title: Role of neutral endopeptidase in bronchial hyperresponsiveness to bradykinin induced by IL-1 beta.
abstract: Interleukin-1 beta (IL-1 beta) induces bronchial hyperresponsiveness (BHR) to bradykinin but not to acetylcholine. We examined whether this was mediated through the inhibition of neutral endopeptidase (NEP) activity and/or through the enhancement of airway microvascular leakage (AML) by IL-1 beta. We administered human recombinant IL-1 beta (500 U) or saline intratracheally and 24 h later measured the airway responses to bradykinin (1 mM; 45 breaths). IL-1 beta-treated rats showed a decrease of 18.5 and 21.1% of NEP activity in the lungs and tracheobronchial tree, respectively (P < 0.05), associated with an augmented response in total lung resistance to bradykinin but with no increase in Evans blue dye extravasation used as a marker of AML. Phosphoramidon (0.1 and 1 mM; 90 breaths), an NEP inhibitor, induced a dose-dependent increase in lung resistance to bradykinin without further enhancing BHR induced by IL-1 beta. Bradykinin-induced AML was not enhanced by phosphoramidon in either saline- or IL-1 beta-treated rats. Similarly, after captopril (1 mM; 90 breaths), an inhibitor of angiotensin-converting enzyme, there was no further enhancement of BHR to bradykinin induced by IL-1 beta. BHR to bradykinin induced by IL-1 beta may result from an inhibition of peptidase activity, such as NEP and angiotensin-converting enzyme, and is not associated with an enhancement of AML.
authors.affiliation: Department of Thoracic Medicine, National Heart and Lung Institute, Royal Brompton Hospital, London, United Kingdom.
authors.forename: H
authors.initials: H
authors.lastname: Tsukagoshi
authors.forename: J
authors.initials: J
authors.lastname: Sun
authors.forename: O
authors.initials: O
authors.lastname: Kwon
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: K F
authors.initials: KF
authors.lastname: Chung
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002216:Captopril / Q000494:pharmacology; D004357:Drug Synergism; D006020:Glycopeptides / Q000494:pharmacology; D007375:Interleukin-1; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000473:pathology
chemical_list: D006020:Glycopeptides; D007375:Interleukin-1; D011994:Recombinant Proteins; D002216:Captopril; D015260:Neprilysin; D001920:Bradykinin; C008890:phosphoramidon