Effect of an inhaled glucocorticosteroid (budesonide) on post-antigen induced increases in airway responsiveness

We examined the effects of an inhaled glucocorticosteroid, budesonide, on antigen-induced early and late bronchial responses and the development 24 h after challenge of increased airway responsiveness to carbachol in allergic sheep. Six allergic sheep were used for this study and, on occasions separated by at least three weeks, they were treated: with placebo (treatment 1); 16 h and 20 min prior to antigen challenge with budesonide (treatment 2); 16 h and 20 min prior to and 8 h after antigen challenge with budesonide (treatment 3); or 16 h and 1 h prior to and 8 h after antigen challenge with budesonide (treatment 4). Airway responsiveness to carbachol was determined prior to and 24 h after antigen challenge by measuring specific lung resistance (sRL) after administering increasing doses of carbachol aerosol (0.5, 1 and 2.5% w/v) and determining the concentration of carbachol needed to increase sRL 150% over baseline (PC150). Placebo treatment did not affect the early or late increases in sRL after airway challenge with Ascaris suum antigen; 24 h after challenge, airway responsiveness to carbachol increased (p less than 0.05); at this time, PC150 was (mean +/- SEM) 0.88 +/- 0.15% as compared to 1.56 +/- 0.26% before challenge. Both treatments 2 and 3 blunted the early response to antigen and blocked the late response, but treatment 2 did not modify the antigen-induced increase in airway responsiveness, whereas treatment 3 did. Treatment 4 blocked both antigen-induced responses and was effective in blunting the increased airway responsiveness. These results suggest that antigen-induced increases in airway responsiveness: occur 24 h after a challenge in allergic sheep with early and late responses; can be blunted by budesonide; and are not dependent on the late response.     

Inhibitory effect of FK-506 on the development of late asthmatic response and on the increased bronchial responsiveness]

We examined the effects of FK-506, a potent immunosuppressive agent, on the development of late asthmatic response (LAR) and on the increased bronchial responsiveness to acetylcholine following LAR in guinea pig model of asthma. Guinea pigs sensitized by repeated inhalation of ovalbumin (OA) were intravenously given metopiron 24 hours before and 30 minutes before antigen challenge and to prevent death from immediate severe bronchoconstriction, chlorpheniramine maleate was also injected. When we defined LAR as the responses with a two-fold increase in respiratory resistance during the late phase of antigen challenge, twelve out of fifteen control animals demonstrated apparent LAR. However, when guinea pigs were treated with FK-506 from the beginning of immunization period, the development of LAR was completely inhibited, although similar magnitude of immediate bronchoconstriction was observed, and a subsequent increase in bronchial responsiveness was significantly blocked. We also measured bronchial responsiveness to acetylcholine before, 24 and 72 hours after antigen challenge. FK-506-treated animals inhibited an increase in bronchial responsiveness to acetylcholine. These results suggest that the involvement of cell-mediated immunity may be important in the development of LAR and an increase in bronchial responsiveness.     

The beta-adrenergic system and allergic bronchial asthma: changes in lymphocyte beta-adrenergic receptor number and adenylate cyclase activity after an allergen-induced asthmatic attack

Beta-adrenergic receptor characteristics and adenylate cyclase responses to different stimuli were measured in lymphocyte membrane preparations of six normal control subjects and five allergic asthmatic patients with mild airways disease and increased bronchial reactivity to histamine and acetylcholine. The determinations were performed just before and 24 hr after inhalation challenge with house-dust mite antigen to investigate the influence of an allergen-induced asthmatic attack on the beta-adrenergic receptor system. Before the house-dust mite challenge, the lymphocyte membranes of the patients showed a normal receptor density, dissociation constant for (-)3H-dihydroalprenolol, and adenylate cyclase response to isoproterenol, guanyl-5'-yl-imidodiphosphate, (GppNHp) and NaF. After the allergen-induced asthmatic reaction, however, the beta-adrenergic receptor number in the patients was significantly reduced by 21%, while the basal adenylate cyclase activity and isoproterenol-, GppNHp-, and NaF-induced cyclic AMP responses were simultaneously reduced by about 40%. The allergen challenge had no significant effect on the lymphocyte membranes of the control subjects. These results suggest (1) that a reduced beta-adrenergic function is not an intrinsic component of allergic bronchial asthma but is rather the consequence of an active disease state, and (2) that next to changes in beta-adrenergic receptor number, alterations distal to the receptor may play an important role in the observed decrease in beta-adrenergic responsiveness.     

