The roles of cholesterol in pulmonary surfactant, insights from comparative and evolutionary studies

In most eutherian mammals, cholesterol (Chol) comprises approximately 8-10 wt.% or 14-20 mol.% of both alveolar and lamellar body surfactant. It is re garded as an integral component of pulmonary surfactant. yet few studies ha ve concentrated on its function or control. Throughout the evolution of the vertebrates, the contribution of cholesterol relative to surfactant phosph olipids decreases. while that of the disaturated phospholipids (DSP) increa ses. Chol generally appears to dominate in animals with primitive bag-like lungs that lack septation. in the saccular lung of snakes or swimbladders w hich are not used predominantly for respiration, and also in immature lungs . It is possible that in these systems, cholesterol represents a protosurfa ctant. Cholesterol is controlled separately from the phospholipid (PL) comp onent in surfactant. For example, in heterothermic mammals such as the fat- tailed dunnart, Sminthopsis crassicaudata, and the microchiropteran bat, Ch alinolobus gouldii, and also in the lizard, Ctenophorus nuchalis, the relat ive amount of Chol increases in cold animals. During the late stages of emb ryonic development in chickens and lizards, the Chol to FL and Chol to DSP ratios decrease dramatically. While in isolated lizard lungs, adrenaline an d acetylcholine stimulate the secretion of surfactant FL, Chol secretion re mains unaffected. This is also supported in isolated cell studies of lizard s and dunnarts. The rapid changes in the Chol to PL ratio in response to va rious physiological stimuli suggest that these two components have differen t turnover rates and may be packaged and processed differently. Infusion of [H-3]cholesterol into the rat tail vein resulted in a large increase in Ch ol specific activity within 30 min in the lamellar body (LB) fraction, but over a 48-h period, failed to appear in the alveolar surfactant fraction. A nalysis of the limiting membrane of the lamellar bodies revealed a high (76 %) concentration of LB cholesterol. The majority of lamellar body Chol is, therefore, not released into the alveolar compartment. as the limiting memb rane fuses with the cell membrane upon exocytosis. It appears unlikely, the refore, that lamellar bodies are the major source of alveolar Chol. It is p ossible that the majority of alveolar Chol is synthesised endogenously with in the lung and stored independently from surfactant phospholipids. The rol e of cholesterol in the limiting membrane of the lamellar body may be to en able fast and easy processing by maintaining the membrane in a relatively f luid state. (C) 2001 Elsevier Science Inc. All rights reserved.