title: Cysteinyl leukotriene antagonism inhibits bronchoconstriction in response to hypertonic saline inhalation in asthma.
abstract: BACKGROUND
  In asthma, cysteinyl leukotrienes (CysLTs) play varying roles in the bronchomotor response to multiple provocative stimuli. The contribution of CysLTs on the airway's response to hypertonic saline (HS) inhalation in asthma is unknown. Whether polymorphisms in the leukotriene biosynthetic pathway affect the contribution of CysLTs to this response is also unknown.
  
  
  METHODS
  In a prospective, randomized, double-blind, placebo-controlled cross-over study, mild and moderate asymptomatic asthmatics underwent inhaled 3% HS challenge by doubling the duration of nebulization (0.5, 1, 2, 4, and 8 min) 2 h after one dose of montelukast (a CysLT receptor 1 [CysLTR1] antagonist) or placebo, and after three-week courses. We examined the effect of the leukotriene C(4) synthase (LTC(4)S) polymorphism (A-444C) on the efficacy of montelukast against HS inhalation in an exploratory manner.
  
  
  RESULTS
  In 37 subjects, 2 h after administration of montelukast, the mean provocative dose of HS required to cause a 20% drop in FEV(1) (HS-PD(20)) increased by 59% (9.17 ml after placebo vs. 14.55 ml after montelukast, p=0.0154). Three weeks of cysLTR1 antagonism increased the HS-PD(20) by 84% (10.97 vs. 20.21 ml, p=0.0002). Three weeks of CysLTR1 antagonism appeared to produce greater effects on blocking bronchial hyper-responsiveness (2 h vs. three-week HS-PD(20) values 14.55 vs. 20.21 ml respectively, p=0.0898). We did not observe an effect of the LTC(4)S polymorphism on the response to CysLTR1 antagonism in this cohort.
  
  
  CONCLUSIONS
  A significant proportion of HS-induced bronchoconstriction is mediated by release of leukotrienes as evidenced by substantial acute inhibition with a CysLTR1 antagonist. There was a trend toward greater inhibition of bronchial responsiveness with three weeks of therapy as opposed to acute CysLTR1 antagonism. Clinicaltrials.gov registration number NCT00116324.
authors.affiliation: Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, PBB Clinics 3, 75 Francis Street, Boston, MA 02115, USA. skazani@partners.org
authors.forename: Shamsah
authors.initials: S
authors.lastname: Kazani
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sadeh
authors.forename: Sreedhar
authors.initials: S
authors.lastname: Bunga
authors.forename: Michael E
authors.initials: ME
authors.lastname: Wechsler
authors.forename: Elliot
authors.initials: E
authors.lastname: Israel
mesh_terms: D000085:Acetates / Q000008:administration & dosage*; D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000368:Aged; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D003521:Cyclopropanes; D003545:Cysteine / Q000037:antagonists & inhibitors*; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D020024:Leukotriene Antagonists / Q000008:administration & dosage*; D015289:Leukotrienes; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011804:Quinolines / Q000008:administration & dosage*; D018077:Receptors, Leukotriene / Q000008:administration & dosage*; D012462:Saline Solution, Hypertonic / Q000008:administration & dosage*; D013440:Sulfides; D055815:Young Adult
chemical_list: D000085:Acetates; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011804:Quinolines; D018077:Receptors, Leukotriene; D012462:Saline Solution, Hypertonic; D013440:Sulfides; C112381:cysteinyl-leukotriene; D003545:Cysteine; C093875:montelukast