In vivo airway eosinophil accumulation induced by polymyxin-B reduces bronchial responsiveness in guinea pigs

BACKGROUND: Chronic desquamative eosinophilic bronchitis and bronchial hyperresponsiveness have been considered essential for bronchial asthma. However, it has not been studied whether airway eosinophils enhance or inhibit bronchial responsiveness in vivo. OBJECTIVE: This study was conducted to elucidate the influence of airway eosinophil accumulation on bronchial responsiveness in vivo. MATERIALS AND METHODS: Guinea pigs were transnasally treated with 75 microg/kg of polymyxin-B or vehicle twice a week for a total of 3 weeks. Guinea pigs were surgically cannulated and artificially ventilated 24 h after the last administration of polymyxin-B or vehicle. Ten minutes after the installation of artificial ventilation, ascending doses of methacholine, acetylcholine or histamine were inhaled for 20 s at intervals of 5 min. Subsequent study was conducted 20 min after treatment of 60 mg/kg of indomethacin in the same manner. Final study was conducted in naive guinea pigs after single inhalation of 75 microg/mL of polymyxin B. RESULTS: The proportion of eosinophils in bronchoalveolar lavage fluid significantly increased in guinea pigs treated with polymyxin-B compared with vehicle. Bronchial responsiveness to inhaled methacholine, acetylcholine and histamine was significantly decreased by the polymyxin-B treatment. This protective effect induced by polymyxin B was abolished by pretreatment of indomethacin. A significant increase in bronchial responsiveness was observed after a single inhalation of polymyxin B. CONCLUSION: These results suggest that in vivo airway eosinophils may reduce non-specific bronchial responsiveness through inhibitory or bronchoprotective prostanoids.     

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.     

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.     

Effects of leukotriene B4 receptor antagonist, LY293111Na, on antigen-induced bronchial hyperresponsiveness and leukocyte infiltration in sensitized guinea pigs

OBJECTIVE AND DESIGN: LY29311 Na, 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy] propoxy] -phenoxy]-benzoic acid sodium salt, is a novel leukotriene B4 (LTB4) receptor antagonist. Its effects on guinea pig models of asthma were compared with those of dexamethasone. METHODS: Effects of LY293111Na were tested in antigen (ovalbumin, OA)-induced bronchial hyperresponsiveness (BHR) and leukocyte accumulation in actively sensitized guinea pigs. Its effects on antigen-induced acute bronchoconstriction in passively sensitized guinea pigs were also studied. RESULTS: LY293111 Na (10 to 30 mg/kg p.o., 1 h before and 6 h after OA challenge) inhibited BHR to acetylcholine. LY293111 Na (3 mg/kg p. o.) significantly inhibited accumulation of neutrophils in bronchoalveolar lavage (BAL) fluid 24 h after antigen challenge but it did not inhibit accumulation of eosinophils and macrophages at any doses used. In contrast, dexamethasone (30 mg/kg p.o., 4 h before OA challenge) not only inhibited BHR but also reduced the infiltration of all three types of leukocytes. A significant increase of LTB4 levels in BAL fluid was noted at 3 and 15 min after the antigen challenge. LY293111Na did not inhibit antigen-induced acute bronchoconstriction in passively sensitized guinea pigs. CONCLUSION: These results indicate that LTB4 may participate in antigen-induced BHR but not in eosinophil infiltration and acute bronchoconstriction in guinea pigs.     

Effects of xiao-qing-long-tang (XQLT) on bronchoconstriction and airway eosinophil infiltration in ovalbumin-sensitized guinea pigs: in vivo and in vitro studies

