Absorptive Clearance After Inhaled Osmotics in Cystic Fibrosis

There is a substantial need for new biomarkers in the study of cystic fibrosis (CF) lung disease. Conventional endpoints, such as rate of FEV1 decline, require prolonged trials and large sample sizes to demonstrate therapeutic efficacy. Ideally such biomarkers would provide a quantitative window to the most basic aspects of CF pathophysiology, allowing for the development and evaluation of therapies prior to large scale clinical trials. The basic defect of CF lung disease occurs in the airways where dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium (ENaC) channels is thought to create an ionic gradient that causes excessive liquid absorption across the epithelium. This results in a dehydrated airway surface liquid (ASL) layer, defective mucociliary clearance, and an increased proclivity for infection and inflammation. Aerosol-based methods have been developed to measure mucociliary clearance in the lung and used to demonstrate the efficacy of inhaled osmotic therapies. We have developed an aerosol technique to measure both mucociliary clearance and the absorptive clearance of a hydrophilic small molecule (diethylenetriaminepentaacetic acid or DTPA) in whole, central, and peripheral lung regions. We estimate DTPA absorption by delivering an aerosol containing both Indium 111 DTPA (In-DTPA) and Technetium 99m sulfur colloid (Tc-SC) to the airways. The clearance of each radiopharmaceutical is imaged independently and two separate clearance curves are calculated. In-DTPA is cleared through both absorption and mucociliary clearance while Tc-SC is cleared only through the mucociliary route. The difference between the clearance rates of the radiopharmaceuticals provides an estimate of In-DTPA absorption rate. Our previous studies have demonstrated that absorption of In-DTPA occurs at a higher rate in central (airway dominated) lung zones of CF subjects compared to controls (42 vs. 32 %/hr, CF n= 9, control n=10, p=0.03). We believe that this increased In-DTPA absorption is being caused by the increased liquid absorption occurring in these airways, however there are other potential causes such as increase in tight junction permeability or epithelial denuding. In this study we propose to measure In-DTPA absorption after the delivery of interventions known to affect liquid absorption in the airways to see if changes in In-DTPA absorption mirror the changes in liquid absorption known to be caused by the interventions.