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Pulmonary and Vascular Effects of Leukotrienes: Involement in Asthma and Inflation

  • Chapter
Drugs Affecting Leukotrienes and Other Eicosanoid Pathways

Part of the book series: NATO ASI Series ((NSSA,volume 95))

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Abstract

The prostaglandins, thromboxanes and leukotrienes comprise a complex system of bioregulators, synthesized on demand in almost every tissue, and demonstrating a broad range of activities. They all derive from some closely related polyunsaturated fatty acids, particularly arachidonic acid, which may be oxidized and further transformed in reactions initiated either by a fatty acid cyclooxygenase or, alternatively by a number of lipoxygenases. Prostaglandins, prostacyclin (PGI2) and thromboxane A2 (TXA2) are formed via the cyclooxygenase pathway, whereas leukotrienes, lipoxins, and related monohydroxy acids are generated by specific lypoxygenases. Most of the products thus formed either contract of relax vascular and nonvascular smooth muscle, and several of them have been implicated a mediator role in various inflammatory and hypersensitivity reactions. The antiflogistic effect of aspirin and related non-steroidal antiinflammatory drug (NSAID:s). is well established, and apparently correlates with the capacity to inhibit the formation of cyclooxygenase products, notably PGE2, PGD2, and PGI2. Although these three substances are considered proinflammatory and potently enhance the response to other stimuli, they do not themselves elicit significant edema, and their pain producing capacity is at best moderate (cf. Kuehl and Egan, 1980; Goetzl, 1981). The same prostaglandins seem to have no effect per se on activation or migration of leukocytes, although they have been reported to enhance chemokinesis (Goetzl et al., 1979) and to inhibit the release of lysosomal enzymes induced by other stimuli (Weissman et al., 1980). In the pulmonary system, PGD2, PGF2a, and TXA2 are potent broncho-constrictors, and most asthmatic patients are remarkable hyperreactive to inhalation of PGF9 (Mathé et al., 1973; Pasarglikian et al., 1977). Moreover, ast~iatic patients provoked by inhalation of specific allergen demonstrate increased plasma levels of 15-keto-13,14-dehydro-PGF2a, major metabolite of PGF2401, and PGD2, in correlation with the severety of the asthmatic attack (Green et al., 1974). However, cyclooxygenase inhibitors do not significantly alleviate the symptoms of asthma, and sometimes they even pre-cipitate a life-threat4n•ing reaction, the so called aspirin asthma.

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References

  • Bach, M.K., Brashler, J.R., Smith, H.W., Fitzpatrick, F.A., Su 6F$F., and McGuire, J.C., 1982, 6,9-deepoxy-6,9-(phenylimino)- -prostaglandin Il, (U-60,257), a new inhibitor of leukotriene C and D synthesis: in vitro studies. Prostaglandins, 23:759771.

    Google Scholar 

  • Barnes, N.C., Piper, P.J., and Costello, J.F., 1984, Comparative effects of inhaled leukotriene C4, leukotriene D4, and histamine in normal human subjects. Thorax, 39: 500–504.

    Article  PubMed  CAS  Google Scholar 

  • Bernström, K., and Hammarström, S., 1982, A novel leukotriene formed by transpeptidation of leukotriene E. Biochem.Biophys. Res.Commun., 109: 800–804.

    Google Scholar 

  • Björk, J., Hedqvist, P., and Arfors, K.-E., 1982a, Increase in vascular permeability induced by leukotriene B4 and the role of polymorphonuclear leukocytes. Inflammation, 6: 189–200.

    Article  PubMed  Google Scholar 

  • Björk, J., Arfors, K.-E., Hedqvist, P., Dahlèn, S.-E., and Lindgren, J.A., 1982b, Leukotriene B4 causes leukocyte migration in vivo. Microcirculation, 2: 271–281.

