EFFECT OF IL-1 AND TNF ON ELASTIN PRODUCTION IN COPD

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DESCRIPTION (adapted from the applicants' abstract) 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.