Acute lung injury such as that seen in the adult respiratory distress syndrome (ARDS) may be induced by hyperoxia or the oxidative products endogenously released by stimulated polymorphonuclear leukocytes (PMNs). Adaptation to the oxidant lung damage of hyperoxia has been reported. We propose to study adaptation to oxidant-induced lung injury produced by intravenous (IV) phorbol myristate acetate (PMA) in rabbits. This model of adaptation is unique in that lung injury is mediated by oxyen radicals released in the lung by PMNs after IV-PMA. Thus, it is similar to proposed mechanisms in human ARDS. We have found that with continued daily IV-PMA, acute hemorrhagic pneumonitis and endothelial cell damage no longer occur after 2-3 days, as assessed by light and electron microscopy and bronchoalveolar lavage. Preliminary findings suggest that this adaptation may be associated with: 1) an increase in lung catalase, 2) a decrease in the production of oxidants by stimulated PMNs or 3) an increase in intracellular PMN catalase content. The objectives of this research are to study the mechanisms involved in this protective adaptation, loss of adaptation, and readaptation. 1) Anti-oxidants (catalase, superoxide dismutase, and the glutathione red-ox system) will be measured in whole lung and in isolated populations of blood PMNs, alveolar macrophages (AMs), and type II pneumocytes from experimental animals during adaptation to PMA-induced acute lung injury. 2) The respiratory burst function of PMNs and AMs will be examined using assays of superoxide production, hydrogen peroxide production (using a flow cytometer for single cell anlysis), oxygen consumption, and hexose monophosphate shunt activity. 3) Results will be correlated with the measurement of exhaled pentane, an in vivo assay of lipid peroxidation. These studies could both define the role of specific anti-oxidant defenses in adaptation to endogenous PMN-oxidant induced lung damage and provide insights into the mechanisms involved in protection against toxic oxygen moieties.
| Salzer, W L; McCall, C E (1990) Primed stimulation of isolated perfused rabbit lung by endotoxin and platelet activating factor induces enhanced production of thromboxane and lung injury. J Clin Invest 85:1135-43 |
| Salzer, W; Gerard, C; McCall, C (1987) Effect of an inhibitor of protein kinase C on human polymorphonuclear leukocyte degranulation. Biochem Biophys Res Commun 148:747-54 |
