The Role of 8-Isoprostane in Oxygen Toxicity <i>In Vivo</i>

Mortality in military casualties following trauma and sepsis is commonly the direct result of Adult Respiratory Distress Syndrome (ARDS). Lung dysfunction is an early and prominent feature of the Multi System Organ Failure (MSOF) seen in this scenario. The major treatment modality for the pulmonary edema and subsequent hypoxemia associated with ARDS is high inspired concentrations of oxygen. However, oxygen exposure of sufficient duration and partial pressure can itself induce the pulmonary edema characteristic of ARDS. Separating oxygen toxicity from established lung injury is all but impossible and has made the study of oxidant induced lung injury extremely difficult. Given the similar clinical manifestations of ARDS from multiple causes, the examination of oxygen toxicity could lead to identification of elements common to all etiologies. Recently a novel group of isomeric prostoglandin compounds has been shown to be produced by oxygen free radical mediated lipid peroxidation. We have observed that one of these compounds, 8-Isoprostane, increases in the media of alveolar macrophages exposed to 90% oxygen for 48 hours. Others have noted the development of pulmonary edema in rabbits when 8-Isoprostane was injected into the pulmonary artery. This investigation proposes to examine the in vivo production of 8-Isoprostane and its effects by: (1) quantifying the synthesis of 8-Isoprostane in the lungs of animals exposed to high oxygen concentrations; (2) determining the ability of exogenously applied 8-Isoprostane to result in altered pulmonary capillary permeability; and (3) assessing the contribution of nitric oxide to free radical mediated production of 8-Isoprostane and lung injury. These specific aims will be studied by: (1) enzyme immunoassay measurement of 8-Isoprostane in the lung lavage fluid of animals exposed to increasing oxygen concentrations for varying time periods; (2) measurement of radiolabeled albumin transfer from the pulmonary vasculature to the interstitial and alveolar space following instillation of 8-Isoprostane in the lungs; and (3) measurement of 8-Isoprostane in the lung lavage fluid of animals pretreated with nitric oxide synthase inhibitors and antioxidants prior to oxygen exposure.