The mechanisms that regulate unrelenting pulmonary fibrosis are incompletely understood. Pulmonary fibrosis can occur in patients with chronic inflammatory diseases such as those associated with connective tissue diseases such as scleroderma, rheumatoid arthritis and polymyositis. Pulmonary fibrosis also occurs in diseases that are not characterized by the same degree of interstitial inflammation such as idiopathic pulmonary fibrosis. We have a identified a novel model system that appears to have a unique role in regulating the lung response to acute non-infectious injury as well as the subsequent inflammatory and fibroproliferative responses. Our preliminary studies have provided evidence that CXCR3 and the cognate chemokine ligand CXCL10 regulates three fundamental aspects of lung injury, inflammation and fibroproliferation: epithelial repair, development of profibrotic alternatively activated (M2) macrophages, and trafficking of fibroblasts to the lung. CXCR3 null mice suffer from progressive fibrosis after acute lung injury. Mice that overexpress CXCL10 in the lung are remarkably resistant to acute lung injury. We propose to determine the mechanisms by which the CXCL10-CXCR3 axis regulates lung repair, inflammation and fibrosis following lung injury in the following specific aims: 1. Determine the mechanisms by which the CXCL10/CXCR3 axis stimulates lung repair following non- infectious lung injury by the recruitment and expansion of progenitor epithelial cells. 2. Characterize the mechanisms by which CXCL10 regulates fibroblast recruitment to the lung through interactions with the proteoglycan syndecan-4. 3. Investigate the mechanisms by which CXCL10-CXCR3 interactions inhibit fibrogenesis by regulating the development of the alternatively activated macrophage phenotype.

Public Health Relevance

This is a competitive renewal of a proposal that focuses on the role of the chemokine CXCL12 and its cognate receptor CXCR3 in the pathobiology of lung injury, inflammation and fibrosis. We have found that CXCL10 and CXCR3 are critical regulators of lung injury and repair in response to non-infectious lung injury through effects on lung epithelial cell repair, fibroblast recruitment to the lung and the development of alternatively activated macrophages. Understanding the roles of the CXCL10/CXCR3 axis in the pathobiology of lung injury and repair could lead to new therapies for progressive pulmonary fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077291-08
Application #
8268397
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Gail, Dorothy
Project Start
2004-07-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$388,575
Indirect Cost
$141,075
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Liang, Jiurong; Jung, Yoosun; Tighe, Robert M et al. (2012) A macrophage subpopulation recruited by CC chemokine ligand-2 clears apoptotic cells in noninfectious lung injury. Am J Physiol Lung Cell Mol Physiol 302:L933-40
Xie, Ting; Liang, Jiurong; Liu, Ningshan et al. (2012) MicroRNA-127 inhibits lung inflammation by targeting IgG Fc? receptor I. J Immunol 188:2437-44
Jiang, Dianhua; Liang, Jiurong; Guo, Rishu et al. (2012) Long-term exposure of chemokine CXCL10 causes bronchiolitis-like inflammation. Am J Respir Cell Mol Biol 46:592-8
Lin, Rui; Degan, Simone; Theriot, Barbara S et al. (2012) Chronic treatment in vivo with ýý-adrenoceptor agonists induces dysfunction of airway ýý(2) -adrenoceptors and exacerbates lung inflammation in mice. Br J Pharmacol 165:2365-77
Li, Yuejuan; Jiang, Dianhua; Liang, Jiurong et al. (2011) Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44. J Exp Med 208:1459-71
Lovgren, Alysia Kern; Kovacs, Jeffrey J; Xie, Ting et al. (2011) ýý-arrestin deficiency protects against pulmonary fibrosis in mice and prevents fibroblast invasion of extracellular matrix. Sci Transl Med 3:74ra23
Tighe, Robert M; Li, Zhuowei; Potts, Erin N et al. (2011) Ozone inhalation promotes CX3CR1-dependent maturation of resident lung macrophages that limit oxidative stress and inflammation. J Immunol 187:4800-8
Liang, Jiurong; Jiang, Dianhua; Jung, Yoosun et al. (2011) Role of hyaluronan and hyaluronan-binding proteins inýýhuman asthma. J Allergy Clin Immunol 128:403-411.e3
Tighe, Robert M; Liang, Jiurong; Liu, Ningshan et al. (2011) Recruited exudative macrophages selectively produce CXCL10 after noninfectious lung injury. Am J Respir Cell Mol Biol 45:781-8
Xie, Ting; Liang, Jiurong; Guo, Rishu et al. (2011) Comprehensive microRNA analysis in bleomycin-induced pulmonary fibrosis identifies multiple sites of molecular regulation. Physiol Genomics 43:479-87

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