Asthma is a chronic inflammatory disease of the airways and viral infections account for the majority of exacerbations and may play a role in its pathogenesis. Bradykinin levels are increased in the lungs of asthmatics and inhaled bradykinin produces bronchoconstriction in asthmatic but not in normal patients. In this study, guinea-pigs were inoculated with parainfluenza and influenza virus to establish airways inflammation and hyperreactivity. The role of bradykinin in the parainfluenza model was examined by using the tissue kallikrein inhibitor, FE999024, and the bradykinin B2 receptor antagonist, MEN16132. Firstly, the effects of bradykinin inhalation in conscious guinea-pigs were characterized by using inhibitors of its breakdown and selective antagonists. Inhaled bradykinin produced a bronchoconstriction only after treatment with the inhibitors of angiotensin converting enzyme and/or neutral endopeptidase, captopril and phosphoramidon respectively. Inhaled bradykinin also increased inflammatory cell influx to the lungs when its breakdown was inhibited with both drugs. Cell influx and bronchoconstriction were blocked by the B2 receptor antagonists icatibant and MEN16132. These responses were therefore B2 receptor-mediated. In ovalbumin sensitized guinea-pigs, inhaled ovalbumin produced early and late asthmatic responses, inflammatory cell influx and airway hyperreactivity to histamine. These were inhibited by dexamethasone. Bradykinin caused bronchoconstriction without using metabolism inhibitors, indicating airways hyperreactivity to bradykinin. Parainfluenza-3 and influenza caused inflammatory cell influx and airways hyperreactivity to histamine. These were inhibited by FE999024, MEN16132 and dexamethasone. Parainfluenza-3 virus inoculated into sensitized guinea-pigs exacerbated the response to inhaled ovalbumin, with a prolonged bronchconstriction replacing early and late phases. This was resistant to dexamethasone. This study supports a role for bradykinin in virus-induced lung inflammation and the use of inhibitors of bradykinin for potential treatment of airway inflammation.
|Source Sets||Ethos UK|
|Type||Electronic Thesis or Dissertation|
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