Exposure of guinea pigs to an aerosol of human recombinant interleukin-2 (IL-2; 30 micrograms) resulted in an increase in the numbers of eosinophils and macrophages recovered from bronchoalveolar lavage fluid (BALF) 24 h later. This was accompanied by a bronchial hyperresponsiveness to intravenous acetylcholine. In guinea pigs sensitized to ovalbumin, exposure to IL-2 caused an increase in the number of macrophages, but not eosinophils in BALF and bronchial hyperresponsiveness to acetylcholine did not develop. In guinea pig skin, intradermal injection of IL-2 (10(-14) to 10(-9) mol/site) had no effect on 111In-eosinophil accumulation, measured over 3 h, suggesting that IL-2 does not act directly to recruit eosinophils. The hypothesis that IL-2 may be acting via release of interleukin-5 (IL-5) was tested using an antibody to IL-5 (TRFK-5; 1 mg/kg). Treatment with TRFK-5 1 h before exposure to IL-2 aerosol had no effect on the numbers of macrophages or eosinophils recovered from BALF 24 h later, although there was a tendency for reduced bronchial hyperresponsiveness to acetylcholine. These results suggest that (1) IL-2 is not a directly acting chemoattractant for eosinophils in the guinea pig, (2) the action of IL-2 to increase bronchial hyperresponsiveness is also indirect, partly via generation of IL-5, and (3) immunological sensitization alters the response of both eosinophils and bronchial smooth muscle to IL-2.

Vasoactive intestinal peptide (VIP, 10 nM) inhibited the release of cyclo-oxygenase products, detected by both bioassay and radioimmunoassay, induced by leukotriene (LT) D4 (3–30 pmol) and bradykinin (BK, 3–30 nmol) from guinea-pig isolated perfused lung. Helodermin (10 nM), a peptide that is structurally related to VIP, and salbutamol (10 nM), a β2-adrenoceptor agonist, evoked a similar inhibitory effect on LTD4-induced release of cyclo-oxygenase products. The generation of TxB2 and 6-keto-PGF1α following stimulation with exogenously administered arachidonic acid (30–300 nmol) was not significantly attenuated in the presence of either VIP, helodermin or salbutamol. These results show that VIP, helodermin and salbutamol are potent inhibitors of the release of cyclo-oxygenase products induced by agonists known to activate endogenous arachidonic acid metabolism in guinea-pig lung. Since the metabolism of exogenously administered arachidonic acid was not inhibited these results suggest that the inhibitory effect may be exerted on events preceding the mobilisation of arachidonic acid and may involve cyclic AMP.

The coronary vascular endothelium of the guinea-pig isolated perfused heart was removed by treatment with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS), a zwitterionic detergent. After CHAPS treatment of the heart the vasoconstrictor responses of leukotriene (LT) C4, LTD4 and angiotensin II (AII) were significantly attenuated whereas the vascular actions of U46619, a thromboxane (Tx) A2 mimetic, and endothelin-1 (ET-1) were unaltered. The endothelium-dependent vasoconstrictor response of LTC4 and LTD4 could not be attributed to the release of TxA2, platelet-activating factor or AII since indomethacin, WEB 2086 and captopril had no effect on LT actions. However, in the presence of cromakalim, a potassium channel activator, the vasoconstrictor effects induced by LTC4, LTD4 and AII were significantly attenuated to a greater extent than the responses of U46619 and ET-1. The results suggest that in the coronary vasculature of the guinea-pig isolated heart the vasoconstrictor responses of LTC4, LTD4 and AII are endothelium-dependent and may involve a cromakalim-sensitive mechanism.

