FUNDAMENTALS OF LUNG SURFACTANT ACTIVITY AND INHIBITION

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This proposal focuses on the surface activity and inhibition of natural and synthetic lung surfactants. Emphasized are the biophysical roles and functional importance of the phospholid and apoprotein constituents of endogenous lung surfactant (LS), along with the development of active synthetic exogenous substitutes for future therapeutic use in the neonatal respiratory distress syndrome (RDS) and in clinical lung injuries manifesting as acute or adult RDS (ARDS). The proposal has four Aims, each involving complementary biophysical measurements and pulmonary pressure volume (P-V) mechanical studies. Aim 1 investigates the component basis of surface and active function in whole and extracted LS and purified subfractions of its hydrophobic constituents (e.g., the complete mix of LS phospholipids, zwitterionic LS phospholipids without anionic phospholipids, LS neutral lipids, phospholipids plus hydrophobic apoproteins, etc). Aims 2 and 3 involved related studies with model surfactants, including dipalmitoyl phosphatidylcholine (DPPC) and other synthetic phospholipids combined with hydrophobic surfactant proteins or synthetic peptides (Aim 2) and novel phosphonolipids and phospholipid analogs synthesized with specific structural variations (Aim 3). Studies of normal activity in Aims 1-3 are supplemented by Aim 4 experiments on the inactivation of LS and exogenous surfactants by physiologically- relevant inhibitors that act by several mechanisms (e.g., plasma proteins, lyso-PC and other membrane lipids, meconium, fatty acids, lytic enzymes). In all Aims, surfactants are studied by multiple interfacial techniques (Wilhelmy balance, oscillating bubble, absorption apparatus) to elucidate the full range of surface tension lowering, respreading, hysteresis , and absorption behaviors relevant for LS. Brewster-angle microscopy, X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy are also used to enhance interpretations at the molecular and film structural levels. To ensure physiological relevance, P-V mechanical correlates of surface activity and inhibition are determined in excised rat lungs within each of the four proposed Aims.