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.
Recommended Citation
Kurundkar, Ashish, "The Matricellular Protein Ccn1 Potentiates Fibrogenic Responses To Lung Injury" (2016). All ETDs from UAB. 2192.
https://digitalcommons.library.uab.edu/etd-collection/2192