BACKGROUND: Xiao-qing-long-tang (XQLT sho-seiru-to), a traditional Chinese medicine, has been used to treat patients with bronchial asthma in Oriental countries for several centuries. However, the therapeutic mechanisms of this Chinese medicine remain a matter of considerable debate. Therefore, a series of experiments using ovalbumin-sensitized guinea pigs was performed to elucidate the possible antiasthmatic effect of XQLT. METHODS: The effect of XQLT on ovalbumin-induced airway inflammation in a guinea pig model of allergic asthma was examined, and early and late asthmatic responses were measured in terms of airway resistance and extent of eosinophil infiltration. Furthermore, the bronchorelaxing effect of XQLT was measured in isolated guinea pig trachea. RESULTS: XQLT significantly inhibited the antigen-induced immediate asthmatic response (IAR) and late asthmatic response (LAR) in actively sensitized guinea pigs. Cumulative administration of XQLT caused concentration-dependent relaxation of the carbachol-precontracted guinea pig trachea. The bronchorelaxing effect of XQLT was reversed by ICI-118551, a selective beta2-adrenoceptor antagonist. Furthermore, examination of bronchoalveolar lavage fluid (BALF) revealed that XQLT significantly suppressed the increase in eosinophils (24 h after antigen challenge) in the airway. In addition, XQLT significantly attenuated the increase in eosinophils at 1, 6, 24, 48, and 72 h after antigen challenge when it was administered once daily from the day of sensitization to the day of challenge. Histopathologic examination results showed that XQLT suppressed eosinophil infiltration into lung tissue. CONCLUSIONS: These results demonstrate that the antiasthmatic effects of XQLT appear to be partly mediated by stimulation of beta2-adrenoceptors, leading to bronchorelaxation, and that XQLT inhibits the infiltration of eosinophils into the airway. Thus, XQLT may be useful for the prevention or treatment of asthma.     

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 beta2-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 beta2-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.     

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.     

Greater involvement of neurokinins found in Guinea pig models of severe asthma compared with mild asthma

BACKGROUND: Involvement of neurokinins in asthma has been previously pointed out by several reports. However, the relationship between neurokinins and the severity of asthma has remained unclear. We developed a model of mild asthma (model I) and severe asthma (model II) in guinea pigs, and investigated the function of neurokinins in both models. METHODS: In models I and II, systemically sensitized guinea pigs were made to inhale ovalbumin once and three times, respectively. Substance P (SP) and neurokinin A (NKA) concentrations in the bronchoalveolar lavage fluid (BALF) were measured in models I and II. Then, the effects of a capsaicin pretreatment, which depletes neurokinins, in both animal models on airway narrowing induced by the last ovalbumin inhalation, airway hyperresponsiveness to inhaled methacholine, and eosinophil accumulation in BALF, were investigated. RESULTS: SP concentration tended to increase and the NKA concentration increased significantly in model II, but not in model I. Capsaicin pretreatment significantly inhibited the late bronchial response that was observed 2-6 h after the last ovalbumin inhalation, airway hyperresponsiveness and eosinophil accumulation in model II. On the other hand, it had no effects on the responses in model I. CONCLUSION: It is suggested that the more severe the disease, the greater the involvement of neurokinins.     

Eosinophil infiltration and enhancement of airway reactivity by leukocyte chemotactic factor, formyl-methionyl-leucyl-phenylalanine (fMLP), in guinea pigs.

N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) is a bacterial-derived chemotactic factor for eosinophils and neutrophils. This study is aimed to examine whether or not eosinophil infiltration induced by intra-airway administration of fMLP causes the damage of the bronchial epithelium and results in airway hyperresponsiveness in normal non-sensitized guinea pigs. In normal guinea pigs fMLP administered by aerosol inhalation or intratracheal injection caused significant infiltration of eosinophils in the tracheal mucosa and enhanced bronchial reactivity to inhaled histamine 6 and 24 hours after exposure. Electron microscopic examination showed damage of the alignment of the epithelial cells in the bronchial mucosa in fMLP-treated guinea pigs. PAF antagonists CV3988 and WEB2086 and a 5-lipoxygenase inhibitor (AA-861) did not prevent fMLP induced eosinophil infiltration, which suggests that fMLP caused eosinophil infiltration mainly by its chemotactic activity, not by the release of platelet activating factor (PAF) or leukotrienes in this experimental condition. These results showed that in normal guinea pigs a bacteria-derived chemoattractant of fMLP could reproduce a sequence of eosinophil infiltration and airway hyperresponsiveness, similar to the inflammatory pathophysiology after antigen challenge in sensitized animals. We concluded that eosinophil infiltration induced by either immunological or non-immunological mechanisms can cause airway damage and airway hyperresponsiveness.     