    Google Scholar 

  • Björk, J., Dahlèn, S.-E., Hedqvist, P., and Arfors, K.-E., 1983, Leukotrienes B4 and C4 have distinct microcirculatory actions in vivo, in: “Advances in Prostaglandin, Thromboxane and Leuko-triene Research”, B. Samuelsson, R. Paoletti and P. Ramwell, eds, Vol. 12, Ch. 81, pp. 1–6, Raven Press, New York.

    Google Scholar 

  • Bray, M.A., Cunningham, F.M., Ford-Hutchinson, A.W., and Smith,M.J. H., 1981, Leukotriene 84: a medator of vascular permeability. Br. J.Pharmacol., 72: 483–486.

    Google Scholar 

  • Brocklehurst, W.E., 1960, The release of histamine and formation of a slow-reacting substance ( SRS-A) during anaphylactic shock. J Physiol (Lond) 151: 416–435.

    Google Scholar 

  • Claesson, H.-E., 1982, Leukotreiens A4 and B4 stimulate the formation of cyclic AMP in human leukocytes. FEBS Lett., 139: 305–308.

    Article  PubMed  CAS  Google Scholar 

  • Dahlèn, S.-E., 1983, The significance of liberated cyclooxygenase products for the pulmonary and cardiovascular actions of leukotriene C in the guinea pig depends upon the route of administra-tion. Acta Physiol Scand, 118: 415–421.

    Article  PubMed  Google Scholar 

  • Dahlèn,S.-E., Hedqvist, P., Hammarström, S., and Samuelsson, B., 1980, Leukotrienes are potent constrictors of human bronchi. Nature, 288: 484–486.

    Article  Google Scholar 

  • Dahlèn,S.-E., Björk, J., Hedqvist, P., Arfors, K.-E., Hammarström, S., Lindgren, J.A., and Samuelsson, B., 1981, Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: In vivo effects with relevance to the acute inflammatory response. Proc.Natl.Acad.Sci.USA, 78: 3887–3891.

    Google Scholar 

  • Dahlèn, S.-E., Hansson, G., Hedqvist, P., Björck, T., Granström,E., and Dahlèn, B., 1983a, Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C4, D4 and E4. Proc.Natl.Acad. Sci.USA, 80: 1712–1716.

    Google Scholar 

  • Dahlèn,S.-E., Hedqvist, P., and Hammarström, S., 1983b, Contractile activities of several cysteine-containing leukotrienes in the guinea pig lung strip. Eur J Pharmacol, 86: 207–215.

    Google Scholar 

  • Dahlèn,S.-E., Hedqvist, P., Westlund, P., Granström, E., Hammar-ström, S., Lindgren, J.A., and RAdmark, 0., 1983c, Mechanisms for leukotriene-induced contractions of guinea pig airways:Leukotriene C4 has a potent direct action whereas leukotriene B4 acts indirectly. Acta Physiol Scand, 118: 393–403.

    Article  Google Scholar 

  • Dahlèn,S.-E., Serhan, C.N., and Samuelsson, B., 1984, Spasmogenic activity of lipoxin A in isolated guinea pig tissues. FEBS Lett, In press.

    Google Scholar 

  • Drazen, 3.M., and Austen, K.F., 1974, Effects of intravenous administration of slow-reacting substance of anaphylaxis, histamine, bradikinin, and prostaglandin F on pulmonary mechanics in the guinea pig. J.Clin.Invest, 53: 1679–1685.

    Article  Google Scholar 

  • Drazen, J.M., Austeen,K.F., Lewis,R.A., Clark,D.A., Goto,G., Marfat, A., and Corey, E.J., 1980, Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro. Proc.Natl.Acad.Sci.USA, 77: 4354–4358.

    CAS  Google Scholar 

  • Folco,G.C., Omini, C., Viganò,T., Brunelli, G., Rossoni, G., and Berti, F., 1982, Biological activity of leukotriene C4 in guinea pigs: in vitro and in vivo studies, in:“Leukotrienes and Other Lipoxygenase Products”, B. Samuelsson and R.Paoletti, eds, pp. 153–167, Raven Press, New York.

