REGULATION OF INFLAMMATORY LIPIDS IN ACUTE LUNG INJURY

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The Adult Respiratory Distress Syndrome (ARDS) is severe, acute lung injury that is frequently lethal. Many lines of evidence suggest that a common feature of the syndrome is unregulated inflammation and conditions in which there is systemic inflammation, such as sepsis, are common precursors. Therapeutic strategies to restore the regulation of the inflammatory response might be effective in either preventing the onset of the syndrome or reversing established disease. Studies in animals and man have implicated platelet-activating factor (PAF), a phospholipid with potent pro-inflammatory actions, as an important mediator in sepsis and lung injury. In the previous funding period, we isolated a cDNA encoding PAF acetylhydrolase (AH), the enzyme that degrades PAF and closely related phospholipids. In addition, we have found that recombinant enzyme blocks the inflammation in animal models, including one of lethal sepsis. These and other findings supported the initiation of clinical trials, in which we are participating, to test recombinant PAF-AH as an intervention to prevent progression from at-risk conditions to ARDS. In this project we will use animal models, including genetically engineered mice, to test the hypothesis that PAF and closely related compounds are on a common pathway to acute lung injury. In the previous funding period we found that a family of phospholipids structurally similar to PAF can be generated by non-enzymatic oxidation, which is likely to occur in ARDS. These compounds, like PAF, support inflammatory responses. PAF-like bioactivity is present in bronchoalveolar fluid of patients with ARDS, and we discovered that surfactant could be oxidized to a lipid with PAF-like bioactivity. Thus, we will test the hypotheses that a substantial fraction of PAF-like bioactivity in severe inflammation results from oxidized phospholipids rather than authentic PAF. This might lead to additional therapeutic approaches if the oxidant-mediated processes are prominent. Finally, PAF can induce cytokine and chemokine synthesis, and stimulate the proliferation of aortic vascular smooth muscle cells. Thus, this project will test whether PAF, or oxidized phospholipids, mediate chronic sequelae in survivors of ARDS, and if PAH-AH can protect against such events.