Document Type

Master's thesis

Date of Degree

2012

Degree Name

MS (Master of Science)

Department

Biomedical Engineering

First Advisor

David A. Stoltz

Abstract

Cystic fibrosis (CF) is an inherited disease leading to disrupted function of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. CF affects many organ systems including the pancreas, liver, intestine, sweat glands, and gallbladder. The leading cause of morbidity and mortality, however, is lung disease. A porcine model of CF was developed, and over time it develops lung disease that recapitulates many of the characteristics observed in humans with CF including airway remodeling, mucus accumulation, infection, and inflammation. At birth, and despite the absence of inflammation and infection, the CF pig airways exhibit a host of abnormalities including tracheal cartilage ring defects, abnormal appearing smooth muscle bundles, reduced trachea diameter, and reduced mainstem bronchi diameter. The primary objectives of this study were to construct an experimental method that allowed for the attainment of airway size information at multiple inflation pressures, to assess the extent of airway narrowing in the newborn CF porcine lung at 20 cmH2O, to determine the tracheal lobe volume for CF and non-CF, and to perform morphologic assessment of the parenchymal airspaces for CF and non-CF newborn pigs.

Micro-computed tomography (micro-CT) was selected as the primary analysis tool. The volumetric, high resolution data sets of micro-CT provided a means to virtually track airways through the three dimensional space of the lung, and to image airways as small as 250 microns in diameter. Due to experimental constraints, only one lobe was analyzed: the tracheal lobe; it is the porcine equivalent of the human right upper lobe. Each excised tracheal lobe was cannulated and micro-CT scanned five times. Each lobe was scanned at multiple inflation pressures ranging from 0 to 20 cmH2O. The airways were segmented with a custom designed, substantially-automated computer algorithm. Quantitative analysis of airway size was done with the Pulmonary Workstation 2 software package. At a pressure of 20 cmH2O, the CF airway narrowing was most pronounced in the large airways of the tracheal lobe, and the percent difference in airway cross sectional area between CF and non-CF lessened for airways of smaller size. The volume of the newborn CF pig tracheal lobe was approximately twenty percent smaller than non-CF, but no differences were observed in tracheal lobe airspace histology between the groups. Airway size deviations at birth imply developmental abnormalities in utero that are dependent upon CFTR function. Additionally, the observation that reduced airway caliber exists only in relatively large airways suggests a time-dependent role of CFTR on airway development, as the large airways develop before the small ones in utero. These findings may provide insight to the early pathogenesis of CF lung disease.

Pages

xiv, 151

Bibliography

126-137

Copyright

Copyright 2012 Ryan J. Adam