    Google Scholar 

  • Ford-Hutchinson, A.W., Bray, M.A., Doig, M.V., Shipley,M.E., and Smith, M.J.H., 1980, Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature, 286: 264–265.

    CAS  Google Scholar 

  • Gleich, G.J., 1982, The late phase of the immunoglobin E-mediated reaction: a link between anaphylaxis and common allergic disease. Clin. Immun., 70: 160–169.

    Google Scholar 

  • Goetzl, E.J., 1981, Oxygenation products of arachidonic acid as mediators of hypersensitivity and inflammation. Med.Clin. North Am., 65: 809–828.

    Google Scholar 

  • Goetzl, E.J., and Pickett, W.C., 1980, The human PMN leukocyte chemotactic activity of complex hydroxy-eicosatetraenoic acids (HETEs). J. Immunol., 125: 1789–1791.

    Google Scholar 

  • Goetzl, E.J., Weller, P.F., and Valone, F.H., 1979, Biochemical and functional bases of the regulatory and protective roles of the human eosinophil, in:“ Advances in Inflammation Research”, G. Weissman, B. Sâmuelsson and R. Paoletti, eds, Vol. 14, pp. 157–167, Raven Press, New York.

    Google Scholar 

  • Greén, K., Hedqvist, P., and Svanborg, N., 1974, Increased plasma levels of 15-keto-13,14-dihydro-prostaglandin F9 after allergen-provoked asthma in man. Lancet, II:141~-1421.

    Google Scholar 

  • Griffin, M., Weiss, J., Leitch,A.G., McFadden, E.R., Corey, E.J., Austen, K.F., and Drazen, J.M., 1983, Effects of leukotriene D on the airways in asthma. N.Engl.J.Med., 308: 436–439.

    CAS  Google Scholar 

  • Hamberg, M., Hedqvist, P., and Rädegren, K., 1980, Identification of 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) as the major metabolite of arachidonic acid in human lung. Acta Physiol Scand, 110: 219–221.

    Article  PubMed  CAS  Google Scholar 

  • Hamel, R., Masson, P., Ford-Hutchinson, A.W., Jones, T.R., Brunet,G., and Piechuta, H., 1982, Differing mechanisms for leukotriene D4-induced bronchoconstriction in guinea pigs following intravenous and aerosol administration. Prostaglandins, 24: 419–432.

    CAS  Google Scholar 

  • Hansson, G., Lindgren, J.A., Dahlèn,S.-E., Hedqvist, P., and Samuels-son, B., 1981, Identification and biological activity of novel 6,)-oxidized metabolites of leukotriene B4 from human leukocytes. FEBS Lett., 130: 107–112.

    Article  PubMed  CAS  Google Scholar 

  • Hedqvist, P., Dahlèn,S.-E., Gustafsson, L., Hammarström, S., and Samuelsson, B., 1980, Biolgical profile of leukotrienes C4 and Dg. Acta Physiol Scand, 110: 331–333.

    CAS  Google Scholar 

  • Hedqvist, P., Dahlèn, S.-E., and Palmertz, U., 1984, Leukotrienedependent airway anaphylaxis in guinea pigs. Prostaglandins, in press.

    Google Scholar 

  • Hua, X.-Y., Dahlèn,S.-E., Hamnarström, S., _arid Hedqvist, P., 1984, Leukotrienes C4, D4 and EA cause extensive plasma extravasation in the guinea pig. Naunyn-Schmiedebergs Arch Pharmacol., in press.

    Google Scholar 

  • Johnson, H.G., Chinn, R.A., McNee, M.L., Miller, M.D., and Nadel,J. A., 1982, Studies in the in vivo canine trachea: pharmacological blockage of leukotriene enhanced mucus secretion. Int. J. Immunopharm. 4: 348 (A52).

