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.     

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.     

Effects of single and multiple inhalations of antigen on airway responsiveness in monkeys

Airway hyperresponsiveness is an important and characteristic feature of asthma. In monkeys, we have reported that antigen (Ag) inhalation induces a prolonged airway eosinophilia, that chronic airway eosinophilia is associated with marked airway hyperresponsiveness, and that chronic Ag inhalations induce airway eosinophilia and hyperresponsiveness. In this study we have determined the effects of acute Ag inhalation(s) on airway responsiveness to obtain a protocol for the study of the mechanisms involved. Anesthetized and intubated adult male cynomolgus monkeys with a naturally occurring sensitivity to Ascaris suum extract were studied. Airway responsiveness (provocative concentration of nebulized and inhaled methacholine that induced a 100% increase in respiratory system resistance [Rrs] [PC100]; twofold decrease regarded as significant) and airway cell composition (bronchoalveolar lavage [BAL]) were determined 1 day before and 20 hours after a single inhalation of Ascaris extract, or 3 days before and 3 days after three alternate-day inhalations of Ascaris extract. The single inhalation of Ag (N = 7) caused an acute increase in Rrs (307% +/- 62%), an increase in BAL leukocytes, and a decrease in PC100 in three animals that was moderate (more than eightfold) in two animals. The mean +/- SE change in log PC100 was only -0.25 +/- 0.24. The multiple inhalations of Ag in the same animals caused acute increases in Rrs (178% +/- 48%, 380% +/- 83%, and 331% +/- 63%, respectively), an increase in BAL granulocytes, and a decrease in PC100 in six of seven animals (mean +/- SE change in log PC100 was -1.36 +/- 0.34) that was moderate in two and severe (more than 80-fold) in three animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

The onset and recovery from airway hyperresponsiveness: relationship with inflammatory cell infiltrates and release of cytotoxic granule proteins

Previous studies from our laboratory have demonstrated a temporal relationship between eosinophil influx into the airways and the onset of airway hyperresponsiveness to inhaled methacholine. The purpose of the present study was to extend this observation by evaluating changes in airway cellular composition and measuring the levels of granulocyte-derived mediators recovered in BAL fluid during the onset and recovery from antigen-induced airway hyperresponsiveness. Airway cellular composition, airway responsiveness to inhaled methacholine and the levels of BAL fluid EPO and MPO were monitored over a 32 day study in eight adult male Ascaris suum sensitive cynomolgus monkeys. Repeated Ascaris suum inhalation (nine challenges during days 0-21) resulted in a selective, sustained airway eosinophilia that was temporally related with the onset and maintenance of airway hyperresponsiveness (r = 0.67, P less than 0.001). The level of BAL eosinophil-derived EPO was increased and remained elevated concurrent with the increase in airway eosinophils and airway responsiveness. During the recovery phase (days 22-32) the actual number of eosinophils remained elevated, while BAL EPO levels were significantly decreased. The recovery phase was also associated with a transient increase in the number of BAL neutrophils and MPO concentration. We conclude that the number and state of activation of airway eosinophils directly correlate with the onset and maintenance of airway hyperresponsiveness. Recovery from airway hyperresponsiveness is associated with a decrease in eosinophil activation and a transient increase in the number of activated neutrophils.     

Betamethasone prevents virus-induced airway inflammation but not airway hyperresponsiveness in guinea pigs

