An imbalance in protease/anti-protease activity is believed to underlie the development of obstructive pulmonary diseases such as emphysema. While elastin degradation is pivotal to this process it is clear that there are other targets of the excessive proteolysis that are involved in regulating the structural integrity of the alveolar wall. Our studies have demonstrated that pulmonary proteoglycans are a major target for elastase degradation. We have demonstrated that heparan sulfate proteoglycans in the extracellular matrix of pulmonary fibroblast are sites of storage for FGF2, a potent down regulator of elastin gene transcription. Within this project we aim to identify the functions and underlying mechanisms of proteoglycans as modulators of elastolytic injury in the lung. Our hypothesis is that elastase-induced lung injury results in the release of proteoglycans, growth factors and cytokines which mediate subsequent matrix repair. In the present project we will focus on the function of released proteoglycans as mediators of growth factor and elastase activity, the synthesis of proteoglycans after injury regulated by cytokines, and the relationship between proteoglycans and elastogenesis.
The specific aims of this project are to: 1) Identify the role of elastase released heparan sulfate proteoglycans in modulating elastase activity, FGF2 receptor activation, and the synthesis of proteoglycans and elastin, 2) Define the role of the small chondroitan sulfate proteoglycan, decorin, in modulating the elastase-induced cellular response, 3) Determine the consequences of elastase digestion on FGF2 nuclear localization and on FGF2 and TGFbeta transport through extracellular matrix, and 4) Examine the effects of elastolytic injury on proteoglycan and growth factor levels in normal mice and mice deficient in IL-1beta and TNFalpha receptors, and decorin. These studies will help identify aspects of the lung response to injury that are mediated by proteoglycans. Ultimately, these studies could provide critical insight into the development of new treatments for obstructive pulmonary diseases targeting the regulatory role of proteoglycans.
| Yang, Shenghong; Nugent, Matthew A; Panchenko, Mikhail P (2008) EGF antagonizes TGF-beta-induced tropoelastin expression in lung fibroblasts via stabilization of Smad corepressor TGIF. Am J Physiol Lung Cell Mol Physiol 295:L143-51 |
| Kuang, Ping-Ping; Zhang, Xiao-Hui; Rich, Celeste B et al. (2007) Activation of elastin transcription by transforming growth factor-beta in human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 292:L944-52 |
| Serlin, David M; Kuang, Ping Ping; Subramanian, Mangalalaxmy et al. (2006) Interleukin-1beta induces osteopontin expression in pulmonary fibroblasts. J Cell Biochem 97:519-29 |
| Spencer, Jean L; Stone, Phillip J; Nugent, Matthew A (2006) New insights into the inhibition of human neutrophil elastase by heparin. Biochemistry 45:9104-20 |
| Subramanian, Mangalalaxmy; Kuang, Ping-Ping; Wei, Lin et al. (2006) Modulation of amino acid uptake by TGF-beta in lung myofibroblasts. J Cell Biochem 99:71-8 |
| Mitsi, Maria; Hong, Zhenning; Costello, Catherine E et al. (2006) Heparin-mediated conformational changes in fibronectin expose vascular endothelial growth factor binding sites. Biochemistry 45:10319-28 |
| Kuang, Ping-Ping; Joyce-Brady, Martin; Zhang, Xiao-Hui et al. (2006) Fibulin-5 gene expression in human lung fibroblasts is regulated by TGF-beta and phosphatidylinositol 3-kinase activity. Am J Physiol Cell Physiol 291:C1412-21 |
| Rishikof, David C; Lucey, Edgar C; Kuang, Ping-Ping et al. (2006) Induction of the myofibroblast phenotype following elastolytic injury to mouse lung. Histochem Cell Biol 125:527-34 |
| DiCamillo, Sandra J; Yang, Shenghong; Panchenko, Maria V et al. (2006) Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-beta on tropoelastin mRNA in lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 291:L232-43 |
| Kuang, Ping-Ping; Lucey, Edgar; Rishikof, David C et al. (2005) Engraftment of neonatal lung fibroblasts into the normal and elastase-injured lung. Am J Respir Cell Mol Biol 33:371-7 |
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