Asthma affects over 17 million people in the United States and the incidence is rising. Research in asthma has focused on the airways, however, little is known about how regional pulmonary perfusion changes during an asthma attack. Recent studies from our lab using positron emission tomography (PET) functional imaging have shown for the first time that dramatic perfusion redistribution, away from patchy areas of low ventilation, take place in spontaneously breathing human subjects with asthma during methacholine-induced bronchoconstriction. The long-term objective of this research is to understand the mechanisms of, and factors that modify, the regional perfusion redistribution during bronchoconstriction in asthma. The main hypotheses to be tested in this project are 1) The redistribution of perfusion away from ventilation defects is primarily caused by hypoxic pulmonary vasoconstriction and is not solely an artifact of methacholine-induced bronchoconstriction and 2) For a given degree of constrictive stimulus, the redistribution of perfusion away from poorly ventilated areas will be less effective in the supine than in the prone position because gravitational forces would tend to oppose the effectiveness of hypoxic vasoconstriction. These hypotheses will be tested using state-of-the-art PET-CT functional imaging of regional perfusion and ventilation with the following specific aims: 1) Assess whether elimination of the hypoxic stimulus by breathing a high oxygen concentration blunts the redistribution of perfusion during methacholine-induced bronchoconstriction (SA-1A). 2) Assess whether a similar perfusion redistribution occurs during bronchoconstriction induced by other bronchoconstrictive stimuli and, if so, evaluate the extent to which hypoxic pulmonary vasoconstriction is involved in that redistribution (SA-1B). 3) Compare the magnitude of redistribution of perfusion away from poorly ventilated regions in the prone and supine positions breathing with and without a high oxygen concentration (SA-2). This research is designed to improve our understanding of the mechanisms that match blood flow and airflow in the lungs during an asthma attack and how these change during recovery from an asthma attack. Knowledge of this important lung function may lead to improved asthma therapy and possibly reduce asthma-related deaths. Asthma affects one out of every twenty Americans. During an asthma attack, the lung tries to match airflow and blood flow in order to maintain oxygen delivery to vital organs. One of the causes of asthma deaths may be impairment in the ability of the lung to perform this important function. This research will study the mechanisms for matching airflow and blood flow during an asthma attack so that better treatments can be developed to prevent asthma deaths.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086717-02
Application #
7577429
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Smith, Robert A
Project Start
2008-03-01
Project End
2013-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
2
Fiscal Year
2009
Total Cost
$441,042
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Kelly, Vanessa J; Hibbert, Kathryn A; Kohli, Puja et al. (2017) Hypoxic Pulmonary Vasoconstriction Does Not Explain All Regional Perfusion Redistribution in Asthma. Am J Respir Crit Care Med 196:834-844
Kelly, Vanessa J; Winkler, Tilo; Venegas, Jose G et al. (2015) Allergic Non-Asthmatic Adults Have Regional Pulmonary Responses to Segmental Allergen Challenge. PLoS One 10:e0143976
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; 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
de Prost, Nicolas; Costa, Eduardo L; Wellman, Tyler et al. (2011) Effects of surfactant depletion on regional pulmonary metabolic activity during mechanical ventilation. J Appl Physiol (1985) 111:1249-58
Ferreira, Juliana C; Bensenor, Fabio E M; Rocha, Marcelo J J et al. (2011) A sigmoidal fit for pressure-volume curves of idiopathic pulmonary fibrosis patients on mechanical ventilation: clinical implications. Clinics (Sao Paulo) 66:1157-63
Vidal Melo, Marcos F; Winkler, Tilo; Harris, R Scott et al. (2010) Spatial heterogeneity of lung perfusion assessed with (13)N PET as a vascular biomarker in chronic obstructive pulmonary disease. J Nucl Med 51:57-65
Wongviriyawong, Chanikarn; Winkler, Tilo; Harris, R Scott et al. (2010) Dynamics of tidal volume and ventilation heterogeneity under pressure-controlled ventilation during bronchoconstriction: a simulation study. J Appl Physiol 109:1211-8
Costa, Eduardo L V; Musch, Guido; Winkler, Tilo et al. (2010) Mild endotoxemia during mechanical ventilation produces spatially heterogeneous pulmonary neutrophilic inflammation in sheep. Anesthesiology 112:658-69
Wellman, Tyler J; Winkler, Tilo; Costa, Eduardo L V et al. (2010) Measurement of regional specific lung volume change using respiratory-gated PET of inhaled 13N-nitrogen. J Nucl Med 51:646-53

Showing the most recent 10 out of 11 publications