Bronchial hyperresponsiveness, epithelial damage, and airway eosinophilia after single and repeated allergen exposure in a rat model of anhydride-induced asthma

Bronchial hyperresponsiveness (BHR) and damage of the epithelium, as well as eosinophilia in the airway wall, induced by trimellitic anhydride (TMA) in sensitized brown Norway rats were studied. Rats were challenged once or seven times with aerosol of TMA conjugated to rat serum albumin (TMA-RSA) 3 weeks after intradermal TMA sensitization. Airway responsiveness (-log PC₃₀₀ of acetylcholine i.v.) was measured 24 h after allergen challenge. Epithelial lesion and eosinophil infiltration in the airway walls were quantified under light microscopy, and TMA-specific IgE and IgG in serum were evaluated with ELISA. High levels of TMA-specific IgE and IgG were found in all rats in the sensitized groups compared to nonsensitized groups ( P < 0.001). Repeated allergen challenges of 0.03% TMA-RSA for 7 consecutive days enhanced the level of TMA-specific IgG, compared to single challenge ( P < 0.05). Single allergen challenge of 0.3% TMA-RSA had a nonsignificant tendency to produce BHR in sensitized rats compared to nonsensitized rats ( P =0.06). However, repeated allergen challenges (0.003% and 0.03% TMA-RSA for 7 consecutive days) produced significant BHR in sensitized rats ( P < 0.05). Furthermore, repeated low-dose (0.003%) TMA-RSA challenge produced more BHR than a 10 times higher single dose (0.03%) ( P < 0.05). Slight damage of the airway epithelium was seen in sensitized and repeat-challenged groups. However, bronchial eosinophilia was found in the sensitized and single-challenged groups, but not in nonsensitized nonchallenged, and sensitized repeat-challenged groups ( P < 0.005). We conclude that the brown Norway rat can be sensitized with TMA, and that repeated low-dose allergen challenges produce slight epithelial damage and BHR which is independent of ongoing eosinophilia in the airway wall.     

Inhibition of antigen-induced bronchial smooth muscle hyperresponsiveness by lovastatin in mice

Statins have been proposed as a novel treatment of respiratory diseases. To determine the beneficial effects of statins on the airway hyperresponsiveness, a characteristic feature of allergic bronchial asthma, the effect of systemic treatment with lovastatin on antigen-induced bronchial smooth muscle hyperresponsiveness was investigated in mice. Male BALB/c mice were sensitized and repeatedly challenged with ovalbumin antigen. Animals were also treated with lovastatin (4 mg/kg/day, i.p.) once a day prior to and during the antigen inhalation period. The bronchial smooth muscle responsiveness to acetylcholine, but not to high K(+)-depolarization, was markedly and significantly augmented in the repeatedly antigen challenged mice. The bronchial smooth muscle hyperresponsiveness to acetylcholine induced by antigen exposure was significantly attenuated by the systemic treatment with lovastatin. Thus, lovastatin might have therapeutic potential to ameliorate airway hyperresponsiveness in allergic bronchial asthma.     

Modification of allergen-induced airway obstruction and bronchial hyperresponsiveness in the allergic rabbit by theophylline aerosol

The effects of theophylline on allergen-induced airway obstruction and bronchial hyperresponsiveness were investigated in allergic rabbits. This allergic rabbit model was developed in our laboratory and stimulates the human model of allergic asthma in several aspects. Four allergic rabbits with hyperreactive airways were challenged with ragweed to elicit early- and late-phase asthmatic responses and subsequent increased airway responsiveness. Two to three weeks later, the rabbits received theophylline (5 mg/ml, nebulized for 3 min) prior to a second allergen challenge. Theophylline significantly inhibited the allergen-induced early- and late-phase asthmatic responses by 38% (P<0.05) and 49% (P<0.05), respectively. Further theophylline inhibited the allergen-induced increase in lung resistance by 42% (P<0.05) during the late-phase responses. Theophylline also inhibited the allergen-induced bronchial hyperresponsiveness by 39% (P<0.05) at 24h. These data suggest a potential anti-inflammatory effect of theophylline in preventing allergen-induced asthmatic responses and bronchial hyperresponsiveness.     

