Although considerable insight has been gained into mechanisms by which allergic sensitization and respiratory infections influence airway inflammation, the contribution and relationship of psychological stress, and more directly, specific brain circuitry activated by stress, to the inflammatory processes in asthma, remain largely unknown and an unmet need in asthma management. Our proposal is designed to first establish the contribution of airway inflammation to activation of specific stress-responsive brain neurocircuits and then the contribution of these neurocircuits to the regulation of inflammation in asthma. We have shown that specific stress-responsive brain circuitry in asthma, as measured by functional magnetic resonance imaging (fMRI) of the brain in asthmatic patients, is activated in response to an allergic reaction in the lung to inhaled antigen (AG) and involves brain regions known to be activated by stress. The investigative groups involved in this application process have extensive experience to probe brain-lung interactions in asthma and to establish how airway inflammation activates stress-sensitive neurocircuits of the brain, and how these stress-sensitive circuits, in turn, regulate airway inflammation. In addition, new preliminary information indicates that the interleukin (IL)-1?/IL-17 pathway may be of central importance to inflammation, brain activation, and stress responses. This proposal will test the hypothesis that activation of stress-sensitive brain circuitry contributes to the pathophysiology of asthma by integrated processes: the neural response to an afferent signal which is activated by allergic inflammation in the airway (Specific Aim 1); and an integration of this afferent signal with the ongoing activity in stress-responsive brain neurocircuits to generate an efferent signal to further enhance airway inflammation (Specific Aim 2). The first specific aim will establish that airway inflammation causes an afferent signal to activate stress-sensitive neurocircuitry. Procedures have been developed to activate airway inflammation by bronchoscopy with antigen challenge and retrieval of bronchial lavage fluid, airway cells, and bronchial brushings to establish that airway inflammation activates the brain (fMRI) and its stress-sensitive circuits.
Specific Aim 2 will determine the brain pathways, using positron emission tomography (PET), that, when activated by stress, integrate this activity with an afferent inflammatory signal and initiate a subsequent efferent signal that modulates the inflammatory response in the airway.
This aim will use a well-validated laboratory psychological stress challenge and, as proposed, will enhance the efferent airway inflammatory response, via activity in stress-sensitive brain circuits. These studies will establish the role and contribution of stress-responsive neurocircuits to asthma and identify the molecular mechanisms through which airway inflammation enhances the activity of stress-sensitive brain circuits, as well as how these brain circuits integrate psychological stress into efferent regulatory signals that promote airway inflammation.

Public Health Relevance

Although many factors contribute to allergic inflammation and asthma severity, there is limited information on how psychological stress and the brain contribute to these processes in asthma. Our research will determine how inflammation activates stress-sensitive regions in the brain to enhance these inflammatory processes in asthma and contribute to disease severity. The results of our studies will provide new insights into treatment for patients where stress contributes to asthma severity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL123284-02
Application #
9278258
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2016-06-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
$621,778
Indirect Cost
$215,387
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715