The Effect of 5-lipoxygenase Inhibition on Ascaris Antigen (Ag)-induced Responses in Atopic Monkeys

Overview

Journal Inflamm Res

Specialties Allergy & Immunology
Pathology

Date 1996 Jan 1

PMID 8821778

Citations 2

Authors

C R Turner

W B Smith

C J Andresen

J F Eggler

J W Watson

Affiliations

Soon will be listed here.

Abstract

The effects of two 5-lipoxygenase (5LO) inhibitors, ZD2138 or Zileuton, on acute, inflammatory responses to aerosolized Ascaris suum (Ag) were determined in atopic Macaca fascicularis monkeys. Monkeys (n = 6 each group) were dosed with vehicle, 3 or 10 mg/kg ZD2138, or 30 mg/kg Zileuton (p.o.). Both ZD2138 or Zileuton significantly inhibited ex vivo LTB4 production in Ca2+ ionophore-stimulated whole blood from these same monkeys (n = 6 each group) by 45.5% (3 mg/kg ZD2138), 82.5% (10 mg/kg ZD2138) and 84.3% (30 mg/kg Zileuton). ZD2138 (10 mg/kg) reduced bronchoalveolar lavage (BAL) LTE4 levels (65.1% inhibition), BAL neutrophils (88.9% inhibition), and IL-6 (54.0% inhibition) 4h post Ag. Zileuton inhibited these responses and also reduced BAL levels of IL-8 (73.4% inhibition). A second study was performed to evaluate the effects of ZD2138 on chronic Ag-induced responses. Treatment with ZD2138 did not prevent pulmonary inflammation or the development of airway hyperresponsiveness (AHR). Based upon these results, 5LO inhibition significantly reduced ex vivo LTB4 and in vivo LTE4 production as well as several acute inflammatory responses to Ag in the lung. However, ZD2138 did not inhibit more chronic responses following multiple Ag exposure.

Citing Articles

Molecular pharmacological profile of a novel thiazolinone-based direct and selective 5-lipoxygenase inhibitor.

Hofmann B, Rodl C, Kahnt A, Maier T, Michel A, Hoffmann M Br J Pharmacol. 2011; 165(7):2304-13.

PMID: 21955369 PMC: 3413864. DOI: 10.1111/j.1476-5381.2011.01707.x.

Molecular pharmacological profile of the nonredox-type 5-lipoxygenase inhibitor CJ-13,610.

Fischer L, Steinhilber D, Werz O Br J Pharmacol. 2004; 142(5):861-8.

PMID: 15197110 PMC: 1575070. DOI: 10.1038/sj.bjp.0705860.

References

McMillan R, Spruce K, Crawley G, Walker E, Foster S . Pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase. Br J Pharmacol. 1992; 107(4):1042-7. PMC: 1907929. DOI: 10.1111/j.1476-5381.1992.tb13404.x. View

Atluru D, Gudapaty S, ODonnell M, Woloschak G . Inhibition of human mononuclear cell proliferation, interleukin synthesis, mRNA for IL-2, IL-6, and leukotriene B4 synthesis by a lipoxygenase inhibitor. J Leukoc Biol. 1993; 54(4):269-74. DOI: 10.1002/jlb.54.4.269. View

Gundel R, Wegner C, Letts L . Antigen-induced acute and late-phase responses in primates. Am Rev Respir Dis. 1992; 146(2):369-73. DOI: 10.1164/ajrccm/146.2.369. View

Bradding P, Feather I, Wilson S, Bardin P, Heusser C, Holgate S . Immunolocalization of cytokines in the nasal mucosa of normal and perennial rhinitic subjects. The mast cell as a source of IL-4, IL-5, and IL-6 in human allergic mucosal inflammation. J Immunol. 1993; 151(7):3853-65. View

Boulet L, Cartier A, Thomson N, Roberts R, Dolovich J, Hargreave F . Asthma and increases in nonallergic bronchial responsiveness from seasonal pollen exposure. J Allergy Clin Immunol. 1983; 71(4):399-406. DOI: 10.1016/0091-6749(83)90069-6. View