Hyperresponsiveness of bronchial but not tracheal smooth muscle in a murine model of allergic bronchial asthma

Objective: To determine a change in airway smooth muscle contractility in a murine model of allergic asthma, the responsiveness of airway smooth muscles isolated from ovalbumin (OA)-sensitized and -challenged mice was compared with that from control animals.Methods: Actively sensitized mice were repeatedly challenged by ovalbumin (OA) antigen inhalation. Twenty-four h after the last antigen challenge, tracheal and bronchial smooth muscle responsiveness to acetylcholine (ACh) and endothelin-1 (ET-1) were measured. Airway microvascular leakage and histochemistry were also determined as indices of airway inflammation.Results: Both the ACh and ET-1 responsiveness of bronchial, but not tracheal, smooth muscles were significantly augmented in OA-challenged mice, whereas no significant change in the expression levels of M₂, M₃ and ET_B receptors was observed. The Evans blue dye extravasation in the main bronchial, but not tracheal, tissue of OA-challenged mice was significantly increased as compared with that of sensitized control animals. A marked inflammatory cells infiltration was also observed in bronchial but not tracheal tissues of OA-challenged mice.Conclusion: Repeated antigen challenge to sensitized mice caused a hyperresponsiveness of bronchial, but not tracheal, smooth muscle accompanied with bronchial tissue inflammation.Received 22 April 2004; returned for revision 10 June 2004; accepted by M. Katori 9 July 2004     

Dose-response curves to inhaled carbachol in asthma and chronic bronchitis

Dose-response curves were established in 19 asthmatic and 19 bronchitic patients by measuring changes in specific airway resistance (sRaw) induced by graded doses of aerosolized carbachol. The shape of the individual curves was classified by the least-square method according to four models: hyperbolic, exponential, linear and logarithmic (with a plateau). The dose-response curves were hyperbolic in 9 asthmatics, exponential in 9, and linear in 1; they were hyperbolic in 2 bronchitics, exponential in 4, linear in 5 and logarithmic in 5. No response could be elicited in 3 bronchitics. Carbachol responsiveness of the bronchitics who had baseline sRaw values in the same range as the asthmatics was much less than that of the asthmatics, i.e. a given dose of carbachol yielded a smaller sRaw increase in the former group. Increased responsiveness to carbachol, resembling that found in the asthmatic group, was observed in most bronchitics whose baseline sRaw values were elevated. These data suggest that bronchitics and asthmatics have different bronchial responses to carbachol, quantitatively and, in some instances, qualitatively.     

Effects of erlotinib on pulmonary function and airway remodeling after sensitization and repeated allergen challenge in Brown-Norway rats

Erlotinib, an EGFR tyrosine kinase inhibitor, can inhibit the proliferation and survival of cancer cells. It has been widely used to treat non-small cell lung cancer. This study aimed to evaluate the effects of erlotinib on bronchial hyperresponsiveness, airway inflammation, and airway remodeling in sensitized, ovalbumin-challenged rats. Two experimental groups of Brown-Norway rats were sensitized and repeatedly challenged by breathing aerosolized ovalbumin. Since Day 1, one group was given oral erlotinib (OA-erlotinib group) while the other group was given only oral saline (OA-saline group). The control group was sensitized and challenged using saline. All were anesthetized and paralyzed, and pulmonary function tests conducted at baseline and after provocation with varying doses of acetylcholine. Lung tissues were examined for airway inflammation, airway remodeling, and Th2-related cytokine mRNA expression. Results showed that the OA-erlotinib group had better pulmonary function and less airway inflammation, Th2-related cytokines and their mRNA expression, and airway remodeling compared to the OA-saline group. In conclusion, erlotinib effectively prevents bronchial hyperreactivity, airway inflammation, Th2-related cytokine mRNA expression, and airway remodeling after sensitization and repeated allergen challenge in Brown-Norway rats.     

