The molecular mechanisms that control tissue remodeling remain incompletely understood. This program has focused on elucidating the role of extracellular matrix in regulating lung inflammation and fibrosis. A critical unanswered question in the pathobiology of chronic lung diseases is what are the determinants of disease progression and irreversible loss of function. Persistent lung inflammation and fibrosis is a cause of major morbidity and mortality whether it occurs in the airways as in chronic asthma or in the interstitium as in idiopathic interstitial pneumonias such an idiopathic pulmonary fibrosis (IPF). We have generated a body of work that has identified the glycosaminoglycan hyaluronan (HA) and its cognate receptors as having important roles in regulating lung inflammation and fibrosis in the context of noninfectious lung injury. HA is an unusual macromolecule in that it is synthesized at the cell membrane and extruded into the extracellular milieu and becomes fragmented during inflammation. Work from our laboratory over the last 17 years has identified distinct functions for HA in noninfectious lung injury depending on both the cellular context of its expression and the form in which it is presented to interacting cells. HA is modified in the context of lung inflammation and breakdown products accumulate that promote inflammation. We have also discovered that HA expressed on the cell surface of lung epithelial cells serves a protective function against noninfectious insults. In contrast, when myofibroblasts are directed to over-express hyaluronan synthase 2 (HAS2),.the result is a severe and progressive fibrodestructive lung disease after injury that causes significant mortality. One of the pathologic hallmarks of IPF is the destruction of basement membrane at the alveolar-endothelial interface and we began to investigate whether fibroblast invasion of matrix could be an important feature of unremitting fibrosis. We have made the exciting observation that fibroblasts isolated from transgenic mice that over-express HAS2 under the direction of the D-smooth muscle actin promoter have an invasive phenotype relative to transgene negative control fibroblasts. We have also developed the first model of targeted deletion of HAS2 in mesenchymal cells and found that the development of fibrosis following lung injury is impaired. In addition, we have found a marked accumulation of HA in lung tissue using a novel chronic model of asthma in mice that causes airway fibrosis. Collectively, this system offers unique approaches to dissect the mechanisms that control persistent fibrosis in two distinct model systems. Furthermore, we have also found that fibroblasts isolated from patients that have severe idiopathic pulmonary fibrosis and chronic asthma demonstrate an invasive phenotype. Based on these data from novel mouse models as well as human diseases we have generated the hypothesis that persistent inflammation and unremitting fibrosis is driven by both the accumulation of HA fragments and the development of an invasive fibroblast phenotype that requires hyaluronan synthase 2 and HA binding proteins such as CD44. We will test this hypothesis in the following Aims:
Specific Aim 1. Determine the mechanisms by which over-expression of hyaluronan synthase 2 (HAS2) and CD44 regulate severe lung fibrosis and the development of an invasive fibroblast phenotype.
Specific Aim 2. Determine the roles of hyaluronan synthase 2 (HAS2) and CD44 in regulating the asthma phenotype and progressive airway remodeling in a chronic model of mouse asthma using mice with targeted over-expression of HAS2 in myofibroblasts and deletion of HAS2 in lung epithelial and mesenchymal cells.
Specific Aim 3. Determine the role of HAS2 and CD44 in regulating the invasive fibroblast phenotype in patients with IPF.

Public Health Relevance

This project (Project 1) is an integral part of the global goal of this program to study the role of endogenous matrix components in driving unremitting lung inflammation and fitirosis by interacting with cognate receptors leading to the development of an invasive fibroblast phenotype. Project 1 will interface closely with Project 2 (Dr. Wright), as these concepts will be investigated in the context of surfactant deficiency. Project 1 will also interface closely with Project 3 (Dr. Kraft) to determine the roles of hyaluronan and its receptors in the pathobiology of asthma in mouse and man.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
4P01HL108793-05
Application #
9111933
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Liang, Jiurong; Liu, Ningshan; Liu, Xue et al. (2018) MK2 Inhibition Attenuates Fibroblast Invasion and Severe Lung Fibrosis. Am J Respir Cell Mol Biol :
Xie, Ting; Wang, Yizhou; Deng, Nan et al. (2018) Single-Cell Deconvolution of Fibroblast Heterogeneity in Mouse Pulmonary Fibrosis. Cell Rep 22:3625-3640
Xie, Ting; Liang, Jiurong; Geng, Yan et al. (2017) MicroRNA-29c Prevents Pulmonary Fibrosis by Regulating Epithelial Cell Renewal and Apoptosis. Am J Respir Cell Mol Biol 57:721-732
Liang, Jiurong; Zhang, Yanli; Xie, Ting et al. (2016) Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice. Nat Med 22:1285-1293
Yu, Yen-Rei A; Hotten, Danielle F; Malakhau, Yuryi et al. (2016) Flow Cytometric Analysis of Myeloid Cells in Human Blood, Bronchoalveolar Lavage, and Lung Tissues. Am J Respir Cell Mol Biol 54:13-24
Li, Yuejuan; Liang, Jiurong; Yang, Ting et al. (2016) Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis. Matrix Biol 55:35-48
Xu, Yan; Mizuno, Takako; Sridharan, Anusha et al. (2016) Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. JCI Insight 1:e90558
Liang, Jiurong; Jiang, Dianhua; Noble, Paul W (2016) Hyaluronan as a therapeutic target in human diseases. Adv Drug Deliv Rev 97:186-203
Xie, Ting; Liang, Jiurong; Liu, Ningshan et al. (2016) Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis. J Clin Invest 126:3063-79
Dong, Yingying; Geng, Yan; Li, Lian et al. (2015) Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice. J Exp Med 212:235-52

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