Emphysema is an abnormal enlargement of the respiratory spaces with destruction of the alveolar wall. Accumulating evidence suggests that repair processes involving elastin re-synthesis by interstitial lung fibroblasts limits alveolar damage and perhaps restore alveolar units. This proposal will focus on the inflammatory processes that hinder the repair of the alveolar matrix following injury. Our preliminary data reveal that mice deficient in the interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) receptors are more resistant to elastase injury than are wild type mice. We postulate that IL-1beta and TNF- alpha down-regulate elastin mRNA following elastase injury and induce apoptosis in the alveolar wall resulting in alveolar rupture and airspace enlargement. Preliminary data indicate that these mediators function to decrease elastin transcription via cis-acting elements located in the proximal elastin promoter. Electrophoretic gel shift assays utilizing nuclear proteins isolated from untreated and IL-1beta treated fibroblasts implicated NF-kappaB and C/EBP-beta proteins. In this proposal, our first aim will determine the mechanism whereby IL-1beta and TNF- alpha down-regulate elastin transcription.
The second aim will characterize the signal transduction pathway utilized by these effector substances to down-regulate tropoelastin mRNA in lung fibroblasts The third aim will further examine the effect of elastolytic injury on mice deficient in the TNF-alpha receptors and type 1 (p80) IL-1beta receptors. We will also use caspace-11 deficient mice to clarify the role of apoptosis in this process. These studies will provide new insights into the pathogenesis of COPD and suggest new treatment options.
| 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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