Changes in pulmonary function and parasite burden in rats infected with Strongyloides venezuelensis concomitant with induction of allergic airway inflammation

The prevalence of allergic diseases such as asthma has increased markedly over the past few decades. To evaluate the possible mutual influence of helminth infection and allergy, the combined effects of experimental allergic airway inflammation and infection with Strongyloides venezuelensis on various parasitological and inflammatory indices were evaluated in the rat. A challenge of immunized rats with aerosolized ovalbumin (OVA) resulted in eosinophilic inflammation that peaked 48 h after the challenge and was accompanied by airway hyperresponsiveness (AHR) to an intravenous acetylcholine challenge. S. venezuelensis infection concomitant with an OVA challenge of immunized rats resulted in prolonged pulmonary inflammation with increased eosinophil infiltration in bronchoalveolar lavage fluid but not in the lung tissue. These rats also showed a significant parasite burden reduction, especially during parasite migration through the lungs. However, the fecundity rates of worms that reached the intestine were similar in allergic and nonallergic animals. Despite airway inflammation, the increased responsiveness of the airways in the experimental asthma model was suppressed during parasite migration through the lungs (2 days). In contrast, parasite-induced AHR was unchanged 5 days after infection in immunized and challenged rats. In conclusion, infection with S. venezuelensis interfered with the onset of AHR following an antigen challenge of immunized rats. The ability of parasites to switch off functional airway responses is therapeutically relevant because we may learn from parasites how to modulate lung function and, hence, the AHR characteristic of asthmatic patients.     

Resolution of allergic airways inflammation but persistence of airway smooth muscle proliferation after repeated allergen exposures

BACKGROUND: Chronic inflammation in asthmatic airways can lead to characteristic airway smooth muscle (ASM) thickening and pathological changes within the airway wall. OBJECTIVE: We investigated the long-term effects of repeated allergen exposure. METHODS: Brown-Norway (BN) rats sensitized to ovalbumin (OVA) were exposed to OVA or saline aerosol every third day on six occasions and studied 24 h, 7 days and 35 days after the final exposure. We measured airway inflammation, ASM cell proliferation (by incorporation of bromodeoxyuridine; BrdU) and bronchial responsiveness to acetylcholine. RESULTS: At 24 h, in OVA-exposed rats, we detected elevated OVA-specific serum IgE, increased numbers of macrophages, eosinophils, lymphocytes and neutrophils in the bronchoalveolar lavage (BAL) fluid and increased numbers of MBP+ (major basic protein) eosinophils and CD2+ T cells within the bronchial submucosa. This coincided with increased numbers of ASM cells expressing BrdU and with bronchial hyper-responsiveness (BHR). At 7 days, BHR was detected in OVA-exposed rats, coincident with increased numbers of macrophages and lymphocytes in BAL fluid together with increased numbers of CD2+ T cells within the bronchial submucosa. This coincided with increased numbers of ASM cells expressing BrdU. By day 35, the number of ASM cells expressing BrdU remained elevated in the absence of cellular infiltration and BHR. CONCLUSION: Repeated OVA-challenge results in persistent ASM cell proliferation in the absence of bronchial inflammation and BHR, which lasts for at least 1 week following cessation of exposure.     

