Abstract

The sequences of events in fibrosis are similar to those in wound healing; however, the normal termination and resolution stages do not take place. The initial cellular response following ionizing radiation involves accumulation of the ECM (extracellular matrix) including collagen, fibronectin and the interaction of many growth factors (cytokines) with their receptors. There are a number of unanswered questions regarding many aspects of radiation-induced fibrosis, including the initial triggers and physical changes that initiate the process. We have confirmed that elevated pKC and other cellular changes following radiation are similar to those found at sites of inflammation. This information leads us to the following hypothesis. We hypothesized that radiation-induced fibrosis was, in part, a result of altered signal transduction which directly modulates integrin expression and may indirectly an effect ECM elaboration. Our objective was to determine whether the increase in pKC post-radiation, leads to an alteration in integrin expression, which may contribute to fibrosis. To test our goal, we used thyroid tissue from Lewis rats.

We measured an accumulation of ECM in the thyroid tissue, which was coincident with a loss of tissue organization and follicularization. There were increased levels of several pKC isoforms post-irradiation, which coincided with modulation of integrin expression. Levels of fibronectin, laminin and collagen proteins were also altered. In vitro modulation of thyroid cultures supported the direct role of pKC in these altered properties.

The animals were proton irradiated in the neck region with a therapeutic dose of 40Gy delivered either as 5Gy per day (8 days) and 10Gy per day (4 days) fractions. The animals were sacrificed 11 weeks post-radiation and thyroid tissue was extracted. We performed H&E staining to document changes in the thyroid tissue pre- and post-irradiation. To visualize ECM accumulation, especially collagen, we performed trichrome staining. Immunohistochemistry was performed to quantify the levels of several isoforms of pKC, integrins, and ECM proteins fibronectin, pan collagen and laminin. Collectively the results document that pKC contributes to alteration of key players in thyroid tissue structures following radiation-induced fibrotic changes.

LLU Discipline

Microbiology and Molecular Genetics

School

Graduate Studies

First Advisor

Lora M. Green

Second Advisor

Daila S. Gridley

Third Advisor

Mark S. Johnson

Fourth Advisor

James M. Slater

Fifth Advisor

Thomas A. Linkhart

Sixth Advisor

John Archambeau

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2007

Date (Title Page)

5-2007

Language

English

Library of Congress/MESH Subject Headings

Radiotherapy -- adverse affects; Fibrosis; Extracellular Matrix -- radiation effects; Protein Kinase C -- radiation effects; Thyroid Neoplasm -- radiotherapy.

Type

Dissertation

Page Count

xv; 128

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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