Annals of the New York Academy of SciencesVolume 629, Issue 1 p. 451-454 Bradykinin-Induced Responses of Human Bronchial Tissues Modulation by Epithelial Removal and Indomethacin ANDREW M. BRAMLEY, ANDREW M. BRAMLEY Department of Pharmacology Hunterian Institute Royal College of Surgeons 35-43 Lincoln's Inn Fields London WC2 A3PN, England St. Paul's Hospital, University of British Columbia Pulmonary Research Laboratory, McDonald Research Wing, Room 100, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada.Search for more papers by this authorPRISCILLA J. PIPER, PRISCILLA J. PIPER Department of Pharmacology Hunterian Institute Royal College of Surgeons 35-43 Lincoln's Inn Fields London WC2 A3PN, EnglandSearch for more papers by this author ANDREW M. BRAMLEY, ANDREW M. BRAMLEY Department of Pharmacology Hunterian Institute Royal College of Surgeons 35-43 Lincoln's Inn Fields London WC2 A3PN, England St. Paul's Hospital, University of British Columbia Pulmonary Research Laboratory, McDonald Research Wing, Room 100, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada.Search for more papers by this authorPRISCILLA J. PIPER, PRISCILLA J. PIPER Department of Pharmacology Hunterian Institute Royal College of Surgeons 35-43 Lincoln's Inn Fields London WC2 A3PN, EnglandSearch for more papers by this author First published: July 1991 https://doi.org/10.1111/j.1749-6632.1991.tb38016.xCitations: 1 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume629, Issue1Advances in the Understanding andTreatment of AsthmaJuly 1991Pages 451-454 RelatedInformation

Annals of the New York Academy of SciencesVolume 629, Issue 1 p. 425-427 Does the Metabolism of Oxygen by Airway Epithelium Contribute towards the Modulation of Smooth Muscle Responses In Vitro? LIONEL K. GUNN, LIONEL K. GUNN Department of Pharmacology Royal College of Surgeons 35-43 Lincoln's Inn Fields London WC2A 3PN, EnglandSearch for more papers by this authorPRISCILLA J. PIPER, PRISCILLA J. PIPER Department of Pharmacology Royal College of Surgeons 35-43 Lincoln's Inn Fields London WC2A 3PN, EnglandSearch for more papers by this author LIONEL K. GUNN, LIONEL K. GUNN Department of Pharmacology Royal College of Surgeons 35-43 Lincoln's Inn Fields London WC2A 3PN, EnglandSearch for more papers by this authorPRISCILLA J. PIPER, PRISCILLA J. PIPER Department of Pharmacology Royal College of Surgeons 35-43 Lincoln's Inn Fields London WC2A 3PN, EnglandSearch for more papers by this author First published: July 1991 https://doi.org/10.1111/j.1749-6632.1991.tb38005.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume629, Issue1Advances in the Understanding andTreatment of AsthmaJuly 1991Pages 425-427 RelatedInformation

The apparent release of relaxant activity from airway epithelium (epithelium-derived relaxing factor, EpDRF) has been examined in a co-axial bioassay system. The endothelium-denuded rat aorta, placed inside either the epithelium-intact guinea-pig trachea or rabbit bronchus relaxed in response to acetylcholinc. In a modification of the standard preparation, the airway was slit longitudinally and immobilised inside a silicone rubber tube. Under these conditions, the acetylcholine-induced relaxation was abolished. Under the conditions of the co-axial bioassay, the oxygen tension in the lumen of either airway tube was lower than that of the bathing fluid. Upon addition of acetylcholine at concentrations which caused relaxation in the co-axial bioassay. the oxygen tension inside the epithelium-intact, but not the epithelium-denuded guinea-pig trachea was depressed to levels which would have affected the contractile reponse of a rat aorta. We suggest that the assay of relaxant activity from airways using co-axial preparations may be complicated by changes in volume and oxygen tension in the lumen of the donor airway and discuss how such problems might be avoided.

Platelet-activating factor (PAF, 10-1000 pmol) induced dose-dependent relaxations of the basal tone of superfused strips of epithelium-intact guinea-pig trachea. Indomethacin (1.4 microM) completely inhibited and WEB 2086 (1 and 10 nM) effectively antagonised these relaxations. Following epithelial removal PAF evoked a single contraction. These results show that the PAF-induced relaxations of guinea-pig trachea are dependent on an intact epithelial layer and are mediated by a cyclo-oxygenase product.