Turner C, Andresen C, Smith W, Watson J . Effects of rolipram on responses to acute and chronic antigen exposure in monkeys. Am J Respir Crit Care Med. 1994; 149(5):1153-9. DOI: 10.1164/ajrccm.149.5.8173755. View

Turner C, Smith W, Andresen C, Swindell A, Watson J . Leukotriene D4 receptor antagonism reduces airway hyperresponsiveness in monkeys. Pulm Pharmacol. 1994; 7(1):49-58. DOI: 10.1006/pulp.1994.1005. View

Gundel R, Gerritsen M, Gleich G, Wegner C . Repeated antigen inhalation results in a prolonged airway eosinophilia and airway hyperresponsiveness in primates. J Appl Physiol (1985). 1990; 68(2):779-86. DOI: 10.1152/jappl.1990.68.2.779. View

Ford-Hutchinson A, Bray M, Doig M, Shipley M, Smith M . Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature. 1980; 286(5770):264-5. DOI: 10.1038/286264a0. View

10.

Resnick M, Weller P . Mechanisms of eosinophil recruitment. Am J Respir Cell Mol Biol. 1993; 8(4):349-55. DOI: 10.1165/ajrcmb/8.4.349. View

11.

Broide D, Lotz M, Cuomo A, Coburn D, Federman E, Wasserman S . Cytokines in symptomatic asthma airways. J Allergy Clin Immunol. 1992; 89(5):958-67. DOI: 10.1016/0091-6749(92)90218-q. View

12.

Wegner C, Gundel R, Abraham W, Schulman E, Kontny M, Lazer E . The role of 5-lipoxygenase products in preclinical models of asthma. J Allergy Clin Immunol. 1993; 91(4):917-29. DOI: 10.1016/0091-6749(93)90350-o. View

13.

Hui K, TAYLOR I, Taylor G, Rubin P, Kesterson J, Barnes N . Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax. 1991; 46(3):184-9. PMC: 463027. DOI: 10.1136/thx.46.3.184. View

14.

Brach M, de Vos S, Arnold C, Gruss H, Mertelsmann R, Herrmann F . Leukotriene B4 transcriptionally activates interleukin-6 expression involving NK-chi B and NF-IL6. Eur J Immunol. 1992; 22(10):2705-11. DOI: 10.1002/eji.1830221034. View

15.

Rouzer C, Matsumoto T, Samuelsson B . Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activities. Proc Natl Acad Sci U S A. 1986; 83(4):857-61. PMC: 322969. DOI: 10.1073/pnas.83.4.857. View

16.

Gundel R, Torcellini C, Clarke C, Desai S, Lazer E, Wegner C . The effects of a 5-lipoxygenase inhibitor on antigen-induced mediator release, late-phase bronchoconstriction and cellular infiltrates in primates. Adv Prostaglandin Thromboxane Leukot Res. 1991; 21A:457-60. View

17.

OSBORN R, Hay D, Wasserman M, Torphy T . SK&F 104353, a selective leukotriene receptor antagonist, inhibits leukotriene D4- and antigen-induced bronchoconstriction in cynomolgus monkeys. Pulm Pharmacol. 1992; 5(3):153-7. DOI: 10.1016/0952-0600(92)90035-f. View

18.

Sim T, Grant J, Hilsmeier K, Fukuda Y, Alam R . Proinflammatory cytokines in nasal secretions of allergic subjects after antigen challenge. Am J Respir Crit Care Med. 1994; 149(2 Pt 1):339-44. DOI: 10.1164/ajrccm.149.2.8306027. View

19.

Wegner C, Jackson A, Berry J, Gillespie J . Dynamic respiratory mechanics in monkeys measured by forced oscillations. Respir Physiol. 1984; 55(1):47-61. DOI: 10.1016/0034-5687(84)90116-6. View

20.

Dahlen S, Hedqvist P, Hammarstrom S, Samuelsson B . Leukotrienes are potent constrictors of human bronchi. Nature. 1980; 288(5790):484-6. DOI: 10.1038/288484a0. View