Tamotsu Takishima

Protection against bradykinin-induced bronchoconstriction in asthmatic patients by neurokinin receptor antagonist

Axon reflex mechanisms may be involved in the pathogenesis of asthma, but there has been no direct evidence that endogenous tachykinins cause bronchoconstriction in asthmatic subjects. We have studied the effect of a tachykinin receptor antagonist (FK-224) on bronchoconstriction induced by inhalation of bradykinin in asthmatic patients. In a double-blind, placebo-controlled, crossover trial, ten subjects with stable asthma were given FK-224 (4 mg) or placebo by inhalation 20 min before challenge with bradykinin (0-1250 micrograms/ml, five breaths of each concentration) given with 5 min intervals. Bradykinin caused dose-dependent bronchoconstriction in all subjects. FK-224 significantly opposed the bronchoconstrictor effect; the geometric mean of the cumulative concentration required to elicit a 35% fall in specific airway conductance was 5.3 micrograms/ml after placebo and 40 micrograms/ml after FK-224 (p < 0.001). Inhalation of bradykinin caused coughing in three subjects, which was inhibited by FK-224 in all three. Antagonism of the tachykinin receptor by FK-224 greatly inhibited both bronchoconstriction and coughing induced by bradykinin in asthmatic patients, suggesting that tachykinin release from the airway sensory nerves is involved in responses to bradykinin. Tachykinin receptor antagonists may be useful in the treatment of asthma.

Surfactant apoprotein-A concentration in airway secretions for the detection of pulmonary oedema

Patients with cardiogenic pulmonary oedema expectorate foamy sputum containing surfactant, which might be expected to include surfactant apoprotein A (SP-A). SP-A is specific for lung surfactant. We have measured the SP-A concentration in airway secretions to determine whether it is useful in distinguishing pulmonary oedema from other disorders. Samples of sputum and of aspirated airway secretion were obtained from 11 patients with cardiogenic pulmonary oedema, seven patients with clinically stable congestive heart failure, five patients with adult respiratory distress syndrome (ARDS) and 20 control patients (10 intubated) with other respiratory diseases. The samples were used for the measurement of SP-A concentration by a two-site simultaneous immunoassay with monoclonal antibodies against SP-A. SP-A concentrations, measured in samples of sputum and aspirated secretions, depended on the diagnosis of the patients from which they had come. In descending order these samples came from patients with: cardiogenic pulmonary oedema (1324 +/- 197 micrograms.mL-1; n = 33); ARDS (311 +/- 47 micrograms.mL-1; n = 23); clinically stable congestive heart failure (78 +/- 10 micrograms.mL-1; n = 21); and control conditions (3.0 +/- 0.6 micrograms.mL-1; n = 30). Concentrations from disease samples did not overlap with controls. In samples from patients with cardiogenic pulmonary oedema, the SP-A concentration correlated with mean pulmonary capillary wedge pressure (PCWP) (p < 0.001; n = 39). These findings indicate that the measurement of the surfactant apoprotein A concentration in airway secretions may be useful for the detection of pulmonary oedema.

Possible mechanisms of airway hyperresponsiveness after late asthmatic response in guinea pigs.

To elucidate the mechanism of airway hyperresponsiveness after late asthmatic response (LAR), we analyzed bronchoalveolar lavage fluid (BALF) and examined the airway smooth muscle contractility to acetylcholine (ACh). On day 1 after LAR, there was a significant positive correlation between the number of neutrophils in BALF and the increase in airway responsiveness after LAR (r = 0.82, p < 0.01). In the in vitro study, the dose response curve to ACh was significantly shifted to the left after removal of the epithelium in control guinea pigs. However, in hyperresponsive animals after LAR, removal of the epithelium had no significant effect on ACh-induced response. These results indicate that infiltration of neutrophils and other inflammatory cells induce epithelial damage and hence the development of airway hyperresponsiveness after LAR.

Mechanisms of Bronchoconstriction after Allergen Ingestion in Sensitized Guinea Pigs

We examined whether oral administration of allergen induced bronchoconstriction in sensitized guinea pigs and investigated the mechanisms of bronchoconstriction. The animals had been immunized intraperitoneally with a mixture of Ascaris suum extract and silica gel, and exposed to ozone. They were then challenged with an oral dose of A. suum extract (6 mg/kg), and respiratory resistance (Rrs) was measured up to 7 h. After oral administration of the allergen, an increase in Rrs was observed. The mean values at 1, 3, 5 and 7 h after oral allergen challenge were 150 +/- 21, 149 +/- 11, 151 +/- 12 and 134 +/- 10% of the baseline value, respectively. When saline instead of the allergen was orally administered, almost no significant increase in Rrs was observed up to 7 h. Moreover, in nonsensitized guinea pigs, oral administration of allergen produced no significant increase in Rrs for up to 7 h. When atropine was administered as an aerosol, the increase in Rrs induced by an oral allergen challenge was attenuated. Three of the five atropine-treated guinea pigs showed temporary increases in Rrs immediately after the oral allergen challenge. The mean values of Rrs in the atropine-treated animals challenged with oral allergen at 1, 3, 5 and 7 h were 106 +/- 3, 106 +/- 5, 115 +/- 5 and 102 +/- 4% of baseline value, respectively. In the animals which received oral allergen, the number of neutrophils in bronchoalveolar lavage fluid (BALF) significantly increased 2.0-fold (p < 0.05), while no significant increase in the number of eosinophils, macrophages, or lymphocytes in BALF was observed.(ABSTRACT TRUNCATED AT 250 WORDS)