OZONE AND HYPEROXIA-INDUCED AIRWAY EPITHELIAL INJURY

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Inhalational exposure to ozone and high concentrations of oxygen can cause diffuse injury to the ciliated airway epithelium accompanied by neutrophil recruitment and airway hyperresponsiveness. Alternations in the prolife of eicosanoids metabolites of arachidonic acid (AA) produced by injured airway epithelial cells have been postulated to contribute to the airway dysfunction induced by these oxidant gases. We have observed that in vitro exposure of cultured human tracheal epithelial (TE) cells to ozone decreases TE cell production of prostaglandin E2 (PGE2), a cyclooxygenase (CO) metabolite with bronchodilator, antiinflammatory and cytoprotective properties, concomitant with preservation of 15- lipoxygenase (15-LO) activity and increased TE after ozone exposure appears to be delayed, and newly generated 15-HETE is retained intracellularly and selectively esterified to phosphatidylinositol (PI), a phospholipid with a central role in signal transduction processes. In several models, adhesion of neutrophils to target cells has been shown to be critical for effective neutrophil-mediated cytotoxicity. We have demonstrated a marked increase in adherence of human neutrophils to ozone-injured TE cells. In the airway, cooperative transcellular AA metabolism between recruited neutrophils and injured airway epithelial cells might directly, or indirectly through increased neutrophil activation, induce further epithelial cell injury. The objectives of these studies are to investigate some of the mechanisms by which exposure of cultured human TE cells to environmentally relevant concentrations of ozone or hyperoxic atmospheres inactivate TE cell CO, and assess the transcriptional and transnational processes regulating recovery of CO activity and increased 15-HETE production following oxidant gas exposure. We will also determine whether cicosanoids generated by oxidant gas- exposed TE cells, alone or through transcellular neutrophil-TE cell processing, directly injure TE cells and/or enhance neutrophil-mediated epithelial injury. Lastly, we will assess whether esterification of 15- HETE to PI alters intracellular signal transduction in cultured human TE cells by characterizing diglycerol (DG) species generated from 15-HETE-PI in response to oxidant gas exposure or activation in intact cells and their interaction with PKC isoenzymes in vitro. A better understanding of the pathologic processes by which ozone or hyperoxia injure airway epithelium and/or promote neutrophil-mediated epithelial damage may suggest therapeutic strategies to prevent or limit such injury in man.