Ozone is a ubiquitous urban air pollutant known to cause alveolar epithelial injury. A characteristic pulmonary reaction to inhaled ozone is an increase in the number of activated alveolar macrophages and type II epithelial cells in the lung. A variety of mediators produced by these cells, in particular the reactive nitrogen intermediates nitric oxide and peroxynitrite, can contribute to tissue injury. Nitric oxide is generated in the cells via the inducible form of nitric oxide synthase (NOS2). One protein that has been identified as a key endogenous mediator of ozone-induced toxicity is heat shock protein 60 (HSP 60). The overall objectives of the proposed studies are to analyze the role of HSP 60 in the production of NOS2 by alveolar macrophages and type II cells in ozone-induced toxicity. Our hypothesis is that HSP 60 contributes to ozone toxicity, not just by inducing nitric oxide production, but also by stimulating the release of proinflammatory cytokines that can synergize with HSP 60 to generate excessive quantities of nitric oxide in the lung which contribute to tissue injury.
