Asthma is a disease of rapidly increasing incidence that already affects more than 17 million people in the United States alone. It is of major importance to understand the mechanisms responsible for underlying mechanical and physiological changes that occur during asthma exacerbations. The long-term objective of this project is to expand the understanding of these mechanisms to provide the foundations upon which to develop improved methods for diagnosing, monitoring and managing asthma. Bronchoconstriction is a cardinal feature of asthma, and its spatial distribution within the lungs has wide implications for diagnosis and therapy. An increasing amount of experimental work suggests that the heterogeneous response of the lung cannot be predicted by the summed independent behavior of individual airways. The central hypothesis to this proposal is that such response is a reflection of the integrated response of the lung including serial and parallel interactions amongst airways and parenchyma. This proposal focuses on three key aspects of this hypothesis: 1) the link between parallel heterogeneity in ventilation in asthma with the integrated response of the airway tree, 2) the regional effect of deep inhalations (Dl's) in the development of and recovery from airway obstruction, and 3) the reopening of ventilation defective regions of the lung with Dl's to improve the serial and parallel uniformity of inhaled aerosol drug deposition and effectiveness. The studies will be conducted in healthy persons and patients with asthma and combine non-invasive topographic assessments of lung function, structure and inhaled aerosol deposition, obtained with positron emission imaging and high resolution CT, with global measurements and modeling of lung mechanics. We expect that this detailed anatomical and functional data will provide new insights into the pathophysiology of the disease that will be directly applicable to patient care and will help advance the field of aerosol therapy. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068011-06
Application #
7428816
Study Section
Special Emphasis Panel (ZRG1-RES-B (03))
Program Officer
Croxton, Thomas
Project Start
2001-09-01
Project End
2011-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
6
Fiscal Year
2008
Total Cost
$604,719
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Greenblatt, Elliot Eliyahu; Winkler, Tilo; Harris, Robert Scott et al. (2016) Regional Ventilation and Aerosol Deposition with Helium-Oxygen in Bronchoconstricted Asthmatic Lungs. J Aerosol Med Pulm Drug Deliv 29:260-72
Johansen, Troels; Winkler, Tilo; Kelly, Vanessa Jane et al. (2016) A method for mapping regional oxygen and CO2 transfer in the lung. Respir Physiol Neurobiol 222:29-47
Johansen, Troels; Venegas, Jose Gabriel (2016) 3D mapping of oxygen and CO2 transport rates in the lung: a new imaging tool for use in lung surgery, intensive care and basic research. Expert Rev Respir Med 10:935-7
Winkler, Tilo; Melo, Marcos F Vidal; Degani-Costa, Luiza H et al. (2015) Estimation of noise-free variance to measure heterogeneity. PLoS One 10:e0123417
Greenblatt, Elliot Eliyahu; Winkler, Tilo; Harris, Robert Scott et al. (2015) Analysis of three-dimensional aerosol deposition in pharmacologically relevant terms: beyond black or white ROIs. J Aerosol Med Pulm Drug Deliv 28:116-29
Wongviriyawong, C; Harris, R S; Greenblatt, E et al. (2013) Peripheral resistance: a link between global airflow obstruction and regional ventilation distribution. J Appl Physiol (1985) 114:504-14
Wongviriyawong, C; Harris, R S; Zheng, H et al. (2012) Functional effect of longitudinal heterogeneity in constricted airways before and after lung expansion. J Appl Physiol (1985) 112:237-45
Harris, R Scott; Fujii-Rios, Hanae; Winkler, Tilo et al. (2012) Ventilation defect formation in healthy and asthma subjects is determined by lung inflation. PLoS One 7:e53216
Harris, R Scott; Venegas, José G; Wongviriyawong, Chanikarn et al. (2011) 18F-FDG uptake rate is a biomarker of eosinophilic inflammation and airway response in asthma. J Nucl Med 52:1713-20
Schroeder, Tobias; Melo, Marcos F Vidal; Venegas, Jose G (2011) Analysis of 2-[Fluorine-18]-Fluoro-2-deoxy-D-glucose uptake kinetics in PET studies of pulmonary inflammation. Acad Radiol 18:418-23

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