In this study the effect of betamethasone was investigated in guinea pigs that demonstrate airway inflammation and airway hyperresponsiveness after a viral respiratory tract infection with parainfluenza-3 (PI3) virus. Guinea pigs were pretreated with saline or betamethasone 8 mg/kg intraperitoneally twice a day for five consecutive days, starting on day 0 and ending on day 4. On day 1, the guinea pigs were inoculated with either control solution (medium) or PI3 virus. On day 5, airway responsiveness was measured. Furthermore, a blood sample was taken, lungs were lavaged, blood leucocytes were counted, and bronchoalveolar lavage (BAL) cells were counted and differentiated. Accordingly, the activity of the bronchoalveolar cells was measured by lucigenin-amplified chemiluminescence. In virus-infected guinea pigs the total bronchoalveolar cell number was increased by 44% compared with medium-treated guinea pigs. This was mainly due to the increase in macrophages (70%, P  < 0.05) and eosinophils (344%, P  < 0.001). The increase in both total and differential (macrophages and eosinophils) cell numbers in virus-infected guinea pigs was completely abolished in animals treated with betamethasone. Moreover, betamethasone prevented the decrease in number of blood leucocytes in virus-infected guinea pigs. In contrast, betamethasone did not prevent the increase in airway responsiveness to both histamine (>200%) and methacholine (>100%) after the virus infection. In conclusion, betamethasone treatment prevents virus-induced airway inflammation but not airway hyperresponsiveness in guinea pigs.     

The effect of a specific thromboxane A2 antagonist, AA-2414 on airway hyperresponsiveness induced by ozone exposure in dogs]

To determine whether thromboxane A2 (TxA2) is involved in airway hyperresponsiveness induced by ozone exposure, we studied the effect of a specific TxA2 antagonist, AA-2414 on ozone-induced airway hyperresponsiveness in seven dogs. Airway responsiveness to inhaled methacholine was determined by modified Astograph (7 Hz oscillation method), and numbers of neutrophils in the peripheral blood, neutrophil counts in bronchoalveolar lavage fluid (BALF), the levels of TxB2 and 6-keto-Prostaglandin F1 alpha (6-keto-PGF1 alpha) in BALF were measured before and after ozone exposure, and after ozone exposure with pretreated AA-2414. Ozone exposure was carried out for 2 hr at an ozone level of 3.06 +/- 0.06 ppm (mean +/- SE). Airway responsiveness to inhaled methacholine increased significantly after ozone exposure (p less than 0.01), and the hyperresponsiveness induced by ozone exposure was inhibited significantly by pretreated AA-2414 (p less than 0.01). Numbers of neutrophils in the peripheral blood and neutrophil counts in BALF increased after ozone exposure, and these increase were not inhibited by pretreated AA-2414. There was no apparent change in the levels of TxB2 in BALF after ozone exposure and after ozone exposure with pretreated AA-2414, however the levels of 6-keto-PGF1 alpha in BALF decreased after ozone exposure and after ozone exposure with pretreated AA-2414 (p less than 0.1). These results suggest that TxA2 plays an important role in the development of airway responsiveness after ozone exposure in dogs, and ozone-induced airway hyperresponsiveness may not be associated with the hyperproduction of TxA2 but with the relative increase of TxA2 due to the decrease of PGI2.     

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.     

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 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)     

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.     

Oral tolerance attenuates airway inflammation and remodeling in a model of chronic pulmonary allergic inflammation

We investigated the effects of oral tolerance (OT) in controlling inflammatory response, hyperresponsiveness and airway remodeling in guinea pigs (GP) with chronic allergic inflammation. Animals received seven inhalations of ovalbumin (1-5mg/mL-OVA group) or normal saline (NS group). OT was induced by offering ad libitum ovalbumin 2% in sterile drinking water starting with the 1st ovalbumin inhalation (OT1 group) or after the 4th (OT2 group). The induction of OT in sensitized animals decreased the elastance of respiratory system (Ers) response after both antigen and methacholine challenges, peribronchial edema formation, eosinophilic airway infiltration, eosinophilopoiesis, and airways collagen and elastic fiber content compared to OVA group (P<0.05). The number of mononuclear cells and resistance of respiratory system (Rrs) responses after antigen and methacholine challenges were decreased only in OT2 group compared to OVA group (P<0.05). Concluding, our results show that inducing OT attenuates airway remodeling as well as eosinophilic inflammation and respiratory system mechanics.     

