Airway remodeling in asthma is a process of structural changes occurring in the airway over time resulting in a component of fixed airway obstruction. The clinical ramifications are significant, in that remodeling can lead to reduced lung function and reduced responsiveness to medications. The mechanisms whereby endogenous mediators of immune responses in asthma lead to the subsequent host response of airway remodeling are poorly understood. We have shown that interleukin (IL)-13, a TH2 cytokine critical to the asthma phenotype, directs several critical and understudied remodeling processes in asthma including airway fibroblast growth and matrix production. We have recently demonstrated that IL-13 also increases the production of hyaluronan (HA), a matrix glycosaminoglycan that is a normal constituent of basement membrane and makes up 10% of the proteoglycan content in the lung. HA can accumulate in the lung via activation of hyaluronan sythases (HAS) by mediators common in asthma, including tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-B). Low molecular weight (LMW) fragments (<500 kDa), but not the native form (> 1000 kDa) of HA can signal via CD44, TLR2 and TLR4 to elicit inflammatory responses and further lung injury. IL-13 also directs airway remodeling through the production and activation of two key groups of mediators, transforming growth factor-beta (TGF-B) and members of the matrix metalloproteinase (MMP) family. We present the exciting observation that IL-13 not only modulates matrix expression in the lung, but in combination with HA also plays a role in transforming the airway fibroblast to an invasive phenotype. We hypothesize that IL-13 is a critical regulator of remodeling that results in alteration in the airway matrix component hyaluronan that modulates the airway fibroblast to produce an invasive phenotype that contributes to remodeling and airway obstruction. To test this hypothesis, we will determine that in mouse and man, IL-13 augments HA production in asthma, is integral for the remodeling phenotype and elicits a robust inflammatory response in airway macrophages (aim 1).
In aim 2, we will demonstrate that IL-13, in combination with HA, produces an invasive fibroblast phenotype in asthma that is responsible for augmented matrix production and associated with a unique gene signature.
In aim 3, we will determine that infectious and non-infectious insults induce LMW HA production by the airway epithelial cell in asthma capable of signaling via TLR2 and TLR4. Thus, accumulation of HA via IL-13,particulariy low molecular weight fragments, in the asthmatic airway due to tissue injury can elicit and perpetuate the inflammatory response.
This project is an integral part of the global goal of this program, which is how production of endogenous matrix components in the context of lung injury drives unremitting lung inflammation and flbrosis by interacting with cognate receptors leading to the development of an invasive pro-flbrotic flbroblast phenotype and perpetuation of remodeling. Project 3 will interface closely with Project 1 (Dr. Noble), as these concepts will be investigated in human and animal models of disease. Project 3 will also interface closely with Project 2 (Dr. Wright) to determine the role of innate immunity, particularly surfactant protein A, in this process.
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|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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