Abstract
Ozone is a ubiquitous urban air pollutant known to damage the lung. Macrophages and inflammatory mediators such nitric oxide are known to contribute to ozone toxicity (3). My research is aimed at elucidating mechanisms regulating nitric oxide production in the lung following ozone inhalation. In preliminary studies we identified heat shock protein 60 (HSP 60) as a key endogenous mediator of macrophage nitric oxide production and ozone-induced tissue injury. Thus, we found that HSP 60 is rapidly upregulated in the lung after ozone inhalation. Moreover, recombinant HSP 60, alone and in combination with inflammatory cytokines, stimulates nitric oxide production by lung macrophages. These findings, together with the observation that nitric oxide production and ozone-induced lung damage are reduced in mice possessing a mutated receptor for HSP 60, the Toll Like Receptor-4 (TLR-4), demonstrate the importance of this molecule. My overall hypothesis is that HSP 60 contributes to ozone toxicity by stimulating the release of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF and interleukin-18 (IL-18), a potent inducer of interferon- (IFN), from alveolar macrophages, and by synergizing with these mediators to generate excessive quantities of nitric oxide. To test this hypotheses, I will determine if (9) ozone-induced increases in alveolar macrophage production of TNF and IL-18 are dependent on HSP 60 and TLR-4 and (7) HSP 60 is required for excessive nitric oxide production in the lung and tissue injury following ozone inhalation. The results of these studies should provide important mechanistic information on ozone toxicity and may lead to the development of new therapeutic approaches to treating or abrogating tissue injury induced by this air pollutant.
Ozone is a ubiquitous urban air pollutant known to damage the lung. Macrophages and inflammatory mediators such nitric oxide are known to contribute to ozone toxicity (3). My research is aimed at elucidating mechanisms regulating nitric oxide production in the lung following ozone inhalation. In preliminary studies we identified heat shock protein 60 (HSP 60) as a key endogenous mediator of macrophage nitric oxide production and ozone-induced tissue injury. Thus, we found that HSP 60 is rapidly upregulated in the lung after ozone inhalation. Moreover, recombinant HSP 60, alone and in combination with inflammatory cytokines, stimulates nitric oxide production by lung macrophages. These findings, together with the observation that nitric oxide production and ozone-induced lung damage are reduced in mice possessing a mutated receptor for HSP 60, the Toll Like Receptor-4 (TLR-4), demonstrate the importance of this molecule. My overall hypothesis is that HSP 60 contributes to ozone toxicity by stimulating the release of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF and interleukin-18 (IL-18), a potent inducer of interferon- (IFN), from alveolar macrophages, and by synergizing with these mediators to generate excessive quantities of nitric oxide. To test this hypotheses, I will determine if (9) ozone-induced increases in alveolar macrophage production of TNF and IL-18 are dependent on HSP 60 and TLR-4 and (7) HSP 60 is required for excessive nitric oxide production in the lung and tissue injury following ozone inhalation. The results of these studies should provide important mechanistic information on ozone toxicity and may lead to the development of new therapeutic approaches to treating or abrogating tissue injury induced by this air pollutant.