Cystic fibrosis (CF) is the most common, fatal, single gene defect in the Caucasian population. The gene encodes a chloride channel that, when defective, causes the lungs to produce unusually thick and viscous mucus that clogs the airways. This leads to poor lung ventilation and creates an ideal breeding ground for lung infections. Current treatments for CF are aimed at improving airway clearance, and preventing or curing infection that is to improve ventilation and decrease inflammation. CF is typically diagnosed in early infancy, and the current median age of survival is approximately 37 years. There are many required daily supportive therapies including specialized (and costly) treatments to alleviate mucus obstruction, control lung infections, and maximize nutrition. Exciting new treatments under development are aimed at the molecular basis of the disease. Such treatments are likely to be quite expensive, like the recently FDA approved Kalydeco (VX770, Vertex, MA) with an estimated annual cost of more than $250,000/patient, and will be tested in only the most common genotypes. The purpose of the proposed work is to optimize and evaluate a new method capable to provide new insights into pulmonary CF and assess the efficacy of treatments for CF. Currently a clinical method does not exist for non-invasively assessing regional inflammation or gas exchange in the lung. A method recently pioneered by our group, based on hyperpolarized Xe-129 gas (hp Xe-129) and magnetic resonance spectroscopic imaging (MRSI), and termed Single Breath-hold Chemical Shift Imaging (3D SB-CSI), is capable of non-invasively assessing, in a single breath hold (less than 15 seconds), regional lung ventilation, inflammation, and gas exchange-uptake without the use of radioactive substances or ionizing radiation. Our promising preliminary results let us hypothesize that this technique will provide new insights into pulmonary CF and its response to treatment.
The first aim of this project is to implement, optimize, and validate improvements to our current 3D SB-CSI technique to increase both the speed and resolution of the acquisition, to improve our ability to separate the tissue and red-blood-cell (RBC) contributions, and to improve the signal- to-noise ratio (SNR).
The second aim i s two-fold: 1) we propose to characterize gas exchange among lung compartments by measuring regional Xe-129 uptake from the alveoli into lung tissue and RBCs. These measurements will be conducted in 15 healthy subjects (ages 12 years-old and up) and will be age matched to the CF subjects studied under the second part of this aim;and 2) perform an exploratory study in 30 subjects with CF (15 subjects with mild-moderate pulmonary disease and 15 subjects with severe pulmonary disease). Since this is a pediatric disease, we propose enrolling subjects as young as 12 years old and up. This will allow us to characterize regional Xe-129 gas uptake into tissue and into RBCs as a function of disease severity. All subjects under this aim will also receive full pulmonary function tests (PFTs) to evaluate the degree of disease severity and to correlate with the results from 3D SB-CSI.
The proposed project aims to improve and optimize a method based on magnetic resonance imaging that provides regional physiological information regarding lung ventilation, gas exchange and gas uptake into the lung and into the red blood cells. The results from the proposed studies in a population of healthy subjects and another of subjects previously diagnosed with cystic fibrosis will set the base for posterior applications since they will: 1) improve our understanding of the functional pulmonary manifestations of CF;2) demonstrate that patients with CF have alterations in regional gas exchange detectable with the new technique;3) correlate with global alterations in gas exchange as measured by other techniques (e.g. DLCO) and with disease severity as measured by spirometry (FEV1);and 4) provide preliminary data for powering future clinical trials with 3D SB-CSI in CF. Our method does not involve any kind of ionizing radiation and can be safely repeated, which it is an important safety issue given CF's pediatric population. Our method also represents a new tool to better understand the complex lung physiology present in CF, as well as in other pulmonary diseases.