All ETDs from UAB

Advisory Committee Chair

Victor J Thannickal

Advisory Committee Members

Joanne E Murphy-Ullrich

Amit Gaggar

Rui-Ming Liu

Yong Zhou

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Normal wound healing is a well-coordinated reparative response to injury aimed at restoring the normal tissue function. The dynamic interactions between cells and ex-tracellular matrix (ECM) regulate and dictate the fate of tissue repair process. Fibrosis is a dysregulated wound healing with excessive deposition of ECM and loss of tissue func-tion. Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic disease of lung with no cure. Matricellular proteins are non-structural matrix proteins which regulates the cellular functions by directly binding to cell surface integrins and/or indirectly modulating growth factor signaling. Matricellular proteins are emerging as critical mediators of tissue injury and repair. CCN1, a dynamically expressed matricellular protein, is an essential regulator of angiogenesis, inflammation and wound repair. In this study, we found CCN1 as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive IPF. Expression of CCN1 was significantly in-creased in lung tissues of IPF subjects undergoing lung transplantation, and was predom-inantly localized to areas of active fibrosis, that is, fibroblastic foci. CCN1 expression in ex-vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, Collagen (Col) 1a1, Col1a2, and fibronectin as well as the myofibroblast marker, α-smooth muscle actin (α-SMA). RNAi mediated knockdown of CCN1 down-regulated the constitutive expression of these pro-fibrotic genes in IPF fibroblasts. Transforming growth factor-β1 (TGF-β1), a key pro-fibrotic cytokine, induces gene and protein expression of CCN1 via a SMAD3-dependent mechanism. Notably, endogenous CCN1 potentiates TGF-β1-induced SMAD3 activation and induction of pro-fibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In-vivo RNAi-mediated silencing of CCN1 attenuates fibrogenic responses to bleomycin-induced lung injury. Overall, these studies support a hitherto unidentified, cooperative interaction between the CCN1 matricellular protein and canonical TGF-β1/SMAD3 signaling that promotes lung fibrosis. Findings of these studies will improve our understanding of pathological wound healing in IPF and aid in the development of effective therapy for IPF.

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