    Google Scholar 

  • Jones, T.R., Davis, C., and Daniel, E.E., 1982, Pharmacological study of the contractile activity of leukotriene C4 and D on isolated human airway smooth muscle. Can.J.Physiol.Phdrmacol., 60: 638–643.

    Article  CAS  Google Scholar 

  • Jubiz, W., Râdmark, 0., Lindgren, J.A., Malmsten, C., and Samuels-son, B., 1981, Novel leukotrienes: products formed by initial oxygenation at C-15. Biochem.Biophys.Res.Commun., 99: 976–986.

    CAS  Google Scholar 

  • Kaijser, L., Dahlèn,S.-E., Hansson, G., Kumlin,M., Hedqvist, P., and Samuelsson, B., 1984, Cardiovascular effects of leukotriene C4 in man. Prostaglandins, in press.

    Google Scholar 

  • Kellaway, C.H., and Trethewie,E.R., 1940, The libration of a slow reacting smooth muscle-stimulating substance in anaphylaxis. Quart.J.Exp.Physiol., 30: 121–145.

    CAS  Google Scholar 

  • Kuehl, F.A., and.Egan,R.,1980, Prostaglandins, arachidonic acid, and inflammation. Science, 210: 978–984.

    Google Scholar 

  • Letts, L.G., and Piper, P.J., 1982, The actions of leukotrienes C4 and D4 on guinea pig isolated hearts. Br.J.Pharmacol. 76: 169–176.

    PubMed  CAS  Google Scholar 

  • Lewis, R.A., Austen, K.F., Drazen, J.M., Clark, D.A., Marfat, A., and Corey, E.J., 1980, Slow reacting substances of anaphylaxis: Identification of leukotrienes C-1 and D from human and rat sources. Proc.Natl.Acad.Sci.USA, 77: 3710–3714.

    Article  PubMed  CAS  Google Scholar 

  • Lewis, R.A., Austen, K.F., Drazen, J.M., Soter, N.A., Figueiredo, J.C., and Corey, E.J., 1982, Structure, function and meta-bolites of leukotriene constituents of SRS-A, in:“Leukotrienes and Other Lipoxygenase Products, SamueTsson,B. and Paoletti, R., eds, pp. 137–151, Raven Press, New York.

    Google Scholar 

  • Lindbom, L., Hedqvist, P., Dahlèn,S.-E., Lindgren, J-A., and Arfors, K.-E., 1982, Leukotriene B4 induces extravasation and migration of polymorphonuclear leukocytes in vivo. Acta Physiol Scand, 116: 105–108.

    CAS  Google Scholar 

  • MacGlashan, D.W., Schleimer, R.P., Peters, S.P., Schulman, E.D., Adams, G.A., Newball, H.N., Lichtenstein, L.M., 1982, Generation of leukotrienes by purified human lung mast cells. J.Clin.Invest., 70: 747–751.

    Article  PubMed  CAS  Google Scholar 

  • Maas, R.L., Brash, A.R., and Oates, J.A., 1981, A second pathway of leukotriene biosynthesis in porcine leukocytes. Proc. Natl.Acad.Sci.USA, 78: 5523–5527.

    Google Scholar 

  • Malmsten, C.L., Palmblad, J., Udén, A.-M., Radmark, 0., Engstedt,L., and Samuelsson, B., 1980, Leukotriene 84: A highly potent and stereospecific factor stimulating migration of polymorphonuclar leukocytes.Acta Physiol Scand, 110: 449–451.

    CAS  Google Scholar 

  • Marom, Z., Shelhamer, J.H., Bach, M.K.,Morton,D.R., and Kaliner,M., 1982, Slow reacting substances, leukotrienes C4 and DA, in-crease the release of mucus from human airways in vitro. Am. Rev.Resp.Dis., 126: 449–451.

    Google Scholar 

  • Mathé, A.A., Hedqvist, P., Holmgren, A., and Svanborg, N., 1973, Bronchial hyperreactivity to prostaglandin F2 and histamine in patients with asthma. Brit.Med.J., 1: 193–196.