Role of sensory neuropeptides in post-allergic propranolol-induced bronchoconstriction in guinea pigs in vivo

Background Administration of propranolol can provoke bronchoconstriction in asthmatic patients. We hypothesized that such bronchoconstriction may result from the inflammatory mediators released by an allergic reaction. We recently developed a guinea pig model for propranolol-induced bronchoconstriction (PIB). Neuropeptides which are released from C-fibre nerve endings have been postulated to induce bronchial hyperresponsiveness through neurogenic inflammation. Objective The purpose of this study was to examine whether sensory neuropeptides are involved in the development of PIB after allergic reaction. Methods Propranolol at a concentration of 10mg/ml was inhaled 20min after antigen challenge in passively sensitized, anaesthetized and artificially ventilated guinea pigs. The animals were treated intravenously with a NK₁ and NK₂ dual antagonist, FK224, in a dose of 1 or 10 mg/kg or vehicle or a selective NK₁ antagonist, FK888, in a dose of 1 or 10mg/kg or vehicle 10min before or 15min after antigen challenge. Results Propranolol inhaled 20 min after antigen challenge caused bronchoconstriction. FK224 or FK888 administered 15 min after antigen challenge as well as 10 min before antigen challenge did not reduce the PIB. Conclusion We conclude that neuropeptides such as neurokinin A and substance P do not directly contribute to the development of PIB after allergic reaction.     

Bronchoprotective effects of atrial natriuretic peptide against propranolol-induced bronchoconstriction after allergic reaction in guinea pigs

OBJECTIVE: To study the effects of intravenous atrial natriuretic peptide (ANP) on antigen-induced bronchoconstriction, propranolol-induced bronchoconstriction (PIB) after antigen challenge, and histamine-induced bronchoconstriction in guinea pigs. METHODS: Allergic bronchoconstriction was evoked by inhalation of ovalbumin (OA) and PIB was caused when 10 mg/mL of propranolol was inhaled 20 min after OA challenge in passively sensitized and artificially ventilated guinea pigs. 25, 50, 100 and 200 microg/mL of histamine were inhaled for 20 s at 5-min intervals in non-sensitized guinea pigs. RESULTS: Pretreatment with ANP in doses of 0.1 and 1.0 nmol/kg injected intravenously 15 min after antigen challenge reduced PIB in a dose-dependent manner, and 5 min before antigen challenge significantly attenuated PIB but not antigen-induced bronchoconstriction. Intravenous ANP significantly reduced bronchial responses to increasing concentrations of inhaled histamine in a dose-dependent manner. CONCLUSION: These results suggest that ANP possesses protective effects against propranolol-induced and histamine-induced bronchoconstriction, albeit by a non-specific mechanism in guinea pig in vivo.     

FK506 aerosol locally inhibits antigen-induced airway inflammation in Guinea pigs

BACKGROUND: Eosinophilic airway inflammation is a common pathological feature of asthma. It has been shown that FK506 given systemically suppresses antigen-induced airway inflammation in animal models. However, it is unknown whether inhaled FK506 can suppress the airway allergic inflammation/immune response and whether it acts locally or systemically. METHODS: We tested the effects of oral FK506 and inhaled FK506 on antigen-induced airway inflammation in guinea pigs. The tissue and blood concentrations of FK506 given via both routes were compared. The effect of inhaled FK506 on the expression of cytokine mRNA in lung and bronchoalveolar lavage fluid (BALF) cells was also tested. RESULTS: Both routes of administration of FK506 suppressed the airway eosinophilia in egg albumin (EA)-sensitized and -challenged animals. The effect of three inhaled puffs was almost equal to that of 1 mg/kg administered by the oral route. Following inhalation of three puffs, FK506 concentration in blood (AUC(0-24 h)) was approximately 1/21 of that following oral FK506 (1 mg/kg). After EA challenge, mRNA expression of interleukin (IL)-5, eotaxin and IL-1beta in BALF cells and IL-5 in the lung increased significantly. FK506 aerosol markedly inhibited IL-5 mRNA expression in the lung. In situ hybridization indicated that in the BALF IL-5 mRNA expression by lymphocyte-like cells was inhibited by FK506 aerosol. In addition, anti-IL-5 antibody injected intratracheally almost completely abolished eosinophilia in this model. CONCLUSION: Inhaled FK506 can suppress airway inflammation in guinea pigs, where the local action, presumably the inhibition of T-cell activation/function in the lung and airways, was primarily important.     

