Abstract
Constriction of mammalian airways is primarily driven by nerves that release the neurotransmitter acetylcholine (ACh). One FDA approved class of drugs blocks ACh-induced constriction in asthma. However, nerves contain other neurotransmitters that may also be targets for asthma treatment. To further characterize the role of various neurotransmitters in modulating airway constriction, nerves in isolated mouse airways were activated using electrical field stimulation (EFS) which causes release of neurotransmitters. Constriction and relaxation caused by neurotransmitters were pharmacologically blocked to decipher their roles in airway function. EFS caused an ACh-mediated constriction phase and a relaxation phase blocked by capsaicin and indomethacin.|Drug distribution models build outward from first principles using computational methods to describe the movement of drugs in an organism. These models create a rigorous mathematical framework to allow for simulation of in vitro and in vivo processes. My hypothesis was that a computational drug distribution model can consolidate experimental data into a mathematical description of the functional role of nerves in mouse airways. Data from isolated trachea experiments informed the design of compartment-based computational models. By minimizing the sum of squares error, the computational models predicted kinetic parameters that described ACh-induced trachea constriction in response to EFS.|Identifying the mediators of the relaxation phase that were eliminated by capsaicin and indomethacin was the second necessary step toward development of a complete functional model. Sensory neuropeptides and prostanoid receptors were pharmacologically blocked to decipher their roles in regulating airway relaxation. Results of experiments indicated that PGE2 is a candidate mediator of the EFS-induced relaxation phase. Therefore, the PGE2 receptor EP2 was incorporated into the drug distribution model. The updated Multiple Neurotransmitter model was able to reproduce biphasic EFS responses, consistent with experimental observations.|This work contributes a novel perspective to the study of the functional neurotransmitter systems in the lung. Coupled with in vitro and in vivo experiments, a more complete model may aid in silico testing of drugs, furthering the development of new therapeutics for the treatment of asthma and other lung diseases.