The Role of Leukotrienes in the Regulation of Tone and Responsiveness in Isolated Human Airways

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Abstract
Cysteinyl-leukotrienes and histamine are the major determinants of inherent tone in isolated human bronchi, which is mainly the result of a balance of continual production and release of contractile mediator, in particular cysteinyl-leukotrienes and to a lesser extent histamine, and on the other side bronchodilating prostanoids. Cysteinyl-leukotrienes are also powerful constrictors of isolated human airways through direct interaction with Cys-LT1 receptors on airway smooth muscle, and with a potency 1,000-fold higher than histamine. On stimulation inflammatory cells such as eosinophils and mst cells produce and release significantly increased amounts of leukotrienes leading to smooth muscle contration in vitro. In isolated human airways, leukotrienes are the most important mediators of allergen and adenosine-induced contractile responses. The induction of allergen responses in passively sensitized airways is not only related to an increased release of leukotrienes and histamines, but also to an enhanced responsiveness of the airway smooth muscle, particularly to LTC4. Studies in isolated human airways in vitro have demonstrated that understanding the regulation of human airway tone and airway reactivity are closely linked to the understanding of baseline and stimulated production of and smooth muscle responsiveness to leukotrienes in vitro and in vivo.