Pulmonary Functional Imaging
We have gained fresh insights into the pathophysiology of ARDS, COPD and asthma from studies using novel non-invasive Positron Emission Tomography methodologies for quantitative assessment of topographical ventilation, perfusion, intrapulmonary shunts, and gas trapping.
Heterogeneity in airway constriction and in ventilation are cardinal features of asthma. Yet, despite detailed knowledge of individual airways and isolated smooth muscle mechanics, the cause of heterogeneity in the asthmatic lung remains unclear. Understanding the mechanisms responsible for such heterogeneity is important, as they affect gas exchange efficiency, overall mechanical obstruction, intrapulmonary delivery of therapeutic agents, and interpretation of diagnostic tests.
The prevailing paradigm in asthma research assumes that knowledge of smooth muscle and individual airway behavior can be extrapolated to predict the behavior of the airway tree. This paradigm implies that heterogeneity of airway constriction has to be the result of either non-uniform application of a constrictive stimulus or of intrinsic differences among airways. However, a number of experimental observations may not be consistent with this conjecture.
Our imaging techniques have demonstrated that the heterogeneity of ventilation in broncho-constricted asthmatics is prominent at large length scales corresponding to lobar and sub-lobar structures. However, this pattern is not the result of severe constriction of central airways feeding those structures, but is instead caused by regional clustering of severely constricted peripheral airways. This unexpected result is explained by a theoretical model of the bronchial tree that includes the interdependent behavior among airways during tidal breathing. The model and our experimental work therefore illustrate the relevance of local and inter-regional interactions within the lung. These new insights are providing the rationale for new strategies in the diagnosis and treatment of this disease.
Using our single isotope (Nitrogen-13) PET imaging method, we have also investigated the derangement of gas transport physiology in animal models of ARDS, demonstrating the topographic location and magnitude of intrapulmonary gas exchange abnormalities. Specifically, a recent study provides a mechanistic explanation for the positive effects of the prone position in ARDS.
We have also developed a new quantitative method to assess local inflammation in the lungs using PET imaging of local neutrophil activity from the uptake rate of 18F-labeled fluoro-2-deoxy-D-glucose (18F-FDG). This method is now being used in COPD patients. We are also looking at animal models of Acute Lung Injury (ALI) in conjunction with measures of local pulmonary ventilation and perfusion. The combined use of functional imaging and inflammation allows us to study the pathogenesis, progression, diagnosis and treatment of COPD and ALI.