The effects of montelukast on tissue inflammatory and bone marrow responses in murine experimental allergic rhinitis: interaction with interleukin-5 deficiency.
The cysteinyl leukotrienes (cysLTs) are potent lipid mediators in allergic disease, acting through the receptors, cysLT1R and cysLTR2, and are produced by eosinophils derived from eosinophil/basophil (Eo/B) bone marrow (BM) progenitors. We have demonstrated the suppressive effects of either interleukin-5 (IL-5) deficiency or montelukast on eosinophil recruitment in murine allergic rhinitis, but neither of them fully abrogated the symptoms caused by residual inflammation and cytokine redundancy in eliciting BM Eo/B responses. We hypothesized that IL-5 deficiency and montelukast act synergistically to suppress tissue inflammatory and BM responses. Our objective was to investigate the effects of the cysLT1R antagonist, montelukast, on in vivo tissue inflammatory and BM responses in murine experimental allergic rhinitis with or without IL-5 deficiency. Three groups of age-matched BALB/c mice with or without IL-5 deficiency were tested: controls (ovalbumin sensitization and challenge, placebo treatment) and two montelukast-treated groups (2.5 mg/kg or 5 mg/kg). Nasal symptoms, BM and nasal mucosal eosinophils, basophils, and BM Eo/B colony-forming units (CFU) were evaluated. Montelukast decreased nasal symptoms in a dose-dependent manner, and significantly decreased the number of eosinophils in both BM and nasal tissue in IL-5-replete mice compared to controls. In IL-5-deficient mice, in which eosinophilia was absent, montelukast significantly decreased both nasal symptoms and basophils in BM and nasal mucosal tissue, and lowered IL-5-responsive Eo/B-CFU ex vivo, compared to controls. The addition of cysLT1R blockade to IL-5 deficiency more fully attenuates symptoms and upper airway inflammation than either factor alone, providing evidence of systemic, BM mechanisms in allergic rhinitis.
Roa
Johanna
J
Division of Clinical Immunology & Allergy, Department of Medicine, McMaster University, Hamilton, ON, Canada.
Morikawa
Hiroshi
H
Crawford
Lynn
L
Baatjes
Adrian
A
Duong
Mylinh
M
Denburg
Judah A
JA
D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001491:Basophils / Q000187:drug effects / Q000473:pathology; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D003114:Colony-Forming Units Assay; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D015848:Interleukin-5 / Q000172:deficiency* / Q000276:immunology; D020024:Leukotriene Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D010047:Ovalbumin / Q000276:immunology; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D012221:Rhinitis, Allergic, Perennial / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013440:Sulfides
D000085:Acetates; D003521:Cyclopropanes; D015848:Interleukin-5; D020024:Leukotriene Antagonists; D011804:Quinolines; D013440:Sulfides; D010047:Ovalbumin; C093875:montelukast