Insulin increases nerve-mediated bronchoconstriction in obesity-related asthma

Project Summary Obesity increases both the incidence and severity of asthma. Obesity-related asthma is associated with more frequent symptom exacerbations and hospitalizations, which respond poorly to current asthma medications leading to increased healthcare costs and decreased quality of life. The molecular mechanisms of obesity-related asthma are yet to be defined, making effective prevention and management of this disease difficult. Parasympathetic and sensory nerves control airway tone and mediate reflex bronchoconstriction. This proposal builds on our previous discoveries that 1) increased insulin, associated with obesity, causes airway hyperreactivity mediated by the vagus nerve in obese rats, 2) that asthma severity is associated with increased density of sensory nerves in the lung, and 3) that obese mice with high levels of insulin have increased reflex bronchoconstriction and increased sensory innervation supplying airway epithelia. Thus, we hypothesize that increased insulin, as seen in obesity, potentiates airway hyperreactivity by changing both sensory and parasympathetic nerves, and that these changes are mediated by insulin receptors on airway nerves. We propose to test whether airway hyperreactivity in obese mice is mediated by increased activation of sensory nerves or parasympathetic nerves or a combination of both, and identify how insulin may change neural control. We will also measure insulin-related changes in airway parasympathetic and sensory nerve structure and density, and changes in neurotransmitter expression and release. Finally, we will identify cell signaling pathways by which insulin promotes sensory innervation and neurotransmitter expression. This project uses cutting edge, innovative techniques developed in our labs, and will significantly increase our understanding of underlying mechanisms by which obese patients with increased insulin are more prone to have asthma with increased severity. The long-term goal of the proposed research is to facilitate identification of novel therapeutic targets for prevention and treatment of obesity-related asthma.