The effect of H1-receptor blockade on the development of early- and late-phase bronchoconstriction and increased bronchial responsiveness in allergen-induced asthma

Background: Allergen challenge of subjects with asthma produces an early asthmatic response, late asthmatic response, and increases bronchial responsiveness. Histamine partly mediates the early asthmatic response, and may play a role in late-phase responses. Azelastine has antiallergic properties and has been proposed as a treatment for asthma. We therefore investigated the contribution of histamine to late-phase responses with the use of the potent H₁-receptor antagonist azelastine.Methods: Ten subjects with atopic asthma were studied in a double-blind, randomized, placebo-controlled trial. Azelastine was administered over 4 days before allergen challenge. Changes in airway caliber were followed with measurements of forced expiratory volume in 1 second, and changes in bronchial responsiveness were followed by methacholine and prostaglandin D₂ bronchial provocation tests.Results: Azelastine significantly inhibited the development of the early asthmatic response. Azelastine had no effect on the late asthmatic response or on the development of allergen-induced increases in bronchial responsiveness. The power of the study was sufficient to have had a high probability of detecting any important differences between placebo and azelastine during the late phase.Conclusions: Azelastine had no significant effect on the late-phase response model of asthma. This study does not support the hypothesis that histamine is an important mediator of the late asthmatic response or allergen-induced increases in bronchial responsiveness.     

Maximal forced expiratory maneuver to measure airway obstruction in allergen challenged mice

Our purpose was to develop a method of using a maximal forced expiratory maneuver (MFEM) for the study of bronchoconstriction and bronchial hyperreactivity (BHR) induced in mice by ovalbumin (OA) inhalation challenge. Eight mice (group I) were sensitized and then provocated with OA. Pulmonary function testing (PFT) at baseline and after varying doses of acetylcholine challenge was performed. Eight weight-matched normal mice served as controls (group II). Pulmonary functions include MFEM, dynamic respiratory system compliance (Crs) and respiratory system resistance (Rrs). The results showed that mice treated with OA had worse PFTs than normal controls, characterized by lower MFEF 50%, FEV0.1 and Crs but higher Rrs. The OA-sensitized mice also had more severe bronchoconstriction in response to acetylcholine, characterized by greater decreases in MFEF 50%, FEV0.1 and Crs but a higher Rrs than the controls. There was a good correlation between PD20MFEF50%Ach and PD20FEV0.1Ach with PD20CrsAch and PD20RrsAch. In conclusion, the MFEM can be used to evaluate airway obstruction and BHR induced in mice by allergen challenge.     

Effects of Ding-Chuan-Tang on Bronchoconstriction and Airway Leucocyte Infiltration in Sensitized Guinea Pigs

Ding-Chuan-Tang (DCT), a traditional Chinese medicine, has been used in treatment of the bronchial asthma for several centuries. However, the therapeutic mechanism of these Chinese medicine are still far from clear. To understand the mechanism of antiasthmatic property of DCT. A guinea pig model of allergic asthma was used to investigate the effects of DCT on ovalbumin-induced early and late asthmatic responses and airway inflammation, particularly the extent of eosinophil infiltration, and examine it direct β2-adrenoceptor agonist activity in guinea-pig isolated trachea. We had used three different protocals in ovalbumin sensitized guinea pigs by administrating 10 g/kg of DCT extracts to sensitized guinea pigs 30 min before antigen challenge (group I), 5 hr after antigen challenge (group II) and 2.5 g/kg once daily from the day of sensitization to the day of challenge. Our result showed that administration of DCT singificantly inhibited the antigen induced immediate asthmatic responses (IAR) in group I and inhibited both IRA and late asthmatic responses (LAR) in actively sensitized guinea pig in group III. DCT caused concentration-dependent relaxations in strips of guinea pig trachea contracted with carbachol, however ICI-118551, a selective β2-adrenoceptor antagonist, didn't significantly competitively inhibit the relaxations caused by DCT. Furthermore, examination of bronchoalveolar lavage fluid (BALF) revealed that DCT significantly inhibited the increase in percent of eosinophils in the airway after antigen challenge in three group. Histopathologic examination showed DCT suppressed the eosinophil infiltration into lung tissue. These results suggest that the antiasthmatic effect of DCT is mainly due to its bronchodilatation effect and its ability to inhibit the eosinophil into the airway and there is prophylactic effect of DCT on allergen-induced airway inflammation.     

