The role of smooth muscle in determining human non-specific bronchial responsiveness

[摘要] This project tested the hypothesis that variation in non specific bronchial responsiveness between individuals could be explained by differences in the sensitivity of the smooth muscle present in the airway. Non-specific bronchial responsiveness (NSBR) is closely associated with asthma and chronic airflow obstruction. The approach used was to measure the NSBR of patients due to undergo thoracic surgery, and compare this with the in vitro sensitivity of bronchial strips obtained from thoracotomy specimens. In vivo measurements: The first part of the project was devoted to developing methods and protocols to measure changes in airway calibre so that responsiveness could be measured. FEV1 is a reliable measure of airway calibre, but reflects overall airway function. As the in vitro measurements were made on larger airways, changes in specific airways conductance (sGAW) were used because they reflect changes in the larger airways. The measurement of sGaw by hand was time consuming and the measurement had large co-efficient of variation. To overcome these problems an automated system for the measurement of sGaw was developed.The second study looked at LTD4 induced bronchconstriction in asthmatic patients, and the effect of verapamil and sodium cromoglycate on this. The asthmatic subjects were more responsive to LTD4 by a factor of 10, but in contrast with the normal subjects verapamil did not inhibit LTD4 induced bronchoconstriction. Possible reasons for this difference are discussed. LTD4 was used as the agonist in the in vivo responsiveness and in vitro sensitivity protocol. There was no relationship between in vivo responsiveness and in vitro sensitivity. In this study the amount of smooth muscle present in the bronchial strips was measured. The quantity of smooth muscle present correlated significantly with the maximum tension produced in vitro but neither muscle quantity nor tension generated per unit mass of muscle was related to in vivo responsiveness. This result suggests that smooth muscle hypertrophy may contribute to NSBR. Using 3 bronchconstrictor agents no relation was found between in vivo NSBR and in vitro smooth muscle. Two asthmatic patients were responsive by in vivo criteria, but smooth muscle obtained from them did not have increased sensitivity. The final chapter of the thesis examines whether passive sensitisation of muscle, to render it atopic as in allergic asthma, alters in vitro sensitivity to histamine. Neither sensitisation per se, nor sensitisation followed by specific allergen challenge altered in vitro sensitivity of human airway smooth muscle. In conclusion, airway smooth muscle sensitivity is not the sole/ sole determinant of NSBR. Smooth muscle hypertrophy did not relate to in vivo responsiveness, although this result was obtained in patients with C. A. O. who may have different mechanisms for NSBR. Increased NSBR is due to a complex interaction between smooth muscle, neural and humoral factors.

[发布机构] University:University of Glasgow

[关键词] Medicine, Immunology, Physiology