    Article  PubMed  Google Scholar 

  • Morganroth,M.L., Reeves, J.T., Murphy, R.C., and Voelkel, N.F., 1984, Leukotriene synthesis and receptor blockers block hypoxic pulmonary vasoconstriction. J. Appl. Physiol., 56: 1340–1346.

    Google Scholar 

  • Palmer,R.M.J., Stephney,R.J., Higgs,.A., and Eakins, K.-E., 1980, Chemokinetic activity of arachidonic acid lipoxygenase products on leukocytes of different species. Prostaglandins, 20: 411–418.

    Article  Google Scholar 

  • Pasarglikian, M., Bianco, S., Allegra, L., Moavaro, N.E., Petrigrini, G., Robuschi, A., and Grugni, A., 1977, Aspects of bronchial reactivity to prostaglandins and aspirin in asthmatic patients. Respiration, 34: 79–91.

    Article  Google Scholar 

  • Peatfield, A.C., Piper,P.J., and Richardson, P.S., 1982, The effect of leukotriene C on mucin release into the cat trachea in vivo and in vitra. Br.J.Pharmacol., 77: 391–393.

    PubMed  CAS  Google Scholar 

  • Peck, M.J., Piper, P.J., and Williams, T.J., 1981, The effect of leukotrienes C and D4 on the microvasculature of guinea pig skin. Prostaglandins, 21: 315–321.

    Article  PubMed  CAS  Google Scholar 

  • Piper, P.J., and Samhoun, M., 1982, Stimulation of arachidonic acid metabolism and generation of thromboxane A2 by leuko-trienes 84, C4, and DA in guinea-pig lung in viEro. Br. J. Pharmacol., 77: 267–275.

    Google Scholar 

  • Piper, P.J., and Tippins. J.R., 1982, Interaction of leukotrienes with cyclo-oxygenase products in guinea pig isolated trachea.in:“Advances in Prostaglandin, Thromboxane and Leukotriene tïisearch”, B. Samuelsson and R. Paoletti,eds, Vol. 9, pp. 183185, Raven Press, New York.

    Google Scholar 

  • Samuelsson, B., 1983, Leukotrienes: mediators of immediate hypersensitivityreactions and inflammation. Science, 220: 568–575.

    Article  PubMed  CAS  Google Scholar 

  • Serhan, C.N., Hamberg, M., and Samuelsson, B., 1984a, Trihydroxytetraenes: a novel series of compounds formed from arachidonic acid in human leukocytes. Biochem.Biophys.Res.Commun., 118: 934–949.

    Article  Google Scholar 

  • Serhan,N.C., Hamberg, M., and Samuelsson, B., 1984b, Lipoxins: a novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proc.Natl.Acad.Sci.USA 81: in press.

    Google Scholar 

  • Serhan, C.N., Radin,A., Smolen, J.E., Korchak, H., Samuelsson,B.,and Weissmannn, G., 1983, Leukotriene 84 is a complete secretagogue in human neutrophils. Biochem.Biophys.Res.Commun. 107: 1006–1012.

    Google Scholar 

  • Sirois, P., Borgeat, P., and Jeanson, A., 1981, Comparative effects of leukotriene B4, prostaglandins 12 and E2,6-keto-PGF1a,tromboxane B2 and histamine on selected smooth muscle prepara-tions. J.Pharm.Pharmacol., 33: 466–468.

    Article  PubMed  CAS  Google Scholar 

  • SmedegArd, G., Hedqvist,P., Dahlèn,S.-E., Revenäs, B., Hammarström, S., and Samue1sson, B., 1982, Leukotrienes C4 affects pulmonary and cardiovascular dynamics in monkey. Nature, 295: 327–329.

    Article  CAS  Google Scholar 

  • Smith, M.J.H., Ford-Hutchinson,A.W., and Bray, M.A., 1980, Leukotriene B: a potent mediator of inflammation. J.Pharm.Pharmacol., 32: 517–518.