Differential effects of low and high-dose estradiol on airway reactivity in ovariectomized rats

The aim of this animal study was to test the hypothesis that low and high doses of 17beta-estradiol (E2) may differentially influence airway responsiveness. Ovariectomized female rats received either placebo or E2 (10 or 100 microg/kg per day) for 21 days. The concentration of inhaled acetylcholine (ACh) required to double pulmonary resistance (EC200 RL) was calculated as the in vivo index of airway responsiveness. Ex vivo airway responsiveness was evaluated by the cumulative concentration-response curve (CCRC) of isolated tracheal segments. Rats treated with low-dose E2 were less responsive to ACh than rats given either placebo or high-dose E2 (P=0.003). Ex vivo, low-dose E2 treatment decreased (P=0.01) and high-dose E2 increased the potency of ACh (P<0.001) compared to placebo. E2 treatment did not alter smooth muscle cross-sectional area or epithelium thickness. Accumulation of liquid within the tracheal mucosa was moderately enhanced by high-dose E2 treatment compared with animals given either placebo or low-dose E2 (P=0.03). We conclude that E2 treatment has differential, dose-dependent effects on airway responsiveness to acetylcholine.     

Bronchial hyperresponsiveness and airway wall remodelling induced by exposure to allergen for 9 weeks.

Prolonged exposure to allergen has been proposed to be important for the development of bronchial hyperresponsiveness and airway remodelling in asthma. The present study was designed to examine the effect of chronic allergen exposure on bronchial responsiveness, eosinophil infiltration, and airway remodelling. We sensitized brown Norway rats with the occupational allergen trimellitic anhydride (TMA) and exposed the animals to TMA conjugated to rat serum albumin (TMA-RSA) on 5 consecutive days each week for 9 weeks, starting 4 weeks after sensitization. IgE and IgG anti-TMA antibodies in serum and bronchial responsiveness to acetylcholine were evaluated before and at weeks 3, 6, and 9 of allergen exposure. Thickness of the airway wall, airway luminal narrowing, and the number of goblet cells and eosinophils in the airway wall were evaluated with an image analysis system in lungs resected after the last assessment of bronchial responsiveness, at the end of the 9-week allergen exposure. All rats developed IgE and IgG anti-TMA antibodies after sensitization. The levels of antibodies increased with allergen exposure until week 6, and then declined. Bronchial hyperresponsiveness to acetylcholine was induced in allergen-exposed rats without ongoing airway eosinophilia. Bronchial hyperresponsiveness induced by chronic allergen exposure via inhalation was accompanied by significantly increased thickness of smooth muscle and airway narrowing in the small airways, and goblet cell hyperplasia in the large airways. We conclude that chronic exposure to allergen can induce bronchial hyperresponsiveness and airway wall remodelling. Airway wall remodelling may contribute to bronchial hyperresponsiveness.     

Airway hyperresponsiveness is associated with inflammatory cell infiltration in allergic brown-Norway rats.

The time course of the development of airway hyperresponsiveness (AHR) to inhaled acetylcholine (ACh) and the associated inflammatory cell recovery in bronchoalveolar lavage fluid (BAL) in actively sensitised Brown-Norway rats was studied following challenge with inhaled ovalbumin (OA). IgE for OA was detected in serum obtained from sensitised rats using passive cutaneous anaphylaxis, at titres of 1:10 to 1:30; none was detected in unsensitised animals. There was no significant change in either airway responsiveness to inhaled ACh or in BAL cell counts in rats challenged with saline over the 24 h. Following challenge with a 1% OA aerosol, airway responsiveness to inhaled ACh increased over the 24-hour period, maximal at 18-24 h (saline-challenged group mean -log PC200 1.95 +/- 0.07 M; OA-challenged group mean -log PC200 2.30 +/- 0.05 M; p < 0.01). The composition of the inflammatory cells in the BAL fluid after allergen inhalation varied over the 24-hour period, with an initial neutrophilia at 5-8 h (p < 0.01), followed at 18-24 h by an increase in lymphocytes (p < 0.01) and marked eosinophilia (p < 0.01). There was a significant correlation between airway responsiveness and eosinophil recovery at 5-8 h (p < 0.05), and at 18-24 h after allergen exposure (p < 0.05). At 18-24 h there was also a significant correlation between neutrophils and airway responsiveness (p < 0.05). There was no difference between baseline lung resistance in matched saline- or OA-challenged animals at each time point.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitric oxide deficiency contributes to impairment of airway relaxation in cystic fibrosis mice

