Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease characterized by fibroblast proliferation and extracellular matrix deposition leading to irreversible destruction of lung architecture. Anti-inflammatory approaches to treating IPF are unsuccessful in most instances leading to a shift in the paradigm of pathogenesis from that of chronic inflammation to a dissociation between the inflammatory response and unrelenting tissue fibrosis. The pathogenic mechanisms in IPF are unknown and one hypothesis to explain the episodic nature of deterioration in patients with IPF is that an abnormal host response to injury exists in a susceptible host resulting in an exaggerated fibrotic response to a routine lung injury. One of the limitations in elucidating pathogenic mechanisms in progressive fibrosis is the lack of model systems to investigate unremitting fibrosis. We have identified a genetic deficiency in mice that leads to progressive fibrosis in the absence of increased lung inflammation following acute non-infectious lung injury. Mice deficient in CXCR3, the receptor for the interferon-gamma inducible CXC chemokines CXC9, 10 and 11 (Mig, IP-10 and ITAC) develop severe and progressive fibrosis after lung injury. This observation has led us to the hypothesis that an important component of progressive pulmonary fibrosis is a failure of endogenous host defense mechanisms to limit the extent of tissue remodeling. Our preliminary data suggest that interferon-gamma is produced as an early response to lung injury and requires the presence of CXCR3. We have identified CXCR3 as an important regulator of both the innate response to lung injury and the subsequent fibroproliferative response. The goals of this proposal are to elucidate the mechanisms leading to unremitting fibrosis in CXCR3 deficiency and identify the mechanisms of the protective effect of interferon-gamma on the fibroproliferative response to lung injury. Identifying mechanisms of progressive fibrosis and failures in host defense could lead to new therapeutic options in patients with IPF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077291-04
Application #
7186704
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Reynolds, Herbert Y
Project Start
2006-09-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$369,395
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Noble, Paul W; Barkauskas, Christina E; Jiang, Dianhua (2012) Pulmonary fibrosis: patterns and perpetrators. J Clin Invest 122:2756-62
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
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
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
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
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
Martinu, Tereza; Kinnier, Christine V; Gowdy, Kymberly M et al. (2011) Innate immune activation potentiates alloimmune lung disease independent of chemokine (C-X-C motif) receptor 3. J Heart Lung Transplant 30:717-25
Liang, Jiurong; Jiang, Dianhua; Jung, Yoosun et al. (2011) Role of hyaluronan and hyaluronan-binding proteins in human 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

Showing the most recent 10 out of 17 publications