Recently, imbalance in angiogenesis, dysregulation of the extra cellular matrix and fibroproliferation rather than inflammation has been postulated to perpetuate lung fibrosis in IPF. Detection of alveolitis may therefore have little prognostic or pathogenic relevance in the assessment of these cases. The heterogeneous pathology of UIP results in BAL and trans-bronchial biopsy (TBBx) to be subject to sampling errors compounding attempts to elucidate pathogenic pathways. A noninvasive mechanism to provide a """"""""morphometric"""""""" assessment of the whole lung on a global and regional basis would be ideal. Quantitative Image Analysis (QIA) of HRCT data has shown a correlation with inflammation, angiogenesis and fibrosis and can identify these independent manifestations of IPF on a global and regional basis not possible with bronchoscopy or visual inspection of HRCT. The hypothesis is: CT-QIA can better detect the presence, extent and progression of inflammation, angiogenesis and fibrosis in patients with ILD and so can be used to distinguish patients with UIP, DIP, NSIP or NSIP with fibrosis not possible with conventional clinical, radiographic and physiologic assessment or with sampling limited BAL and TBBx.
The specific aims are to 1) develop a CT-QIA model of pulmonary fibrosis in a murine model capable of assessing the development and progression of pulmonary fibrosis 2) develop a CT-QIA model of IPF capable of distinguishing inflammation, angiogenesis and fibrosis to better characterize patients with clinically diagnosed ILD with respect to pathologically defined UIP, DIP, NSIP and NSIP with fibrosis and 3) to determine the relative progression of inflammation, angiogenesis and fibrosis in patients with clinically assessed IPF treated with Prednisone alone, or IFN-gamma and low-dose prednisone or azathioprine plus prednisone. The main objective of this project is to distinguish between angiogenesis, inflammation and fibrosis in the pathogenesis of IPF in order to better characterize their relationship to the pathogenesis of IPF and to distinguish patients with UIP, DIP, NSIP or NSIP with fibrosis not possible with conventional techniques.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL067665-01
Application #
6506792
Study Section
Special Emphasis Panel (ZHL1)
Project Start
2001-09-05
Project End
2006-07-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2001
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Belperio, John A; Keane, Michael P; Lynch 3rd, Joseph P et al. (2006) The role of cytokines during the pathogenesis of ventilator-associated and ventilator-induced lung injury. Semin Respir Crit Care Med 27:350-64
Belperio, John A; Keane, Michael P; Burdick, Marie D et al. (2005) Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome. J Clin Invest 115:1150-62
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Strieter, Robert M; Belperio, John A; Phillips, Roderick J et al. (2004) Chemokines: angiogenesis and metastases in lung cancer. Novartis Found Symp 256:173-84; discussion 184-8, 259-6
Ma, Bing; Zhu, Zhou; Homer, Robert J et al. (2004) The C10/CCL6 chemokine and CCR1 play critical roles in the pathogenesis of IL-13-induced inflammation and remodeling. J Immunol 172:1872-81
Kao, John; Kobashigawa, Jon; Fishbein, Michael C et al. (2003) Elevated serum levels of the CXCR3 chemokine ITAC are associated with the development of transplant coronary artery disease. Circulation 107:1958-61
Phillips, Roderick J; Burdick, Marie D; Lutz, Marin et al. (2003) The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am J Respir Crit Care Med 167:1676-86
Strieter, Robert M; Belperio, John A; Keane, Michael P (2003) Host innate defenses in the lung: the role of cytokines. Curr Opin Infect Dis 16:193-8
Strieter, Robert M; Belperio, John A; Keane, Michael P (2003) CXC chemokines in vascular remodeling related to pulmonary fibrosis. Am J Respir Cell Mol Biol 29:S67-9
Belperio, John A; Keane, Michael P; Burdick, Marie D et al. (2003) Role of CXCL9/CXCR3 chemokine biology during pathogenesis of acute lung allograft rejection. J Immunol 171:4844-52

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