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RADIATION INDUCED LUNG INJURY IN NON-HUMAN PRIMATES

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abstract
Radiation-induced lung injury (RILI) is a progressive disease; an early acute exudative phase occurs in about 4-13 weeks post-irradiation, followed by the proliferative phase (3-9 months). Both phases are clinically classified as radiation pneumonitis (RP). Severe injury and persistent damage may lead to a late phase of irreversible lung fibrosis (LF).The overall aim of this study was to understand the differential susceptibility to RILI in response to a single dose of 10 Gy thorax irradiation and to define the pathogenesis and molecular changes occurring at early and late phase of RILI in a controlled study of nonhuman primates (NHPs). To achieve this goal, animals were investigated longitudinally over a long time-span of up to 8 months. The work presented in this thesis involves two separate studies which utilized 17 NHPs exposed to a single dose of 10 Gy whole-thorax lung irradiation (WTLI) and compared to three non-irradiated controls. Post- WTLI exposure, animals were categorized as non-survivors, reaching a predefined clinical endpoint based on higher respiratory rates, and survivors surviving to the end of the study (8 months). In Chapter 2, our results revealed that non-survivors developed more severe RILI relative to survivors. However, irradiation induced significant lung fibrosis in both the irradiated groups (survivors and non-survivors) with an abundance of M2-like macrophages. Transcriptional profiling of lung tissues differentiated survivors, non-survivors, and controls. This work highlights new molecular targets at the mRNA and protein level. Chapter 3 was a follow-up study that expanded on longitudinal quantitative CT analysis focussed on threshold-based summary statistics obtained from whole lung CT scans. The entire segmented lungs' histograms were extracted to measure lung average density, hyper-dense lung volume (PCHV), hyper-dense lung volume as a percent of entire lung volume (PCHV/TV). All three density parameters showed a significant increase in lung injury in non-survivors relative to survivors. However, PCHV was the most sensitive parameter that detected a significant increase in radiodense volume, at time points when differences were not detected by the other two parameters. In conclusion, our studies provide strong clinical and molecular data that provide valuable insight into the evolution of RILI to fibrosis in a NHP model.
subject
CT scans
lung fibrosis
macrophages
radiation pneumonitis
Radiation-induced lung injury
RNA sequencing
contributor
THAKUR, PRIYANKA (author)
Cline, J. Mark JMC (committee chair)
Brown, Doris R (committee member)
Furdui, Cristina M (committee member)
Jackson, Isabel L (committee member)
Howard, Timothy (committee member)
date
2021-06-03T08:36:05Z (accessioned)
2021-06-03T08:36:05Z (available)
2021 (issued)
degree
Molecular Medicine and Translational Science (discipline)
identifier
http://hdl.handle.net/10339/98796 (uri)
language
en (iso)
publisher
Wake Forest University
title
RADIATION INDUCED LUNG INJURY IN NON-HUMAN PRIMATES
type
Dissertation

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