The interstitial lung diseases are comprised of a large collection of heterogenous pulmonary disorders having in common an initial phase of inflammation followed by a phase of exuberant fibrosis. The inexorable fibrosis is paralleled by a course of relentless respiratory insufficiency. As a group, treatment of patients with these disorders have been largely disappointing. Alveolar macrophages play a vital role in idiopathic pulmonary fibrosis by secreting growth factors that are essential for fibroblast proliferation and activation. Of the many growth factors expressed by macrophages, insulin-like growth factor-I (IGF-1) has been strongly linked to the pathogenesis and progression of pulmonary fibrosis by stimulating fibroblasts to proliferate and to synthesize collagen. Previous work from this laboratory has shown that the expression of IGF-I is augmented by TNFalpha and is dramatically inhibited by IFNgamma at the transcriptional level in murine macrophages. The overall goal of this proposal is to determine the mechanism by which these two critical processes occur. Based on previous findings that TNFalpha is known to activate both the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) and c-Jun kinase/stress-activated protein kinase (JNK/SAPK) signal transduction pathways (which can activate c-Fos and c-Jun, respectively) and that the IGF-I promoter contains a recognition site for the AP- I transcription factor (composed of either a homodimer of c-Jun or a heterodimer of c-Jun-c-Fos), we propose to test the hypothesis that the increased expression of IGF-I in response to TNFalpha is mediated by the joint activation of the MAPK/ERK and JNK/SAPK pathways which then enhance transcription of the IGF-I gene by the formation of the AP-1 transcription factor. Based on previous reports that the down-regulation of IGF-I expression by IFNY is not due to IGF-I MRNA instability but rather a process that requires active protein synthesis, we propose to test the hypothesis that IFNY silences IGF-I expression by inducing and/or activating repressor protein(s), the trans acting factor, that binds to the 5'-flanking region of the IGF-I gene, the cis-acting element. Based on the first hypothesis that the transcriptional enhancer complex AP- I is critical in IGF-I synthesis, we will test the hypothesis that components of AP-1, c-jun and c-Fos, will be found in increased abundance in the lungs of patients with pulmonary fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003625-03
Application #
2857549
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (O1))
Project Start
1997-01-01
Project End
2001-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Bryant, Katherine J; Bidgood, Matthew J; Lei, Pei-Wen et al. (2011) A bifunctional role for group IIA secreted phospholipase A2 in human rheumatoid fibroblast-like synoviocyte arachidonic acid metabolism. J Biol Chem 286:2492-503
Patel, Manish I; Singh, Jaskirat; Niknami, Marzieh et al. (2008) Cytosolic phospholipase A2-alpha: a potential therapeutic target for prostate cancer. Clin Cancer Res 14:8070-9
Li, Andrew C; Binder, Christoph J; Gutierrez, Alejandra et al. (2004) Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest 114:1564-76
Sved, Paul; Scott, Kieran F; McLeod, Duncan et al. (2004) Oncogenic action of secreted phospholipase A2 in prostate cancer. Cancer Res 64:6934-40
Chan, Edward D; Choi, Hyung-Seok; Cool, Carlyne et al. (2002) Interleukin-18 expression in cystic fibrosis lungs. Chest 121:84S-85S
Chan, E D; Chan, J; Schluger, N W (2001) What is the role of nitric oxide in murine and human host defense against tuberculosis?Current knowledge. Am J Respir Cell Mol Biol 25:606-12
Chan, E D; Morris, K R; Belisle, J T et al. (2001) Induction of inducible nitric oxide synthase-NO* by lipoarabinomannan of Mycobacterium tuberculosis is mediated by MEK1-ERK, MKK7-JNK, and NF-kappaB signaling pathways. Infect Immun 69:2001-10
Chan, E D; Kong, P M; Fennelly, K et al. (2001) Vertebral osteomyelitis due to infection with nontuberculous Mycobacterium species after blunt trauma to the back: 3 examples of the principle of locus minoris resistentiae. Clin Infect Dis 32:1506-10
Li, A C; Brown, K K; Silvestre, M J et al. (2000) Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 106:523-31
Minamino, T; Yujiri, T; Papst, P J et al. (1999) MEKK1 suppresses oxidative stress-induced apoptosis of embryonic stem cell-derived cardiac myocytes. Proc Natl Acad Sci U S A 96:15127-32

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