Inhibition of aeroallergen-induced bronchial eosinophilia by azelastine in guinea pigs.

The ability of azelastine to influence allergic bronchial eosinophil infiltration in guinea pigs was studied. Aeroallergen challenge of actively sensitized guinea pigs produces eosinophil infiltration in bronchoalveolar lavage fluid collected 20-24 h after aeroallergen exposure. Azelastine and methylprednisolone, administered orally 2 h before challenge, inhibited eosinophilic infiltration yielding the ED50s of 1.55 and 4.48 mg/kg, respectively. WEB-2086, a platelet-activating factor antagonist (3 mg/kg), and theophylline, a phosphodiesterase inhibitor (30 mg/kg), also suppressed allergic bronchial infiltration of eosinophils by 44%. The data obtained in this study demonstrate that azelastine exerts direct bronchial anti-inflammatory activity in guinea pigs.     

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.     

Effect of surfactant inhalation on allergic bronchoconstriction in guinea pigs

Background In the small airway, surfactant reduces surface tension, prevents liquid filling of bronchioles, thereby maintaining patency in the small airways. Recent reports demonstrated that surfactant dysfunction develops in experimental asthma in immunized guinea pigs. However, there are few reports concerning surfactant and lung function in an experimental asthma model. Objective To examine whether inhaled surfactant improves lung mechanics in antigen-induced bronchoconstriction in guinea pigs. Method We developed a passively immunized guinea pig model for allergic bronchoconstriction induced by antigen inhalation. Using this model, we investigated the effect of inhaled exogenous surfactant, surfactant TA. on the airway opening pressure (Pao) after antigen challenge. Results Aerosol antigen challenge produced a gradual and long-lasting increase in Pao. Twenty minutes after antigen challenge, aerosolized surfactant TA, 20 mg/ml. was inhaled for 90 s, and it significantly reduced the Pao by 32.8% in 12 min, while a 10.2% reduction was observed in a control group in the same period. When surfactant TA was administered by 90-s inhalation before antigen challenge, it inhibited the Pao increase in a dose-dependent manner: mean inhibitory rates of Pao were 33.6% in surfactant TA 10 mg/ml and 61.9% in surfactant TA 20 mg/mI, respectively. Conclusion Inhaled surfactant showed preventive and recovery effects on antigeninduced bronchoconstriction in an immunized guinea pig model.     

豚鼠哮喘模型气道重建对气道反应性的影响

目的:通过小剂量致敏原反复致敏建立豚鼠慢性哮喘模型,设定不同时点(4、6、8周)观察气道结构及气道反应性的变化,探讨气道重建对气道反应性的影响。方法:采用低剂量卵白蛋白反复致敏、激发豚鼠,制作哮喘动物模型,应用氯化乙酰胆碱静脉注射进行支气管激发实验,进行支气管肺泡灌洗并计数灌洗液的白细胞总数及分类。应用图像分析系统对豚鼠气道进行形态学测量。结果:哮喘8周组以纤维组织增生及平滑肌厚度增加最为显著。气道高反应性以哮喘4周组增高最明显,而随着与致敏原接触时间的延长,气道高反应性逐渐降低,到哮喘8周组与正常对照组相比已无显著差异。结论:长时间卵白蛋白吸入致敏可以引起哮喘豚鼠气道反应性的变化,这种变化与气道重建的发生相关联。     

The mechanism of airway hyperresponsiveness following immediate bronchial response in ovalbumin (OA)-sensitized guinea pigs]

We have previously demonstrated that airway responsiveness was enhanced following a late bronchial response (LBR) after an allergen challenge in ovalbumin (OA)-sensitized guinea pigs. The purpose of the present studies was to evaluate whether airway responsiveness to methacholine increased after an immediate bronchial response (IBR) and the possible involvement of the beta-adrenoceptor dysfunction in OA-sensitized guinea pigs. Guinea pigs were actively sensitized by aerosolized OA. Following OA exposure, IBR appeared. After IBR when specific airway resistance returned to the base line value, airway responsiveness to methacholine increased significantly. Before OA exposure, propranolol induced bronchoconstriction (PIB) was not provoked, however, after IBR, PIB was provoked and the guinea pigs died because of severe bronchoconstriction. These results suggest that airway responsiveness to methacholine increases significantly after IBR. Furthermore, the dysfunction of the beta-adrenoceptor may be a mechanism of this hyperresponsiveness in OA-sensitized guinea pigs.     

