Date of Award

Spring 4-3-2023

Embargo Period

6-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

Additional Department

Medicine

College

College of Graduate Studies

Additional College

College of Medicine

First Advisor

Carol Feghali-Bostwick

Second Advisor

Amy Bradshaw

Third Advisor

Jeffrey Jones

Fourth Advisor

Steven Rosenzweig

Fifth Advisor

Don Rockey

Abstract

Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune disorder that affects the connective tissues and has the highest mortality rate among the rheumatic diseases. One of the hallmarks of SSc is fibrosis, which may develop systemically, affecting the skin and virtually any visceral organ in the body. Fibrosis of the lungs leads to interstitial lung disease (ILD), which is currently the leading cause of death in SSc. The identification of effective treatments to stop or reverse lung fibrosis has been the main challenge in reducing SSc mortality and improving patient outcomes and quality of life. Currently, only two drugs are approved by the Food and Drug Administration (FDA) for SSc, but these merely reduce progression of ILD rather than stop or reverse it. Thus, there is a need to investigate novel molecular pathways involved in fibrosis, especially lung fibrosis in the context of SSc, to find potential therapeutic treatments.

The presented thesis describes two novel mechanisms that are interrelated and implicated in SSc lung fibrosis. The 1st identifies Cathepsin L (CTSL) as a protein protective against lung fibrosis, whose expression and secretion into the extracellular milieu is suppressed in SSc lung tissue and fibroblasts. Cathepsin L is the main enzyme that cleaves endostatin from the c-terminus of Collagen XVIII, activating its potent antifibrotic activity. We further show that reduced secretion of CTSL is partly due to its packaging into extracellular vesicles (EVs) in its inactive form. This finding prompted us to explore another mechanism of lung fibrosis that hasn’t been thoroughly studied, investigating the role of EVs in the progressive nature of SSc-related lung fibrosis. While most SSc research has focused on the pathology of the fibrosis itself, the mechanism mediating the fibrotic spread remains unclear. Our findings show that EVs from experimentally activated or SSc fibroblasts and lung tissues carry an active fibrotic cargo capable of transmitting a potent fibrotic response to healthy fibroblasts in-vitro, human lung tissue ex-vivo, and mice lungs in-vivo. Moreover, reducing EV release systemically ameliorated the lung fibrosis in-vivo. We thus show that EVs play a crucial role in the spread of lung fibrosis in SSc.

In conclusion, our findings suggest that identifying therapies to boost CTSL endogenous levels in SSc patients, or suppress EV release, activity, and/or fibrotic cargo, could serve as viable therapeutic strategies to halt lung fibrosis and its progression, improving SSc mortality.

Rights

Copyright is held by the author. All rights reserved.

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