The objective of this project is to define cellular and biochemical mechanisms responsible for alterations in neural control in models of airways dysfunction. Work during the current grant period demonstrates that airway exposure to allergen in animals with allergen-specific IgE leads to significant alterations in airway function. Prominent among these changes is enhanced cholinergic input into airways as manifest by increased release of acetylcholine (ACh) from nerve endings upon stimulation of nerves. In addition, there is a significant decrease (allergen sensitization) or loss in function (allergen sensitization plus airway exposure to allergen) of the airway neurally mediated relaxant pathway: the nonadrenergic noncholinergic inhibitory (NANCi) system. This produces an imbalance in neural control in that mechanisms that obstruct airways are more prominent than mechanisms that prevent obstruction. Studies to date in a murine model suggest lymphocytes are critical in the orchestration of these responses, and an influx of eosinophils is important in terms of altering ACh release. A major objective of this proposal is to study the mechanisms by which eosinophils are drawn into the airway and alter airway function. As part of these studies, we will define the contribution of mast cells to this cascade of events. This series of experiments will utilize the expertise of both Drs. Gelfand (allergen-specific monoclonal antibodies) and Irvin (pulmonary physiology within murine species). The ability of polycations to increase ACh release will be addressed directly by measurement of this neurotransmitter. Studies with Dr. Carl White will also be conducted that use transgenic mice to assess the contribution of toxic oxygen species to the cholinergic abnormalities noted above. In terms of functional loss of the NANCi system, changes in the cyclic 3',5'-adenosine monophosphate pathway that may be T cell cytokine-induced as a consequence of allergen sensitization and challenge will be addressed with Dr. Gary Johnson. Alterations in the activity of phosphodiesterase enzymes as well as G proteins within airways as a consequence of allergen sensitization and challenge will be measured in assessing this pathway. These studies of airway biology in mammalian species complement the clinical projects in this program by allowing us to ask basic mechanistic questions that are impossible to address in humans.
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