    CAS  Google Scholar 

  • Soter, N.A., Lewis, R.A., Corey, E.J., and Austen, K.F., 1983, Local effects of synthetic leukotrienes (LTC4, LTD A, LTE4, and LTB4) in human skin. J.Invest.Dermatol., 80: 15–119.

    Article  Google Scholar 

  • Terashita, Z.I., Fukui, H., Hirata, M., Terao,S., Ohkawa,S., Nishi- kawa, K., and Kikuchi,S., 1981, Coronary vasoconstriction and PGI22 release by leukotrienes in isolated guinea pig hearts. Eur.J.Pfiarmacol., 73: 357–361.

    CAS  Google Scholar 

  • Thureson-Klein,A., Hedqvist, P., and Lindbom, L., 1984a, Ultra-structure of polymorphonuclear leukocytes in postcapillary venules after exposure to leukotriene B4 in vivo. Acta Physiol Scand 122: 221–224.

    Article  Google Scholar 

  • Thureson-Klein,A, Hedqvist, P., and Lindbom, L., 1984b, Ultra-structural effects of LTB4 on leukocytes and blood vessels. Prostaglandins, in press.

    Google Scholar 

  • Weichman, B.M., Muccitelli,R.M., Osborn,R.R., Holden, D.A., Gleason,J.G., and Wasserman, M.A., 1982, In vitro and in vivo mechanisms of leukotriene-mediated bronchoconstriction in the guinea pig. J.Pharm.Exp.Ther., 222: 202–208.

    CAS  Google Scholar 

  • Wedmore, C.V., and Williams, T.J., 1981, Control of vascular permeability by polymorphonuclear leukocytes in inflammation. Nature, 289: 646–650.

    Article  PubMed  CAS  Google Scholar 

  • Weiss, J.W., Drazen, J.M., Coles, N., McFadden, E.R., Weller, P.W., Corey, E.J., Lewis, R.A, and Austen, K.F., 1982, Bronchoconstrictor effects of leukotriene C in humans. Science, 216: 196–198.

    Article  PubMed  CAS  Google Scholar 

  • Weissmann, G., Smolen, J.E., and Korchak, H., 1980, Prostaglandins and inflammation: Receptor/cyclase coupling as an explanation of why PGEs and PGI inhibit functions of inflammatory cells. in:“Advances in Prottaglandin and Thromboxane Research”, Simuelsson,B., Ramwell, P.W. and Paoletti,R., eds, Vol. 8, pp. 1637–1646, Raven Press, New York.

    Google Scholar 

  • Yokochi,K.,011ey,P.M.,Sideris,E.,Hamilton,F.,Huhtanene,D,and Coceani,F., 1982, Leukotriene D4: A potent vasoconstrictor of the pulmonary and systemic circulations in the newborn lamb, in: “Advances in Prostaglandin, Thromboxane and Leukotriene Research, Samuelsson,B.and Paoletti,R., eds, Vol. 9, pp.211–214, Raven Press,New York.

    Google Scholar 

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Authors and Affiliations

  1. The National Institute of Environmental Medicine and Department of Physiology, Karolinska Institutet, S-104 01, Stockholm, Sweden

    Per Hedqvist & Sven-Erik Dahlén

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  1. Per Hedqvist
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  2. Sven-Erik Dahlén
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Editors and Affiliations

  1. Karolinska Institute, Stockholm, Sweden

    B. Samuelsson

  2. University of Milan, Milan, Italy

    F. Berti  & G. C. Folco  & 

  3. University of Verona, Verona, Italy

    G. P. Velo

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Hedqvist, P., Dahlén, SE. (1985). Pulmonary and Vascular Effects of Leukotrienes: Involement in Asthma and Inflation. In: Samuelsson, B., Berti, F., Folco, G.C., Velo, G.P. (eds) Drugs Affecting Leukotrienes and Other Eicosanoid Pathways. NATO ASI Series, vol 95. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-7841-9_8

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