Date of Award

1-2004

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Physiology and Pharmacology

Supervisor

P.M. O'Byrne

Abstract

Cysteinyl leukotrienes (LTC4 , D4 , E4 ) play an important role in the pathophysiology of asthma. They produce bronchoconstriction, microvascular leakage and eosinophil infiltration into the airway mucosa. They mediate the airway responses following allergen inhalation and exercise. This thesis examined new effects of cysteinyl leukotrienes on three cells in human airways: an antigen presenting cell (dendritic cell), a key inflammatory cell (eosinophil) and a structural cell (smooth muscle). Dendritic cells initiate allergen-induced airway responses by presenting the allergen to lymphocytes. Cysteinyl leukotrienes are necessary for the migration of dendritic cells from tissues to the regional lymph nodes. We observed that they also regulate the recruitment of myeloid dendritic cells from peripheral blood following an allergen inhalation. In a clinical trial, we observed that two weeks of treatment with a leukotriene receptor antagonist prevented the allergen-induced decrease in the number of circulating myeloid, but not plasmacytoid, dendritic cells in atopic asthmatic subjects. This was in keeping with our observation that greater proportion of myeloid dendritic cells than plasmacytoid dendritic cells expressed the CysLT1 receptor. Esoinophilic infiltration of the airway is a characteristic feature of asthma pathology. We observed that inhalation of cysteinyl leukotrienes caused an increase in the number of eosinophils in airway mucosa and lumen in subjects with atopic asthma. We also observed that leukotriene E4 caused greater eosinophilia than leukotriene D4 . We further examined bone marrow eosinophilopoiesis as one of the mechanisms by which leukotrienes cause airway eosinophilia. Treatment of atopic asthmatic subjects with a leukotriene-receptor antagonist for two weeks attenuated allergen-induced increase in the number of eosinophl/basophil colony forming units in the bone marrow. This was the first in-vivo observation of a direct role of cysteinyl leukotrienes in regulating eosinophilopoiesis in humans. The first recognized biological effect of cysteinyl leukotrienes was their ability to contract smooth muscles. We observed that they could also modulate another property of human airway smooth muscle, i.e., migration. We observed that human airway smooth muscle cells show chemotaxis towards platelet-derived growth factor. Although leukotrienes by themselves were not chemoattractants, they caused chemokinesis of smooth muscle cells and augmented chemotaxis towards platelet-derived growth factor. A leukotriene receptor antagonist inhibited this. The mechanism was not dependent on increased integrin expression on smooth muscle, or Src-kinase or phosphatidylinositol 3-kinase phosphorylation. (Abstract shortened by UMI.)

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