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Multiscale Mathematical Modeling of the Absorptive and Mucociliary Pathophysiology of Cystic Fibrosis Lung Disease

Markovetz, Matthew (2017) Multiscale Mathematical Modeling of the Absorptive and Mucociliary Pathophysiology of Cystic Fibrosis Lung Disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Markovetz, Matthewmrm163@pitt.edumrm1630000-0003-3931-0594
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairParker, Robertrparker@pitt.edurparker
Committee CoChairCorcoran, Timothycorcorante@upmc.educorcorante
Committee MemberBertrand, Carolcbertra@pitt.educbertra
Committee MemberShoemaker,
Committee MemberMyerburg, Michaelmyerburgm@upmc.edumyerburgm
Committee MemberBodnar,
Date: 14 June 2017
Date Type: Publication
Defense Date: 13 December 2016
Approval Date: 14 June 2017
Submission Date: 14 March 2017
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 162
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Chemical Engineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Cystic Fibrosis, Mathematical Modeling, Epithelial Transport, Mucociliary Clearance, Airway Surface Liquid Absorption
Date Deposited: 14 Jun 2017 17:44
Last Modified: 14 Jun 2017 17:44


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