) Emphysema is defined as an abnormal enlargement of the respiratory spaces with destruction of the alveolar wall. Loss of elastic recoil of the lung and loss of alveolar attachments to small airways cause irreversible airway obstruction. Epidemiological evident suggest that the disease develops because of complex interactions between inflammatory events, alveolar structures and repair processes. Accumulating evidence suggest that repair processes involving elastin resynthesis by myofibroblasts limit 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. The investigators' preliminary data reveal that interleukin1 (IL-1) and tumor necrosis factor-(TNF-) down-regulate elastin mRNA and subsequently reduce the accumulation of elastin in the extracellular matrix by lung fibroblasts in culture. These mediators are present in the alveolar space following lung injury and thus may impair elastin production in the alveolar wall. IL-1 decreases the rate of transcription of the elastin gene by more than 80 percent as determined by nuclear run-on assays. Transient transfection experiments indicate that IL-1 and TNF- function through cis- acting elements in the proximal elastin promoter. Electrophoretic gel shift assays utilizing nuclear proteins isolated implicate C/EBP- proteins and an unidentified zinc finger type protein in mediating this down-regulation. Mice deficient in TNF- receptors (double receptor knockout) sustained less injury following intratracheal elastase administration as assessed by measurements of tissue density. The investigators will determine the molecular mechanisms whereby these effector substances regulate elastin transcription. The investigators will investigate the signaling pathway utilized by IL-1 and TNF- to decrease elastin transcription. The investigators postulate that this down-regulation of elastin production limits lung repair in vivo. The investigators will test their hypothesis using wild-type and IL-1 and TNF- receptor knockout mice treated with intratracheal pancreatic elastase administration or exposure to cigarette smoke. These studies will provide new insights into the pathogenesis of emphysema and suggest new treatment options.
| 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 |
| 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 |
| 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 |
| 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 |
| Rishikof, David C; Kuang, Ping-Ping; Subramanian, Mangalalaxmy et al. (2005) Methods for measuring type I collagen synthesis in vitro. Methods Mol Med 117:129-40 |
| Berk, John L; Hatch, Christine A; Morris, Shirley M et al. (2005) Hypoxia suppresses elastin repair by rat lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 289:L931-6 |
| Kuang, Ping-Ping; Goldstein, Ronald H (2005) Regulation of elastin gene transcription by proteasome dysfunction. Am J Physiol Cell Physiol 289:C766-73 |
| Rishikof, David C; Ricupero, Dennis A; Liu, Hanqiao et al. (2004) Phenylbutyrate decreases type I collagen production in human lung fibroblasts. J Cell Biochem 91:740-8 |
| Kuang, Ping-Ping; Goldstein, Ronald H (2003) Regulation of elastin gene transcription by interleukin-1 beta-induced C/EBP beta isoforms. Am J Physiol Cell Physiol 285:C1349-55 |
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