Multiscale Mathematical Modeling of the Absorptive and Mucociliary Pathophysiology of Cystic Fibrosis Lung Disease
Year: 2017
Type: article
Abstract: Airway disease is the primary cause of mortality for the over 70,000 patients with Cystic Fibrosis (CF) worldwide. It is characterized by lung infection, inflammation, and impaired mucociliary clearance (MCC) arising from depletion of the airway surface liquid (ASL) at the organ-scale. Dysfunction in the CF transmembrane conductance regulator protein causes dysregulation in ion and liquid transport alone and via other transport-related proteins. Analysis of cell-system interactions is experimentally complex, however, and motivates the use of mechanistic mathematical models that can also be used to design and optimize treatments for the disease. Tc99m or In111-labeled DTPA (DTPA) are small-molecule radiological probes that allow for observation of paracellular liquid convection and solute transport at cellular and organ scales, respectively. Previous work has shown that DTPA is hyperabsorbed in CF in a manner that strongly correlates with ASL hyperabsorption. The models of this dissertation describe, in part, the mechanisms that underlie this correlation. At the lung-scale, a physiologically motivated pharmacokinetic model was developed to describe the action of hypertonic saline (HS) as an inhaled therapy in CF. This model predicts that MCC is reduced in patients with CF because they have a reduced fraction of functional ciliated airway -- a model parameter -- that is increased via HS-induced airway rehydration. This prediction was verified \textit{in vitro} in human bronchial epithelial (HBE) cultures. A separate, cell-scale model accurately characterizes transcellular liquid transport in HBE cultures using transport parameters that agree well with previously reported values, producing ion flux estimates from the model fit to ASL and DTPA absorption that were similar to known physiological values. It also implicates diminished constitutive Cl¬- secretion in ASL dehydration but suggests that reduced paracellular integrity is the predominant factor leading to hyperabsorption in CF. The cell- and lung-scale models were then used to analyze treatment failure and suggest modifications of a clinical trial, which is the first indication of the utility of airway transport models in designing treatments for patients with CF.
Author: Matthew R. Markovetz
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2736921439