Polymyxin B-induced bronchial neutrophilia does not alter airway responsiveness to methacholine in cynomolgus monkeys.

The purpose of this study was to develop a primate model of chronic bronchial neutrophilia to investigate the role of neutrophils in the pathogenesis of airway hyperresponsiveness. Ten adult male cynomolgus monkeys (Macaca fascicularis) were anaesthetized and intubated for each study. Six animals each received a total of seven inhalation treatments with polymyxin B (200 micrograms) over a 24 day period. Four control animals received an identical treatment regime with vehicle inhalations. Airway cellular composition was assessed by bronchoalveolar lavage (BAL). Airway responsiveness was assessed by methacholine cumulative dose response determinations. There were no significant changes in airway cellular composition or airway responsiveness in the control group. In contrast, Polymyxin B inhalation resulted in an influx of neutrophils (PMN) into the lungs which peaked at day 10 of the study (%PMN in BAL fluid rose from 5 +/- 2 to 51 +/- 8, P less than 0.001) and persisted out to day 24 (41 +/- 8, P less than 0.01). Increases in PMNs were associated with an increase in BAL levels of myeloperoxidase (MPO levels in BAL fluid increased from 2 +/- 3 to 180 +/- 23 OD P less than 0.05). Although airway PMN percentages and MPO concentrations were chronically elevated, airway responsiveness did not change. These results suggest that the neutrophil does not play a functional role in the onset of hyperresponsive airways in primates.     

Sodium cromoglycate attenuates pulmonary inflammation without influencing bronchial responsiveness in healthy subjects exposed to organic dust

BACKGROUND: Inhalation of organic dust from a pig house induces airway inflammation and increases bronchial responsiveness to methacholine in healthy subjects. OBJECTIVE: To study whether sodium cromoglycate influences the airway inflammatory reaction and the increase in airway responsiveness induced by inhalation of organic dust. METHODS: Bronchoalveolar and nasal lavages, and bronchial methacholine challanges were performed and blood samples were drawn in 32 healthy subjects before and after exposure to dust in a pig farm. Sodium cromoglycate was inhaled (20 mg, twice a day) and administered intranasally (5.2 mg, twice a day) by 16 and a corresponding placebo was given to the other 16 healthy controls for two weeks prior to exposure. RESULTS: Exposure induced a significant increase in inflammatory cells and soluble components (pro-inflammatory cytokines, inflammatory mediators) in bronchoalveolar and nasal lavage fluid in both groups. The increase in neutrophils, interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha as well as myeloperoxidase and soluble intracellular adhesion molecule (ICAM)-1 in bronchoalveolar lavage (BAL) fluid was significantly reduced by treatment with sodium cromoglycate. Although sodium cromoglycate inhalation largely influenced a variety of inflammatory indices in bronchoalveolar lavage fluid it had no effect on the increase in bronchial responsiveness to methacholine. CONCLUSION: Sodium cromoglycate alters the airway inflammatory response to inhaled organic dust without influencing the dust-induced increase in bronchial responsiveness to methacholine.     

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.     

Late asthmatic response by recruitment of homocytotropic antibody from circulating blood to the airway wall in guinea pig

Many reports have been published about the late asthmatic response (LAR) of animal model. But most of the animals used were sensitized actively and it is considered generally that it is impossible to generate LAR in passively sensitized animals, especially in guinea pig. About the mechanism of LAR, most discussion are focused on airway hyperreactivity, inflammation and chemical mediators. But little is known about the direct initiator of the late phase bronchoconstriction. Instead of the circulating antibody which is generated by antibody producing cells in actively sensitized animals, anti-serum was administered to guinea pigs intravenously as passive sensitization fifteen minutes prior to antigen inhalation. Four to eight hours after antigen inhalation, we investigated bronchoconstriction. Eight hours after antigen challenge, bronchoalveolar lavage (BAL) were performed. In the BAL fluid, macrophages decreased and neutrophils increased significantly. These results suggest that LAR can occur without airway inflammation and the inflammation might be the result of antigen-antibody reaction at the airway wall, and that the direct initiator of late phase bronchoconstriction might be the recruitment of homocytotropic antibody from circulating blood to the airway wall.     

