Asthma is a disease of increasing incidence that already affects more than 17 million people in the United States alone. It is therefore of major importance to understand the mechanisms responsible for the 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 and provide the foundations upon which to develop improved methods for diagnosing, monitoring and managing asthma. Specifically, this proposal will study the phenomenon of airway closure and gas trapping (GT) during bronchoconstriction (BC). Total closure of pulmonary airways resulting in distal GT has long been suspected to occur in asthma and has been proposed as a major mechanism contributing to the impairment of gas exchange and increased work of breathing during severe BC. Unfortunately, until recently, there has only been indirect evidence about airway closure and direct observation of closed airways during whole-lung BC has remained elusive. Using Positron Emission Tomography (PET) we demonstrated the development of large contiguous areas of pulmonary GT in broncho-constricted animals and in an asthmatic subject. These data are consistent with segment-size ventilation defects recently visualized with MRI in asymptomatic asthmatics. The main hypotheses guiding this proposal are: 1) the changes in pulmonary mechanics during severe BC in asthma can be explained in great part by airway closure and distal gas trapping and 2) the pattern of heterogeneity in ventilation (VA) and GT during asthmatic BC should be considerably affected by heterogeneous constriction of large pulmonary airways. Our novel PET imaging technique measures the local elimination kinetics of an IV injected saline solution bolus of the isotope gas Nitrogen-13 (13 NN) and yields three- dimensional data on the topographic distribution of pulmonary perfusion (Q) and VA, and on the location and extent of gas trapped regions within the lung. We plan to use this technique, in combination with sophisticated oscillatory mechanics measurements, in normal subjects and in symptomatic and asymptomatic asthmatics, in order to achieve the following specific aims: 1) Assess the relationship between changes in global lung mechanics and in the topographic distribution of VA, and the length scale and extent of GT, during agonist-induced BC. And 2) Quantify the contribution of factors affecting the temporal and spatial constancy of these local effects such as the heterogeneous distribution of the agonist and the history of lung expansion. The experimental data to be gathered is expected to provide unique insights in the process of BC in asthma and this will serve to validate and refine the theoretical models of gas exchange and lung mechanics required to develop advanced methodologies for the diagnosis, monitoring and management of asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL068011-01
Application #
6364878
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Croxton, Thomas
Project Start
2001-09-01
Project End
2005-07-31
Budget Start
2001-09-01
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$557,315
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
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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