The PK/PD Core will provide 1) pharmacokinetic (PK) measurements of drug concentrations over time in airway surface liquid (ASL) from all three projects and 2) in-vivo pharmacodynamic (PD) measurements of mucociliary and cough clearance (MCC/CC) for the animal and human projects (Projects II and 111). 1. Pharmacokinetics. The pharmacological activities of drugs that affect mucus hydration are a reflection of their concentrations on airway surfaces. Measuring airway drug concentrations in human subjects is difficult using traditional methods. Bronchoscopic lavages suffer from variable dilutions and uncertainties about site sampled, and sputum likely reflects an abnormal secretion that originates primarily from large airway surfaces. Accordingly, we will develop mass spectrometric methods to accurately measure ASL concentrations of drugs, drug metabolites, and markers of ASL dilution that can be applied both to non-invasive airway samples such as exhaled breath condensate (EBC) and to other ASL samples obtained from all three projects. 2. Pharmacodynamics. Quantifying the response of mucociliary function to treatments targeted for chronic obstructive airways disease requires accurate, sensitive in-vivo measurements of MCC/CC for both animal and human models. Accordingly we will: a. Measure mucociliary clearance in mice by tracking tracheal velocities of fluorescently labeled beads for baseline and drug interventions that parallel those in the clinical projects. b. Measure MCC/CC in human subjects using techniques that standardize radiotracer deposition. Both baseline MCC/CC and the effects of mucolytic treatments will be assessed as described in Project 111. Measures of airways obstruction, ciliary dependent clearance (MCC), cough-dependent clearance (CC), and novel endpoints to describe heterogeneity of clearance will be made available to Project investigators. c. Engineer and produce novel particles of controlled size and shape for deposition on airway surfaces that 1) accurately track the movement of mucus from the lung and 2) permit multi-modal imaging (e.g. single photon emission computed tomography, positron emission tomography [PET], or MRI) to better delineate the degree and site of MCC abnormalities within the lungs of patients when combined with diagnostic imaging of lung structure (CT and MRI) and inflammation (PET).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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University of North Carolina Chapel Hill
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Abdullah, Lubna H; Coakley, Raymond; Webster, Megan J et al. (2018) Mucin Production and Hydration Responses to Mucopurulent Materials in Normal versus Cystic Fibrosis Airway Epithelia. Am J Respir Crit Care Med 197:481-491
Yu, Dongfang; Saini, Yogesh; Chen, Gang et al. (2018) Loss of ? Epithelial Sodium Channel Function in Meibomian Glands Produces Pseudohypoaldosteronism 1-Like Ocular Disease in Mice. Am J Pathol 188:95-110
Muhlebach, Marianne S; Hatch, Joseph E; Einarsson, Gisli G et al. (2018) Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: a multisite study. Eur Respir J 52:
Livraghi-Butrico, Alessandra; Wilkinson, Kristen J; Volmer, Allison S et al. (2018) Lung disease phenotypes caused by overexpression of combinations of ?-, ?-, and ?-subunits of the epithelial sodium channel in mouse airways. Am J Physiol Lung Cell Mol Physiol 314:L318-L331
Chen, Gang; Volmer, Allison S; Wilkinson, Kristen J et al. (2018) Role of Spdef in the Regulation of Muc5b Expression in the Airways of Naive and Mucoobstructed Mice. Am J Respir Cell Mol Biol 59:383-396
Bennett, William D; Zeman, Kirby L; Laube, Beth L et al. (2018) Homogeneity of Aerosol Deposition and Mucociliary Clearance are Improved Following Ivacaftor Treatment in Cystic Fibrosis. J Aerosol Med Pulm Drug Deliv 31:204-211
Ge, Ting; Grest, Gary S; Rubinstein, Michael (2018) Nanorheology of Entangled Polymer Melts. Phys Rev Lett 120:057801
Esther Jr, Charles R; Hill, David B; Button, Brian et al. (2017) Sialic acid-to-urea ratio as a measure of airway surface hydration. Am J Physiol Lung Cell Mol Physiol 312:L398-L404
Kesimer, Mehmet; Ford, Amina A; Ceppe, Agathe et al. (2017) Airway Mucin Concentration as a Marker of Chronic Bronchitis. N Engl J Med 377:911-922
Wagner, Caroline E; Turner, Bradley S; Rubinstein, Michael et al. (2017) A Rheological Study of the Association and Dynamics of MUC5AC Gels. Biomacromolecules 18:3654-3664

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