considered to have AHR. The prevalence of a parent who smoked was 68.7%. The prevalence of AHR was 45.0%. The sensitization rate to common inhalant allergens was 32.6%. Nasal symptoms such as rhinorrhea, sneezing, nasal itching, and nasal obstruction were present in 42.7%. Asthma symptoms such as cough and wheezing were present in 55.4%. The asthma symptoms were significantly more prevalent in children who had a parent who smoked than in those whose parents did not. The nasal symptoms, atopy, and AHR did not differ according to whether a parent smoked. In a multiple logistic regression model, the asthma symptoms and atopy were independently associated with AHR, when adjusted for confounding variables. Passive smoking contributed to asthma symptoms in schoolchildren and was not an independent risk factor of airway hyperresponsiveness in an epidemiological survey.     

Effect of nedocromil sodium on SO2-induced airway hyperresponsiveness and citric acid-induced cough in dogs

In anaesthetized dogs exposed to SO2, nedocromil sodium prevented the increase in bronchial responsiveness to histamine challenge and suppressed the cellular changes taking place in the lung. In conscious dogs challenged with citric acid, by inhalation, nedocromil sodium prolonged the time to onset of coughing and had an inhibitory effect on the total number of coughs in each episode. Nedocromil sodium has been observed to stimulate bronchial C fibers, and it is suggested that this activity may relate to the antitussive effect of the compound.