Ozone mediated hyperresponsiveness is mediated by the vagus nerves. However, the mechanisms of ozone induced hyperreaactivity change over 3 days after a single exposure to ozone. Acutely, hyperreactivity is due to loss of inhibitory neuronal M2 receptor function and subsequent increased acetylcholine release. Chronically, hyperreactivity is mediated by substance P, also from parasympathetic nerves. Eosinophils mediate neuronal M2 dysfunction immediately after ozone, and 2 days later still mediate increased acetylcholine release but now by a mechanism separate from M2 receptor loss. 3 days after a single ozone exposure, eosinophils stimulate parasympathetic nerves to express and release substance P, a neurotransmitter normally limited to sensory nerves. Eosinophils mediate all of these effects, as eosinophil depletion or blockade of migration into the lungs prevents ozone induced changes in nerve function. It is our hypothesis that ozone induced hyperreactivity requires an interaction between eosinophils and airway nerves that leads to acute and chronic changes in expression and release of ACh, substance P and their receptors by the parasympathetic nerves. To address this hypothesis we will 1) determine in isolated parasympathetic nerves what mechanisms (eotaxin, ICAM , VCAM) mediate eosinophil recruitment to airway-nerves and how TNF( and IL-1(, cytokines increased by ozone exposure, affect eosinopihl recruitment. 2) Determine how eosinophils induce expression of substance P in parasympathetic nerves. 3) These studies include examining signalling mechanisms initiated by eosinophils adhesion or release of cytokines such as nerve growth factor and LIF from eosinophils that induce substance P expression. 4) Using blocking antibodies and receptor antagonists to determine mechanisms by which ozone, via eosinophiils, induces substance P in parasympathetic nerves in vivo. It is anticipated that these studies will lead to a greater understanding of the interaction of eosinophils with nerves and the multiple mechanisms underlying hyperreactivity to ozone.
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