Date

December 2011

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Physiology and Pharmacology

Institution

Oregon Health & Science University

Abstract

Parasympathetic nerves in the lung provide the dominant control over airway smooth muscle tone. In asthmatic humans and in animal models of allergic asthma the airways are hyperresponsive to nonspecific contractile stimuli, and this hyperresponsiveness is mediated by increased acetylcholine release from parasympathetic nerves. Airway hyperresponsiveness is associated with eosinophil recruitment to airway nerves. In animals, treatments that prevent eosinophils from associating with airway nerves prevent airway hyperresponsiveness, and in humans, treatments that reduce lung eosinophils reduce asthma exacerbations. Furthermore, surgical denervation of the airways in humans with asthma decreases airway responsiveness and abolishes sputum eosinophils, suggesting parasympathetic nerves are important both for airway hyperresponsiveness and eosinophil recruitment. The hypothesis tested in this thesis is that in allergic asthma parasympathetic nerves in the lungs regulate inflammation leading to airway hyperresponsiveness, both through release of the neurotransmitter acetylcholine and through release of eosinophil chemoattractant proteins. Data presented in this thesis demonstrate that selective blockade of M[subscript 3] muscarinic acetylcholine receptors with tiotropium during inhaled antigen challenge prevents subsequent airway hyperresponsiveness in a guinea pig model of asthma. Surprisingly, airway hyperresponsiveness was prevented by a mechanism that does not involve inhibition of bronchoconstriction, since vagally induced bronchoconstriction was not inhibited in control animals that were not exposed to antigen. Instead, the mechanism may be anti-inflammatory as both total and nerve-associated eosinophils were reduced in lung sections. These data suggest selective M[subscript 3] muscarinic receptor antagonists may have benefits in asthma separate from inhibition of bronchoconstriction. Data in this thesis also show that neuronal cells grown in culture produce several ligands for CCR3 chemokine receptors on eosinophils in response to tumor necrosis factor alpha, a cytokine that is increased in asthma. Human SK-N-SH cells produce mRNA transcripts and protein for CCL5 (RANTES), CCL7 (MCP-3), and CCL11 (eotaxin), while guinea pig parasympathetic neurons only produce one chemokine, CCL7. However, in vivo data presented in this thesis do not support the hypothesis that eosinophils are recruited to airway nerves via neuronally produced CCR3 chemokines. Instead, these data suggest a model where eosinophils are recruited to the lungs via CCR3 chemokines produced by nonneuronal cells, and this general increase in eosinophils results in a proportional increase in nerve-associated eosinophils. The results extend previous observations of nerve-associated eosinophils, since they show eosinophils associate with both cholinergic and noncholinergic nerves following antigen challenge. Thus, eosinophils may interact with parasympathetic, sensory, or possibly sympathetic neurons in the lung to mediate airway hyperreactivity. The implications of these findings are that selective M[subscript 3] muscarinic receptor antagonists may be beneficial for long-term treatment in asthma via an anti-inflammatory mechanism. In particular, they may reduce asthma exacerbations by reducing nerve-associated eosinophils (parasympathetic, sensory, or sympathetic) and preventing subsequent increases in airway hyperresponsiveness.

Identifier

doi:10.6083/M4DJ5CMK

School

School of Medicine

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