Ozone is a ubiquitous urban air pollutant known to damage the lung and compromise respiratory function. Our laboratories have been investigating mechanisms mediating the toxicity of ozone, in particular, the role of macrophages in the pathogenic process. We have discovered that macrophages responding to ozone-induced lung injury release mediators that not only contribute to tissue injury, but also, and perhaps more importantly, to tissue repair. Of particular interest is tumor necrosis factor-alpha (TNF-(), which appears to be involved in both of these processes. The major receptor mediating the reparative actions of TNF-( is TNFR1 (p55), which is localized in caveolin-1 (Cav-1)-containing plasma membrane lipid rafts, or caveolae. These are specialized organelles that sequester and negatively regulate various cell-signaling molecules. In rodent models, we observed that ozone-induced injury is associated with a marked suppression of Cav-1 in the lung, and the release of signaling molecules mediating type II alveolar epithelial cell proliferation and tissue repair. In preliminary studies we identified TNF-( as a major mediator regulating Cav-1 expression. We hypothesize that down regulation of Cav-1 by TNF-( initiates tissue repair by sensitizing alveolar type II cells to proliferate in response to endogenous mitogens. Down-regulation of Cav-1 after ozone inhalation is associated with activation of the (-catenin/cyclin D1 pro-mitogenic signaling pathway. We speculate that this is a key step leading to proliferation of type II cells and repair of damaged epithelium following ozone-induced injury. The experiments described in this proposal are designed to analyze the role of Cav-1 in ozone toxicity. Studies are planned to assess mechanisms by which Cav-1 is down regulated in type II cells following ozone inhalation in mice and to elucidate the role of TNF-( in this process. We will also determine if TNF-(-induced suppression of Cav-1 leads to activation of (-catenin signaling and type II cell proliferation. The results of these studies will provide new mechanistic clues about the pathways leading to repair of acute lung damage and may suggest innovative therapeutic approaches for abrogating tissue injury associated with exposure to inhaled pollutants, as well as episodic inflammatory lung diseases such as asthma.
Ozone is a ubiquitous urban air pollutant and the main component of photochemical smog. It remains one of the most problematic air pollutants to control because it is formed from intermediates originating from many different sources. Inhaled ozone has been shown to irritate and damage the lung in both healthy and susceptible individuals, including children and the elderly. Epidemiologic studies in the U.S. have demonstrated that for every 10 ppb increase in daily ozone levels, the total death rate for that day and for the two following days increases by 0.87%. Potential adverse effects of ozone are even greater in large cities in the developing world where ozone levels can be significantly higher than in the U.S. with a concomitantly greater health burden. Thus, elucidating the specific mechanisms contributing to the toxicity of ozone is highly relevant in terms of developing new strategies for reducing tissue injury induced by air pollutants, and potentially for other inflammatory lung diseases.
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