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).
| 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 |
| Jacobson, David R; McIntosh, Dustin B; Stevens, Mark J et al. (2017) Single-stranded nucleic acid elasticity arises from internal electrostatic tension. Proc Natl Acad Sci U S A 114:5095-5100 |
| Ge, Ting; Kalathi, Jagannathan T; Halverson, Jonathan D et al. (2017) Nanoparticle Motion in Entangled Melts of Linear and Nonconcatenated Ring Polymers. Macromolecules 50:1749-1754 |
| Zeman, Kirby L; Balcazar, Juan Rojas; Fuller, Fred et al. (2017) A Trans-Nasal Aerosol Delivery Device for Efficient Pulmonary Deposition. J Aerosol Med Pulm Drug Deliv 30:223-229 |
Showing the most recent 10 out of 76 publications
