Lung transplant (LT) is an option for advanced lung diseases; unfortunately, due to post-transplant complications, both infections and non-infections (i.e., rejections), which leads to chronic lung allograft dysfunction (CLAD) it is only a treatment and not a cure. The hallmark of CLAD is the displacement of normal epithelium by a relentless deposition of extracellular matrix. Currently, there are no effective therapies for the prevention or treatment of CLAD. This proposal will use both a novel mouse orthotopic-transplant-with-regrafting to model the pathobiology of CLAD and human translational studies to evaluate mechanisms that lead to epithelial progenitor cell (EPC) loss and fibrogenesis during CLAD. We have previously shown that a type 1/17 inflammatory environment promotes acute rejection (AR), while the type 2 fibroproliferative environment supports the development of fibrosis in CLAD. Our preliminary data suggests that loss of epithelial progenitor cell reserves (EPCR) leads to fibroplasia and CLAD. Additionally, we propose that IL-22, in part through a p53-dependent pathway, functions differently at different stages post-transplantation. During the early stages of allograft injury, IL-22 is beneficial by promoting EPCR expansion. However, later on, IL-22 influences fibroblasts thereby stimulating the development of fibrosis in CLAD. The consequence of IL-22 upon the lung allograft depends on the cell type on which its receptor is expressed. During the inflammatory type 1/17 phase, the EPCR expresses the heterodimeric IL-22 receptor (IL-22R1 and IL-10R2), while fibroblasts do not. Thus, during early injury stages post-LT, IL-22 mediates downregulation of p53 signaling just in epithelial cells, thereby allowing progenitor cells to proliferate and regenerate the lung epithelium. Conversely, when continued insults to the lung allograft leads to a fibroproliferative type 2 environment, the IL-22 receptor expression is induced on fibroblasts and reduced on EPCR. Thus, at this later stage, IL-22 interacts preferentially with its receptor on fibroblasts, skewing them towards an invasive, fibrotic phenotype resulting in CLAD. Our preliminary pre-clinical data in murine models suggest that manipulating IL-22 and p53 can affect the outcome of CLAD, either protective via promotion of EPC regeneration or harmful via promotion of fibroplasia. Moreover, we will insure the relevance of these pathways in humans using lung transplant (LT) recipients biological samples that include BALF protein and cultured fibroblasts as well as brushing of the allograft airway epithelial cells.

Public Health Relevance

Lung transplant (LT) is an option for advanced lung diseases; unfortunately, due to the complications after the lung transplant, both infections and non-infections (i.e., rejections) it is only a treatment and not a cure. Based on our preliminary data we believe this proposal will demonstrate that IL-22, in part, through a p53 dependent pathway has a dual function: 1) protective - in an acute inflammatory environment were an epithelial progenitor cell reserve (EPCR) is present and expressing the IL-22 receptor allowing IL-22 to expand the epithelium and preventing chronic lung allograft dysfunction (CLAD); 2) detrimental - in a late fibroproliferative environment were the EPCR is exhausted and the IL-22 receptor is induced in fibroblasts allows IL-22 to stimulate an invasive fibroblast phenotype eventually leading to CLAD. Thus, this proposal will lead to a clinical trial for the prevention and treatment of CLAD by altering specific parts of these pathways post lung transplantation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Craig, Matt
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cedars-Sinai Medical Center
Los Angeles
United States
Zip Code
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

Showing the most recent 10 out of 23 publications