Idiopathic pulmonary fibrosis (IPF) is a devastating disease with less than a 50% five-year survival. Thus novel therapeutic strategies are cleariv needed. A developing paradigm views pulmonary fibrosis as an """"""""IFNgamma deficiency disorder"""""""" the therapeutic replacement of IFNgamma has shown promise in preliminary clinical trials. In the current study we will investigate the capacity of the potent type 1 cytokine interleukin 7 (IL-7) to limit pulmonary fibrosis by both IFNgamma-dependent and independent pathways. In marked contrast to the current forms of therapy for IPF, IL-7 potently enhances cell-mediated immunity. In addition to its capacity to induce IFNgamma, IL-7 downregulates both TGF-beta production and TGF-P signaling in pulmonary fibroblasts. In this 1 proposal we hypothesize that IL-7 can augment antifibrotic responses by: 1) stimulating IFNgamma production, 2) downregulating fibroblast TGF-beta synthesis and TGF-beta signaling and. 3) promoting epithelial survival by induction of cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production. Our preliminarv studies indicate that IL-7 potently upregulates IFNgamma, downregulates both TGF-beta production and signaling and significantly inhibits bleomycin-induced pulmonary fibrosis in vivo. The specific alms are: 1) To assess the determinants of the IL-7-mediated anti-fibrotic response in in vivo models of pulmonary fibrosis. 2) To assess the efficacy and mechanisms of IL-7-mediated inhibition of human fibroblast TGF-beta production and signaling. 3) The longitudinal variation of expression of COX-2 and PGE2 in IPF patients will be correlated with clinical parameters of therapeutic response during IFNgamma therapy. Although IL7 shares several biological effects with IFNgamma, its capacity to induce endogenous IFNgamma production in vivo contrasts with the effect of administration of recombinant IFNgamma. These activities, together with the capacity to promote epithelial cell survival, make IL-7 a compelling cytokine for investigation in IPF. The development of pathogenesis-based. biological therapy for IPF offers an entirely new avenue for translational investigation that will lead to new therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL067665-01
Application #
6506812
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
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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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