Date

January 2011

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Physiology and Pharmacology

Institution

Oregon Health & Science University

Abstract

Asthma exacerbations are caused by respiratory virus infections. Toll-like receptor 7 (TLR7) of the innate immune system recognizes single-stranded RNA viruses and mounts an immune response to clear the infection. TLR7 polymorphisms are associated with asthma. While its role in innate immune defense in the lung is appreciated, little is known about the acute effects of TLR7 signaling on airway physiology. The results in this thesis demonstrate that TLR7 agonists are rapid bronchodilators in guinea pigs, mice, and humans, abolishing airway smooth muscle contraction within minutes of administration (Chapter III). Depending on species and ligand, the bronchodilating effect is mediated in part by TLR7, and in part by another target, most likely TLR8 (Chapter IV). TLR7-dependent bronchodilation is mediated by nitric oxide, and TLR7-independent bronchodilation is mediated by prostaglandins and large conductance calcium-gated potassium channels (Chapter IV). There is dysfunction in the bronchodilating effect with reduced ligand potency in allergen-sensitized and virus-infected guinea pigs in vivo, which may account in part for the more severe response to respiratory virus infections in humans with asthma (Chapter V). It may also explain why TLR7 polymorphisms are closely associated with asthma. Though the bronchodilating potential is reduced in models of asthma, TLR7 agonists are still bronchodilators, suggesting that TLR7 may serve as a valuable therapeutic target in asthma. This novel finding represents an endogenous protective mechanism to maintain breathing during the inflammation necessary to clear respiratory virus infections. It also suggests that TLR7 agonism may be a potent rescue therapy during active bronchoconstriction associated with asthma attacks. Others have proposed TLR7 agonists as prophylactic therapy for asthma by harnessing the immunomodulatory capabilities of this receptor in skewing the immune system in the airways away from Th2-type and towards Th1-type immunity (a form of anti-allergic inflammation). Combined with their prophylactic capabilities, the acute bronchodilation mediated by TLR7 agonists demonstrated here suggests a novel and unique combined prophylactic and rescue therapy for asthma in one medication. Current standard of therapy for asthma uses one medication to prevent airway inflammation, and a second medication to limit bronchoconstriction. As these are often combined into one formulation, it is not uncommon for these patients to have a third rescue medication for acute bronchoconstriction during asthma attacks. As individual medications are all associated with some side effects, reducing the number of medications administered may potentially reduce side effects.

Identifier

doi:10.6083/M4MC8X1V

School

School of Medicine

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