The pulmonary disease of cystic fibrosis (CF) is characterized by persistent airway obstruction, which has been attributed to chronic endobronchial infection and inflammation. The levels of exhaled nitric oxide (NO) are reduced in CF patients, which could contribute to bronchial obstruction through dysregulated constriction of airway smooth muscle. Because airway epithelium from CF mice has been shown to have reduced expression of inducible NO synthase, we examined airway responsiveness and relaxation in isolated tracheas of CF mice. Airway relaxation as measured by percent relaxation of precontracted tracheal segments to electrical field stimulation (EFS) and substance P, a nonadrenergic, noncholinergic substance, was significantly impaired in CF mice. The airway relaxation in response to prostaglandin E2 was similar in CF and non-CF animals. Treatment with the NO synthase inhibitor NG-nitro-L-arginine methylester reduced tracheal relaxation induced by EFS in wild-type animals but had virtually no effect in the CF mice. Conversely, exogenous NO and L-arginine, a NO substrate, reversed the relaxation defect in CF airway. We conclude that the relative absence of NO compromises airways relaxation in CF, and may contribute to the bronchial obstruction seen in the disease.     

Inhibition of antigen-induced late asthmatic response and bronchial hyperresponsiveness by cyclosporin A

We have previously demonstrated that Cyclosporin A (CyA), a T lymphocyte-selective immunosuppressive agent, reduced the delayed-phase bronchial eosinophil infiltration after antigen challenge in a guinea pig model of asthma. In the present study, we studied the effects of CyA on antigen-induced late asthmatic response (LAR) and bronchial hyperresponsiveness following LAR. Guinea pigs immunized by repeated exposure to aerosolized ovalbumin (OA) were intravenously given metopirone, a cortisol synthesis inhibitor, 24 hours before and 30 minutes before antigen challenge, and to prevent death from immediate severe bronchoconstriction, chlorpheniramine maleate was also injected. After antigen challenge with high dose of OA, LAR occurred in twelve of fifteen animals (80%) and the bronchial responsiveness to acetylcholine was significantly increased. However, when guinea pigs were treated with CyA from the beginning of immunization period, the development of LAR was completely inhibited, although similar magnitude of immediate bronchoconstriction was observed, and a subsequent increase in bronchial responsiveness was partially but significantly blocked. Since CyA has been shown to suppress activation of guinea pig T lymphocytes and their production of lymphokines, these results suggest that T cell factor(s) may be important for the elicitation of LAR and the antigen-induced bronchial hyperresponsiveness.     

The effect of allergen-induced airway inflammation on airway remodeling in a murine model of allergic asthma

OBJECTIVE AND DESIGN: We examined the effect of airway inflammation on airway remodeling and bronchial responsiveness in a mouse model of allergic asthma. MATERIALS AND METHODS: BALB/c mice were sensitized to ovalbumin (OA), and exposed to aerosolized OA (0.01, 0.1 and 1%). Twenty-four hours after the final antigen challenge, bronchial responsiveness was measured, and bronchoalveolar lavage (BAL) and histological examinations were carried out. RESULTS: Repeated antigen exposure induced airway inflammation, IgE/IgG1 responses, epithelial changes, collagen deposition in the lungs, subepithelial fibrosis associated with increases in the amount of transforming growth factor (TGF)-beta1 in BAL fluid (BALF), and bronchial hyperresponsiveness to acetylcholine. The number of eosinophils in BALF was significantly correlated with TGF-beta1 production in BALF and the amount of hydroxyproline. Furthermore, significant correlations were found between these fibrogenic parameters and the bronchial responsiveness. CONCLUSION: These findings demonstrated that in this murine model airway eosinophilic inflammation is responsible for the development of airway remodeling as well as bronchial hyperresponsiveness in allergic bronchial asthma.