Inhaled sodium fluoride decreases airway responsiveness to acetylcholine analogs in vivo

The study was conducted to characterize the action of NaF, which had relaxing property in carbachol precontracted isolated bovine bronchus, on airway responsiveness challenged by acetylcholine receptor agonists in rats and asthmatic humans.Tracheal flow rate and airway resistance were measured in anaesthetized rats. NaF was delivered either before carbachol challenge or together with carbachol. Patients with mild asthma were challenged with methacholine aerosol, and NaF was delivered when FEV1 fell by more than 20%. The results indicated that: (1) in rats NaF significantly inhibited carbachol-induced bronchial constriction when inhaled prior to carbachol challenge as airway resistances in the NaF and NaF+verapamil groups were significantly lower than those in the control group; (2) NaF significantly reversed carbachol or methacholine-induced bronchial constriction in asthmatic patients. In conclusion, NaF, delivered in form of aerosol, reduced bronchial responsiveness to carbachol in rats and had a bronchodilating effect on rat and human airways precontracted by inhalation of acetylcholine analogs.     

Airway responses to histamine, acetylcholine, and propranolol in anaphylactic hypersensitivity in guinea pigs

Using changes in tidal volume and dynamic lung compliance, airway responses to histamine, acetylcholine, and propranolol were investigated in different groups of guinea pigs before and after active or passive sensitization. The threshold doses to inhaled histamine, acetylcholine, and propranolol were identical before and after sensitization. Similarly, the slope of dose response curves to these drugs and the time course of recovery from airway constriction were comparable in control and sensitized animals. The slopes of dose response curves to histamine and acetylcholine were parallel. Threshold doses to acetylcholine (T_ACH) and histamine (T_H) were proportional. The average ratio T_ACH/T_H was 7.7. There was no correlation between threshold doses and slopes of dose response curves for propranolol and those for histamine or acetylcholine. Antigen challenge resulted in decreases of dynamic lung compliance and in increases of airway resistance and frequency, which were maximal 60 to 130 seconds after challenge. When functional parameters after antigen challenge had returned to normal, bronchial responses to histamine, acetylcholine, and propranolol were exaggerated. These exaggerated responses were reproducible, transient, variable from animal to animal, and related to the antigen dose. Guinea pig anaphylaxis does not lead to the prolonged hypersensitivity to chemical mediators, which characterizes human reaginic asthma, but to a temporary enhancement of responses to acetylcholine, histamine, and propranolol.     

Effect of aerosolized administration of KF19514, a phosphodiesterase 4 inhibitor, on bronchial hyperresponsiveness and airway inflammation induced by antigen inhalation in guinea-pigs

BACKGROUND: Although phosphodiesterase (PDE) 3 and 4 inhibitors have received much attention for the treatment of bronchial asthma, systemic adverse effects have also been reported. OBJECTIVE: The purpose of this study was to investigate the effect of inhaled olprinone, a newly developed PDE3 inhibitor, and KF19514, a PDE1 and 4 inhibitor, on antigen-induced airway reactions in guinea-pigs. METHODS: Fifteen minutes after inhalation of olprinone (0.1 or 1.0 mg/mL) and KF19514 (0.1 or 0.01 mg/mL), animals were given an antigen challenge. Bronchial hyper-responsiveness and bronchoalveolar lavage fluid cell analysis were performed 24 h after the antigen challenge. RESULTS: Inhalation of olprinone and KF19514 caused a dose-related inhibition of antigen-induced bronchoconstriction. Antigen inhalation significantly increased bronchoconstrictor responses to methacholine, and airway accumulation of neutrophils and eosinophils, 24 h after the antigen challenge. These responses were dose-dependently prevented by KF19514, but not by olprinone. CONCLUSION: The results indicate that inhaled PDE inhibitors might be useful for treatment of bronchial asthma.