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BACKGROUND: Inhaled drug delivery can be limited by heterogeneous dose distribution. An additive that would disperse drug over the internal surfaces of the lung after aerosol deposition could improve dosing uniformity and increase the treated area. Our previous studies demonstrated that surfactant additives can produce surface tension-driven (Marangoni) flows that effectively dispersed aerosol-delivered drugs over mucus surfaces. Here we sought to determine whether the addition of a surfactant would increase transport of an aerosol between lung regions and also improve dosing uniformity in human lungs. METHODS: We compared the deposition and postdeposition dispersion of surfactant (10 mg/mL dipalmitoylphosphatidylcholine; DPPC) and saline-based liquid aerosols, admixed with Technetium 99m (Tc99m) diethylenetriaminepentaacetic acid, using gamma scintigraphy. Deposition images were obtained ex vivo in eight pairs of ventilated human lungs. The trachea was intubated and the mainstem bronchi were alternately clamped so that saline was delivered to one lung and then DPPC to the other (sides alternated). The lungs were continually imaged for 15 minutes during delivery. We assessed transport of the deposited aerosol by quantifying the percentage of Tc99m in each of four lung quadrants over time. We quantified dose uniformity within each lung quadrant by measuring the coefficient of variation (CV = standard deviation of the pixel associated radioactive counts/mean of the counts within each quadrant). RESULTS: There was no change in the percentage of Tc99m in each quadrant over time, indicating no improvement in transport with the addition of the surfactant. The addition of surfactant was associated with a statistically significant decrease in CV in the lower inner lung quadrant at each of the three time points, indicating an improvement in dosing uniformity. CONCLUSION: These preliminary results indicate the possible utility of adding surfactant to aerosols to improve drug distribution uniformity to lower inner lung regions.

BACKGROUND: Although mucus plugging is a well-reported feature of asthma, whether asthma and type 2 inflammation affect mucociliary clearance (MCC) is unknown. RESEARCH QUESTION: Does type 2 inflammation influence mucus clearance rates in patients with mild asthma who are not receiving corticosteroids? STUDY DESIGN AND METHODS: The clearance rates of inhaled radiolabeled particles were compared between patients with mild asthma with low (n = 17) and high (n = 18) levels of T2 inflammation. Fraction exhaled nitric oxide (Feno) was used to prospectively segregate subjects into T2 Lo (Feno < 25 ppb) and T2 Hi (Feno > 35 ppb) cohorts. Bronchial brush samples were collected with fiber-optic bronchoscopy, and quantitative polymerase chain reaction was performed to measure expression of genes associated with T2 asthma. MCC rate comparisons were also made with a historical group of healthy control subjects (HCs, n = 12). RESULTS: The T2 Lo cohort demonstrated increased MCC when compared with both T2 Hi and historic HCs. MCC within the T2 Hi group varied significantly, with some subjects having low or zero clearance. MCC decreased with increasing expression of several markers of T2 airway inflammation (CCL26, NOS2, and POSTN) and with Feno. MUC5AC and FOXJ1 expression was similar between the T2Lo and T2Hi cohorts. INTERPRETATION: Increasing T2 inflammation was associated with decreasing MCC. High rates of MCC in T2 Lo subjects may indicate a compensatory mechanism present in mild disease but lost with high levels of inflammation. Future studies are required to better understand mechanisms and whether impairments in MCC in more severe asthma drive worse clinical outcomes.

Aim: Inhaled hypertonic saline increases mucociliary clearance, improves pulmonary function, and decreases exacerbations in cystic fibrosis (CF) but contributes to the already significant treatment burden of CF. Overnight delivery of inhaled medications via a specially designed nasal cannula-aerosol device (Trans-nasal Pulmonary Aerosol Delivery [tPAD]) is an alternative approach. Here, we test whether overnight inhalation of hypertonic saline via tPAD improves mucociliary clearance and assess the tolerability of the device. Method: In this study, 12 CF subjects inhaled 7% hypertonic saline (HS) for 8 h overnight using the tPAD system. Safety and tolerability were assessed and measurements of mucociliary and absorptive clearance (MCC/ABS) were performed after the treatment. Comparisons were made versus sham treatment where the same subjects wore the nasal cannula overnight but did not receive aerosol. Results: Both the HS and sham treatments were well-tolerated. Only one subject did not complete the overnight HS treatment. There were no significant differences in MCC associated with HS inhalation at any time point (90 min, 3 h, 6 h) in any lung zone. Changes in FEV1 on both study days were similar. There were no differences in quality of sleep between HS and sham nights as assessed with the modified Leeds Sleep Evaluation Questionnaire (mLSEQ). Sino-Nasal Outcome Test (SNOT-14) questionnaires demonstrated significant increases (worsening) in 2/14 symptom categories with HS. Conclusions: The most likely cause for the failure to accelerate MCC was under-dosing of HS relative to the active transport of salt from the airways.

Airway surface liquid hyperabsorption and mucus accumulation are key elements of cystic fibrosis lung disease that can be assessed in vivo using functional imaging methods. In this study we evaluated experimental factors affecting measurements of mucociliary clearance (MCC) and small-molecule absorption (ABS) and patient factors associated with abnormal absorption and mucus clearance.Our imaging technique utilises two radiopharmaceutical probes delivered by inhalation. Measurement repeatability was assessed in 10 adult cystic fibrosis subjects. Experimental factors were assessed in 29 adult and paediatric cystic fibrosis subjects (51 scans). Patient factors were assessed in a subgroup with optimal aerosol deposition (37 scans; 24 subjects). Paediatric subjects (n=9) underwent initial and 2-year follow-up scans. Control subjects from a previously reported study are included for comparison.High rates of central aerosol deposition influenced measurements of ABS and, to a lesser extent, MCC. Depressed MCC in cystic fibrosis was only detectable in subjects with previous Pseudomonas aeruginosa infection. Cystic fibrosis subjects without P. aeruginosa had similar MCC to control subjects. Cystic fibrosis subjects had consistently higher ABS rates.We conclude that the primary experimental factor affecting MCC/ABS measurements is central deposition percentage. Depressed MCC in cystic fibrosis is associated with P. aeruginosa infection. ABS is consistently increased in cystic fibrosis.