Molecular and cellular processing of lung surfactant ¹

Abstract

Pulmonary surfactant, a complex material that lines the alveolar surface of the lung, is synthesized in the type II pneumocyte. Surfactant consists largely of phospholipids, of which phosphatidylcholine is by far the most abundant component, and is mainly responsible for surface activity. Surfactant also contains four unique proteins, surfactant protein (SP)-A, SP-B, SP-C, and SP-D, which are synthesized in a lung-specific manner. SP-A and SP-D are glycoproteins (M(r) approximately 30,000-40,000) whereas SP-B and SP-C are small (M(r) approximately 5,000-18,000), extremely hydrophobic proteolipids released from large precursors by proteolysis. Synthesis of surfactant lipids and proteins is developmentally regulated in fetal lung and can be accelerated by glucocorticoids and other hormones. Developing fetal lung in vivo and in organ culture has been used extensively to study regulation of surfactant synthesis and gene expression. Glucocorticoids stimulate the rate of fetal lung phosphatidylcholine biosynthesis and the activity of the rate-regulatory enzyme, cholinephosphate cytidylyltransferase (CYT). The hormone, however, does not increase the amount of CYT; there is evidence that the increase in activity is mediated by increased fatty biosynthesis due to enhanced expression of the fatty acid synthase gene. Glucocorticoids also regulate expression of the SP-A, SP-B, and SP-C genes in the late gestation fetal lung. Hormone response elements and other cis-acting regulatory elements have been identified in the 5'-flanking regions of the SP-A, SP-B, and SP-C genes. Surfactant phospholipids are stored in lamellar bodies, secretory granules in the type II cell, and secreted by exocytosis. Lamellar bodies are also rich in SP-B and SP-C but there are conflicting data on the cellular distribution of SP-A. Secretion of SP-A may be constitutive and occur independently of lamellar bodies. Phosphatidylcholine secretion is a regulated process, and in isolated type II cells it can be stimulated by physiological and other agents that act via at least three signal-transduction mechanisms. After secretion, surfactant is transformed into tubular myelin, and the lipid and protein components are separated as the lipid is inserted into a monolayer at the air-liquid interface. The majority of surfactant is removed from the alveolar space by reuptake into the type II cell by mechanisms that may include receptor-mediated endocytosis. Some components of surfactant are directly recycled into new surfactant whereas other components are degraded.

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase

“…The PLD pathway has been implicated in a number of physiological functions, including secretion. For example, as elaborated in LPPs and lung function, surfactant secretion can be controlled in this manner (209,212).…”

“…Surfactant secretion can be stimulated in isolated alveolar type II cells through three distinct signal transduction pathways: 1) A 2␤ -adenosine or ␤ 2 -adrenergic receptors influencing activation of adenyl cyclase; 2) stretch and other receptors leading to influx of Ca 2ϩ and activation of calcium-calmodulin effectors; and 3) P2Y2 purinergic receptors resulting in PI-PLC activation, DAG activation of PKC, and elevation of intracellular Ca 2ϩ by IP 3 . Considerable cross talk occurs between these systems (152,209,210,212).…”

“…Current experimental results are consistent with, but do not prove, the notion that LPP hydrolysis contributes to the secondary more prolonged DAG peak. Available data show an elevation in arachidonate-containing DAG species, which theoretically would be more likely to arise from PI than from PC (212).…”

Molecular Structures and Interactions of Pulmonary Surfactant Components

“…For further details, several reviews and books covering the processing (Beers and Fisher, 1992;Rooney et al, 1994), regulation (Weaver and Whitsett, 1991), host-defense properties (Robertson et al, 1992;Pison et al, 1994), proteins Joliansson et al, 1994a;Vandenbussche et al, 1995;Whitsett et al, 1995) and clinical aspects (Robertson and Taeusch, 1995) of pulmonary surfactant are available.…”

Targeted Disruption of Ig-Hepta/Gpr116 Causes Emphysema-like Symptoms That Are Associated with Alveolar Macrophage Activation

“…Pulmonary surfactant plays an essential role in reducing the surface tension of the air-liquid interface of the alveoli, thereby preventing alveolar collapse (atelectasis) during expiration (16). A growing body of evidence has suggested that pulmonary surfactant is correlated with the development of COPD.…”