RESUMO
BACKGROUND: Airway liquid hyper-absorption is a key pathophysiological link between the genetic mutations of cystic fibrosis (CF) and the development of lung disease. Here we consider whether the clearance of radiolabeled diethylene triamine pentaacetic acid (DTPA) might be used to detect changes in airway liquid absorption. METHODS: Tc99m-DTPA was added to the apical (luminal) surface of primary human bronchial epithelial cell cultures from CF and non-CF lungs. Liquid absorption rates were assessed using an optical method and compared to DTPA absorption rates. Measurements of transepithelial electrical resistance (TER) were made to determine the effect of epithelial permeability. DTPA absorption was assessed after stimuli known to influence liquid absorption (volume addition and osmotic gradients) and in cultures containing different proportions of CF and non-CF cells. RESULTS: DTPA absorption rate was increased in CF cultures matching previous in vivo studies in individuals with CF. DTPA and liquid absorption rates were proportional. There was no relationship between TER and DTPA absorption rate when measured in individual cultures. Apical volume addition increased both DTPA and liquid absorption rates. DTPA absorption increased in a dose-dependent manner after basolateral mannitol addition was used to create transepithelial osmotic gradients favoring liquid absorption. Conversely, apical mannitol (a candidate therapy) slowed DTPA absorption in CF cultures. CONCLUSIONS: These results imply that DTPA absorption is directly related to liquid absorption, consistent with increased rates of airway surface liquid absorption in the CF airway, and that modification of liquid absorption from osmotic therapies might be detectable through DTPA absorption measurements in vivo. TRIAL REGISTRATION: none.
RESUMO
BACKGROUND: Aerodynamic forces provide the primary means of distributing aerosol medications within the lungs. Partial airway obstructions can limit both air flow and aerosol penetration into diseased zones. We hypothesize that low surface tension additives may help to disperse aerosol medications after deposition in the airways, improving dose uniformity and drug delivery to underventilated regions. To test this, we performed a pilot scintigraphy study of surfactant and saline deposition and postdeposition dispersion. METHODS: Because inhaled antibiotics for cystic fibrosis provide an example of where self-dispersing medications may be useful, we administered calfactant and saline aerosols with added Technetium 99m sulfur colloid (Tc-SC; 100 nm filtered) on different days in randomized order to eight cystic fibrosis (CF) subjects (average FEV(1)%, p=85 ± 12%). Nebulized delivery was matched (similar aerosol sizes and volume delivery rates, fixed breathing patterns). Tc-SC distribution in the lungs was imaged continuously for 30 min after delivery. RESULTS: Both aerosols were well tolerated. Aerosol distribution was mostly peripheral (58/42%) and initially similar for saline and surfactant. Changes in whole lung counts after 30 min were also similar. Peripheral lung activity decreased more rapidly on average with calfactant though the difference versus saline was not statistically significant. Central to peripheral count ratio decreased with saline and increased with calfactant and c/p changes approached significance (-0.05 ± 0.16 vs. 0.10 ± 0.10; p=0.07 Wilcoxon). CONCLUSIONS: Our results lack statistical significance, but suggest that inhaled calfactant increased peripheral clearance, due to either surfactant-based dispersion or mucociliary effects. Further studies are needed to define the potential for low surface tension carriers to improve drug delivery.