1 Leukotrienes (LTs) arepotent pro-inflammatory mediators withactions relevant to thepathophysiology ofcystic fibrosis (CF), including increased mucusproduction, bronchoconstriction, leucocyte chemotaxis, andincreased vascular permeability. We have therefore investigated thepotential role ofLTsinchildren withCF.Leukotriene E4levels wereassessed intheurine of30normal (N)children (aged 1.3-12.7 years) and30CF children (1.6-14.3 years). Sputum from13 of theCFchildren wasanalysed fromLTB4, LTC4,LTD4,andLTE4.LTswereseparated byreversed-phase h.p.l.c. andquantitated byradioimmunoassay. 2 Urinary LTE4levels werelognormally distributed, withgeometric meanvalues (95% confidence intervals) ofN:88.4 (71.3-111) pmolmmol-1 creatinine (n=30), andCF:112 (70.6-177) pmolmmol-1 creatinine (n= 30;P > 0.05). OftheCFsubjects, 33%had urinary LTE4levels above200pmolmmol-1 creatinine, compared with3.3%oftheN children. 3 Insputum, mean(±s.e. mean) LTconcentrations were(pmol g-1), LTB4:44.3± 10.8, LTC4:4.9± 1.3, LTD4:1.8±0.9, andLTE4:67.7 ± 18.9 (n= 13). 4 Urinary LTE4levels correlated significantly withsputum LTE4levels (r= 0.673, P= 0.012), andwithsputum levels oftotal cysteinyl-LTs (r= 0.660, P = 0.014). 5 Inconclusion, total cysteinyl-LT content insputum is10-fold higher thanpreviously reported, consisting primarily (91%)ofLTE4.Thehighlevels ofLTE4andLTB4in sputum suggest involvement ofLTsinthepathophysiology ofCF.Urinary LTE4levels mayproveuseful asamarker forcysteinyl-LT production insputum.

Conference Article| August 01 1988 Leukotrienes in the cardiovascular system PRISCILLA J. PIPER; PRISCILLA J. PIPER 1Department of Pharmacology, Royal College of Surgeons, Lincoln's Inn Fields, London WC2A 3PN, U.K. Search for other works by this author on: This Site PubMed Google Scholar A. W. B. STANTON; A. W. B. STANTON 1Department of Pharmacology, Royal College of Surgeons, Lincoln's Inn Fields, London WC2A 3PN, U.K. Search for other works by this author on: This Site PubMed Google Scholar H. B. YAACOB; H. B. YAACOB 1Department of Pharmacology, Royal College of Surgeons, Lincoln's Inn Fields, London WC2A 3PN, U.K. Search for other works by this author on: This Site PubMed Google Scholar J. ANTONIW J. ANTONIW 1Department of Pharmacology, Royal College of Surgeons, Lincoln's Inn Fields, London WC2A 3PN, U.K. Search for other works by this author on: This Site PubMed Google Scholar Author and article information Publisher: Portland Press Ltd Received: January 27 1988 Online ISSN: 1470-8752 Print ISSN: 0300-5127 © 1988 Biochemical Society1988 Biochem Soc Trans (1988) 16 (4): 482–483. https://doi.org/10.1042/bst0160482 Article history Received: January 27 1988 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation PRISCILLA J. PIPER, A. W. B. STANTON, H. B. YAACOB, J. ANTONIW; Leukotrienes in the cardiovascular system. Biochem Soc Trans 1 August 1988; 16 (4): 482–483. doi: https://doi.org/10.1042/bst0160482 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: LT, leukotriene, PAF, platelet-activating factor This content is only available as a PDF. © 1988 Biochemical Society1988 Article PDF first page preview Close Modal You do not currently have access to this content.

