Date

June 2008

Document Type

Thesis

Degree Name

M.S.

Department

Dept. of Physiology and Pharmacology

Institution

Oregon Health & Science University

Abstract

The novel results presented in this thesis demonstrate that human and guinea pig eosinophils express muscarinic receptors, which inhibit eosinophil activation in vitro (Chapter V). Furthermore, I have demonstrated that muscarinic blockade during antigen challenge significantly increases eosinophil activation and subsequent vagally mediated hyperreactivity in guinea pigs (Chapter III and IV) via a mechanism involving eosinophils (Chapter III) and nerve growth factor (NGF) (Chapter IV). These data suggest that the inhibitory muscarinic receptors I have identified in vitro are functional in vivo. Previous work has demonstrated that antigen-induced airway hyperreactivity in guinea pigs is mediated by eosinophil major basic protein (MBP) and neuronal M2 receptor dysfunction. In this thesis, I have identified an alternative mechanism by which eosinophils mediate hyperreactivity in antigen challenged guinea pigs that is not mediated by loss of neuronal M2 function. In this newly identified pathway, both eosinophils and NGF play a critical role since anti-IL-5 and anti-NGF antibodies prevent antigen-induced airway hyperreactivity. NGF may be acting upstream of eosinophil activation, since anti-NGF antibodies prevent increased eosinophil activation. One possible explanation is that NGF induces eosinophils to release a mediator that alters nerve function, and release of this factor is inhibited by acetylcholine. Eosinophils produce a number of mediators that may alter nerve function, including NGF. One key effect of neurotrophins is that they can alter neuronal neurotransmitter content, a phenomenon called neural plasticity. Thus, eosinophils mediate airway hyperreactivity via multiple mechanisms, one involving MBP blockade of neuronal M2 receptors and the other involving NGF and possibly neural plasticity. The implications of these findings are clinically relevant, considering the poor performance of anticholinergics in management of chronic asthma. Anticholinergic drugs are effective bronchodilators when given during an asthma exacerbation. However, these drugs are not as effective as predicted from animal studies and are not recommended for chronic treatment of asthma. The findings in this thesis provide an explanation for this paradox, and suggest that timing of anticholinergic administration is very important. Anticholinergics after antigen challenge are effective bronchodilators, but if administered prophylactically, as would be the case if given chronically, may make hyperreactivity worse. In summary, I have discovered a novel interaction between the parasympathetic nerves and eosinophils. While it has been known that eosinophils can affect parasympathetic nerve function, I have identified a potential mechanism by which nerves may inhibit eosinophil function. This potential mechanism may be a negative feedback loop in which acetylcholine release from nerves dampens the negative effects of eosinophils on neuronal M2 receptor function in allergic asthma. These observations are clinically important because they may explain why anticholinergics treatments that should be effective in managing asthma are not, despite the current body of knowledge in this field and may provide a rationale for new approaches to pharmacological control of the lungs. These findings are significant because they contribute to our understanding of the complex interactions between the immune and nervous systems and because they will influence future therapeutics for treating diseases characterized by increased eosinophil activation, such as asthma.

Identifier

doi:10.6083/M46W981T

School

School of Medicine

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