Bronchial responsiveness to methacholine during airway cooling in normal subjects

In order to investigate the effects of airway cooling on bronchial responsiveness in normal subjects, we measured bronchial responsiveness to inhaled methacholine with and without the inhalation of cold air. Two out of seven subjects showed an increase in baseline respiratory resistance (Rrs) during cooling of the airway but the other five subjects showed little change in their baseline Rrs. All subjects increased bronchial responsiveness to methacholine. Additionally, the threshold dose of methacholine decreased to one-third of the control dose with cooling of the airway. We speculate that airway cooling increased bronchial responsiveness to methacholine in normal subjects presumably due to increased vagal tone, increased alpha-adrenergic activity and/or a release of chemical mediators.     

Effects of an ATP-sensitive K+ channel activator, JTV-506, on antigen-induced early and late asthmatic responses in sensitized guinea pigs]

Effects of an ATP-sensitive K+ channel activator, JTV-506, on dual asthmatic responses and airway inflammation after antigen inhalation challenge were investigated in asthma model of guinea pigs. The animals were given an oral dose of 1 mg/kg of JTV-506 or vehicle (0.5% carboxymethyl cellulose sodium) 1 hour before and 3 hours after antigen inhalation challenge. Measurement of pulmonary resistance for 6 h was followed by bronchoalveolar lavage. After antigen challenge, all guinea pigs in the vehicle group displayed dual-phase airway obstruction and accumulation of eosinophils in the airways. After the treatment with JTV-506, the early asthmatic response was significantly inhibited, although the late asthmatic response or the recruitment of eosinophils into the airways were not inhibited. Therefore, we suggested that JTV-506 may inhibit airway smooth contraction induced by chemical mediators, but not function of CD4+ T lymphocytes.     

Allergen-induced late bronchoconstriction and airway hyperresponsiveness in guinea pigs

Allergen-induced bronchoconstrictive responses were examined in a guinea pig model actively sensitized by the inhalation of aerosolized ovalbumin (OA), which showed reproducible late bronchial responses (LBR). OA-challenge was performed under cover of mepyramine through the inhaled route in spontaneous breathing without anesthesia. The respiratory resistance (Rrs) was measured by the oscillation method for 96 h after OA challenge. All of the 22 guinea pigs displayed immediate bronchial responses (IBR), followed by 2 or 3 phase LBR that peaked at 6-8 h and 24 h after OA challenge. Examination of bronchoalveolar lavage fluid (BALF) revealed a significant increase in neutrophils at 1 h (p less than 0.01) and eosinophils at 7 h and 96 h (each p less than 0.01) after OA challenge. OA-challenge induced airway hyperresponsiveness to histamine (p less than 0.01) at 96 h that was associated with a significant increase in eosinophils (p less than 0.01) in BALF compared with lavages at 7 h. Intravenous administration of 1% OA induced a significant increase of leukotriene (LT)B4, C4, D4 in tracheal lavage fluids at IBR phase in each control (p less than 0.01). The increases of Rrs in LBR were inhibited almost completely by the pretreatment of KC-404, which is reported to have antagonistic action against LTC4/D4. These results suggest that allergen-induced late broncho-constrictions accompanied by airway hyperresponsiveness in guinea pigs are associated with the extensive infiltration into the airway lumen of inflammatory cells, and are concerned with the release of LTs. We also suggest that this LBR guinea pig model is useful in studying the mechanisms of the occurrence of LAR in humans, and in evaluating the action of anti-allergic drugs in LAR.     

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.