Prior studies have described the presence of neutrophil proteases and reactive oxygen intermediates ROIs in the lungs of patients with ARDS. Biochemical and functional abnormalities of lung surfactant have been elucidated, and loss of surface tension lowering function has been shown to be an effect of exposure of lung surfactant to ROIs. We now plan to study the effects on lung surfactant components of exposure to proteases and ROIs, presented either discretely or as produced by stimulated phagocytes, and to discover the resultant modifications of surfactant components that are responsible for loss of function. Apoprotein that has undergone proteolysis or modification by products of lipid peroxidation, or phospholipid that has been subjected to peroxidation, will be recombined with unmodified components and function will be determined. In addition, we shall extend studies of the structure/function relationships of the surfactant apoproteins (SP). Peptide analogs of SP-B such as arg(leu4arg)4, in association with phospholipid, reduce surface tension in vitro, have greater resistance to inhibition by protein of this function than natural surfactant, and restore function to lungs of premature surfactant-deficient rhesus monkeys. Analysis of surfactants containing hydrophobic or acidic residues substituted for arg suggest that SP-B-phospholipid charge interactions induce stabilization of the phospholipid layer and thereby enhance surface tension lowering function. We will analyze the mechanisms of interaction of synthetic SP-B- and SP-C-like peptides with phospholipid to gain further insight into structure/function relationships. In addition, using acute lung injury models, we will assess biophysical, physiologic, and anti-inflammatory effects of synthetic peptide-based surfactants. Because our preliminary studies indicate a marked effect of porcine surfactant on the respiratory burst of neutrophils, we shall study in detail the effects of natural and synthetic surfactant on neutrophil function. Aerosolization of surfactant may provide more homogeneous delivery and optimal restoration of function, and techniques to deliver synthetic surfactant by aerosol will be tested. Finally, as our recent clinical studies indicate therapeutic benefit of exogenous surfactant administered by instillation to patients with a cute lung injury, the use of synthetic surfactant in a well defined clinical example of acute lung injury will be tested, and we will evaluate the physiologic and anti-inflammatory effects of this intervention that has been developed entirely under the sponsorship of the Acute Respiratory Failure SCOR.
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