The formation of leukotrienes (LTs) from arachidonic acid derived from phospholipids of the cell membrane is initially catalysed by 5-lipoxygenasel. Metabolism of the unstable epoxide LTA4 leads to the formation of LTB4 and the cysteinyl-containing LTs C4, D4 and E4. All these LTs have potent, although different, biological activities. LTB4 is a powerful chemotactic agent for leukocytes whereas LTs C4, D4 and E4 have potent smooth muscle stimulating actions and account for the biological activity of the allergic mediator previously known as slow-reacting substance of anaphylaxis (SRS-A)2. Leukotriene B4 has pro-inflammatory actions but little smooth muscle stimulating activity of its own whereas cysteinyl-containing LTs have potent actions in the cardiovascular system and in the airways in vitro and in vivo (see3,4).

Ovalbumen (100μg)‐induced coronary vasoconstriction and decrease in cardiac developed tension were studied in isolated perfused hearts from sensitized guinea‐pigs. Leukotriene‐like material released in the cardiac effluent was assayed against synthetic leukotriene C 4 (LTC 4 ). LTC 4 was released in a time‐dependent fashion, and release was enhanced when hearts were challenged in the presence of indomethacin (2.8 μ m ). The release was maximal at 2–3 min and detectable for as long as 10 min following ovalbumen challenge. Immunoreactive (ir) thromboxane‐B 2 (TxB 2 ) was also detected in cardiac effluent which had been partially purified using C 18 Sep‐Paks. CGS 8515 (0.03–1.0 μ m ), an inhibitor of 5‐lipoxygenase, dose‐dependently inhibited ovalbumen‐induced coronary vasoconstriction and leukotriene‐C 4 release. CGS 8515 inhibited ovalbumen‐induced decreases in cardiac developed tension at 0.3 and 1.0 μ m , but did not antagonize coronary vasoconstriction induced by synthetic LTC 4 . The release of cyclo‐oxygenase products following ovalbumen challenge was not inhibited by CGS 8515, but was markedly inhibited by indomethacin (2.8 μ m ) pretreatment. We conclude that leukotrienes have a major role in guinea‐pig cardiac anaphylaxis, and that CGS 8515 has a cardio‐protective action. The results obtained in these experiments in vitro show that CGS 8515 is a potent and selective 5‐lipoxygenase inhibitor.

1 Theinvolvement ofprostacyclin (PGI2) inthevasodilator responsestoacetylcholine (ACh), A23187 andbradykinin (Bk) hasbeeninvestigated inguinea-pig, isolated, Krebs-perfused hearts. 2 ACh(0.01-lOnmol), A23187 (0.1-1.Onmol) andBk(0.3-lOpmol) eachelicited dose-related and shortlasting (-2min)reductions inperfusion pressure.Larger maximal responseswereobtained in preparations with coronaryvascular toneelevated byplatelet-activat ing

Annals of the New York Academy of SciencesVolume 524, Issue 1 p. 133-141 Release of Leukotrienes from Porcine and Human Blood Vessels by Immunological and Nonimmunological Stimulia PRISCILLA J. PIPER, PRISCILLA J. PIPER Department of Pharmacology Royal College of Surgeons London, WC2A 3PN United KingdomSearch for more papers by this authorJ. W. ANTONIW, J. W. ANTONIW Department of Pharmacology Royal College of Surgeons London, WC2A 3PN United KingdomSearch for more papers by this authorA. W. B. STANTON, A. W. B. STANTON Department of Pharmacology Royal College of Surgeons London, WC2A 3PN United KingdomSearch for more papers by this author PRISCILLA J. PIPER, PRISCILLA J. PIPER Department of Pharmacology Royal College of Surgeons London, WC2A 3PN United KingdomSearch for more papers by this authorJ. W. ANTONIW, J. W. ANTONIW Department of Pharmacology Royal College of Surgeons London, WC2A 3PN United KingdomSearch for more papers by this authorA. W. B. STANTON, A. W. B. STANTON Department of Pharmacology Royal College of Surgeons London, WC2A 3PN United KingdomSearch for more papers by this author First published: April 1988 https://doi.org/10.1111/j.1749-6632.1988.tb38536.xCitations: 7 a This work was supported financially by Grant No. 84/54 from the British Heart Foundation. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume524, Issue1Biology of the LeukotrienesApril 1988Pages 133-141 RelatedInformation