Assessment of Dissolved Phase 129Xe as a Biomarker for gas-exchange and vascular function in asthma

About This Grant

PROJECT SUMMARY Asthma, the most common respiratory disease in the US, affects nearly 10% of the population and costs nearly $50 billion annually. While many asthma patients can control their asthma with inhaled medications, some patients cannot. Although asthma is a disease characterized by airway inflammation and impaired ventilation, recent evidence suggests that anomalies in pulmonary vasculature may also contribute to asthma presentation and severity. This is a difficult hypothesis to address however because it requires a test that can accurately assess pulmonary vasculature non-invasively with high spatial and temporal resolution. Furthermore, for diseases such as asthma which are known to be spatially heterogeneous within the lung, regional vascular function is necessary to understand the spatially heterogeneous nature of the disease – something which global measures of gas exchange function such as DLCO lack. Treatments for asthma often target one component of the underlying pathophysiology (airways/ventilation) while leaving anomalies in gas-exchange/perfusion unaddressed and unmanaged. Thus, the lack of a robust, sensitive, non-invasive biomarker for pulmonary vascular function presents an unmet need in understanding and managing individual asthma patients. Hyperpolarized 129Xe MRI is a technique in which the nuclear magnetic moment of 129Xe is greatly enhanced in situ such that the gas itself can be imaged by MRI. Subjects inhale a small quantity of xenon during an MR exam, and the gas is imaged as it is physiologically distributed within the lung airspaces. The xenon can also diffuse slightly into the tissue and blood whereupon it experiences an MR chemical shift. This allows for the xenon to be separately imaged in three distinct physiological environments: alveolar airspaces (gas), tissue and blood plasma (membrane), and in red blood cells (RBC). The RBC component further demonstrates oscillation due to cardiac activity – another marker of cardiopulmonary function. Thus, within a single breath-hold 129Xe MRI can be used to image three components of lung function: ventilation, perfusion, and gas exchange. Because hyperpolarized 129Xe MRI provides quantitative, regional measures of both perfusion and gas-exchange we hypothesize it is a technique which can reveal the precise nature of vascular involvement in asthma. In this work we hypothesize that in some patients with asthma, 129Xe MRI will depict abnormalities of lung perfusion spatially separate from ventilation abnormalities and that the abnormalities of lung ventilation, perfusion and gas exchange will respond to treatment with bronchodilator (albuterol). We will perform 129Xe MRI in mild, moderate, and severe asthma patients and healthy controls before and after administration of albuterol. We will quantify abnormalities in pulmonary vascular function, measure the percent of lung with impaired ventilation and perfusion in individual subjects, and evaluate regional responses of 129Xe MRI to bronchodilators and pulmonary vasodilators. We anticipate that there will be significant variability in the degree of pulmonary ventilation and perfusion impairments among asthmatics of the same severity.