Airway surface microenvironment and mucociliary clearance

ASL height measured with confocal microscopy
(ASL height of human bronchial epithelium (HBE) was measured with confocal microscopy before and after addition of IL-13)

Functional imaging research (Corcoran, Garoff, Myerburg, Parker, Pilewski, Reed, Tilton, Przybycien):  The nuclear imaging technique used by Dr. Corcoran to measure mucociliary clearance (MCC) is unique in that it provides, in parallel, information on the rate of airway surface liquid absorption (termed ABS) in the lungs.  A radiolabeled small molecule probe is delivered along with the larger particle probe, and the absorption rate of the small molecule is calculated. Dr. Corcoran recently utilized this novel MCC/ABS technique to assess the effects after overnight delivery of inhaled hypertonic saline via nasal cannula and in studies on the effects of airway surface dehydration in asthma. He is currently enrolling a study comparing the efficacies of inhaled 7% hypertonic saline and inhaled mannitol using the MCC/ABS technique. The technique is also currently being used to support the collaborative epithelial systems modelling work, which is described below. The MCC/ABS techniques have been used in 7 NIH, CFF, and pharma studies since 2015. Dr. Corcoran performed 99 MCC or MCC/ABS scans involving 50 CF subjects during that period. The group recently published an analysis of factors predicting depressed mucociliary clearance in CF patients using a combined dataset assembled from their current and previous studies. This analysis revealed that colonization with P. aeruginosa was a predictor of depressed clearance while age, gender, and a previous history of Staphylococcus infections were not. They hypothesize that P. aeruginosa infection may depress MCC in the lungs contributing to the patterns of chronic infection characteristic of CF, instigating a new collaboration with Dr. Bomberger and Core C.

Assays to study the airway surface liquid (Myerburg, Frizzell, Bruchez): Historically, the airway surface liquid (ASL) was difficult to examine because of the exceeding low volume of this fluid.  Recent advances in imaging techniques have provided novel assays that have overcome these difficulties.  Investigators in The Cell and Tissue Core have developed and validated several of these assays to allow for directly measure the ASL volume, height, pH, and viscosity.  As discussed in The Assay Core, these assays and measures of ciliary function and mucus transport are routinely performed and are available to understand how the airway surface is dysregulated in CF and other inflammatory airway disease.

Systems Modeling of Airway Physiology (Corcoran, Parker, Myerburg, Pilewski): Through a collaboration between Drs. Tim Corcoran and Robert Parker (Adult Pulmonary and Chemical Engineering) the Center has developed in silico systems models of lung physiology at both the cell and organ level.  These in silico models provide a framework of differential equations that describe how basic physiological processes interact and contribute to experimental outcomes. This work recently was funded through a five-year award from NIH (U01 HL131046). These investigators will link in vitro and in vivo responses by sampling nasal cells and culturing HNEs from both non-CF and CF subjects (a painless, non-invasive procedure) and a series of physiological assessments including functional imaging scans. These in silico models will allow them to consider the interaction of multiple testing and outcome variables and better differentiate the contribution of specific physiological mechanisms to therapeutic responses at the organ/patient level.  Ultimately, we envision that nasal cell sampling and interpretation through in silico models will provide a detailed characterization of disease phenotype and a path to personalized therapeutics.  As of June, 2017, nine subjects have been enrolled.

Optimizing drug delivery (Corcoran, Garoff, Tilton, Przybycien, Pilewski): Drs. Garoff, Tilton, and Przybycien from the Departments of Physics and Biomedical Engineering at Carnegie Mellon University have continued to develop surfactant-based inhaled antibiotics that produce surface tension gradients to drive two-dimensional transport of aerosolized medications after deposition on the ASL. They considered the post-deposition spreading of individual aerosol droplets and two-dimensional expansion of a field of aerosol droplets, when deposited at low fluxes that are representative of aerosol deposition in the small airways. These colleagues used a system that mimics and adequately captures the full miscibility but slow penetration of entangled macromolecular chains of the ASL into the deposited drug. The CMU physicist’s results suggest that aerosolized surfactant formulations may provide the means to maximize deposited drug uniformly in, and provide access to, a new entire airway generation or more in peripheral airways.