Pulmonary surfactant development

For multifetal pregnancies, separate specimens should be analyzed for each fetus. Infrequently, more than one fetus shares an amniotic fluid cavity. In such a case, a mature result is less predictive of maturity, because it represents a mixture of pulmonary surfactant from multiple fetuses. In the case of twins, the smaller is more likely to develop RDS than the larger. ... 

Stith, I.E. and Das, S.K. (1981). Pulmonary surfactant lipids studies on cholinephosphotransferase in developing guinea pig lung. Indian Biologist 13, 120-8. 

Artificial pulmonary surfactant therapy has dramatically reduced premature infant death caused by RDS and appears to have reduced overall mortality for all babies bom weighing less than 700 g (about 1.5 pounds). Advances such as this have come about as a result of research on the makeup of body tissues and secretions in both healthy and diseased individuals. Often, such basic research provides the information needed to develop effective therapies. 

The synthetic 21-amino acid polypeptide KL4 [(KL4)4K] was developed as a pulmonary surfactant to be used in treatment of respiratory distress syndrome (RDS) in infants (IRDS) and in adults (ARDS). KL4 is designed to contain intermittent hydrophobic (Leucine) and hydrophilic (Lysine) regions to mimic the structure of the natural surfactant protein B (SP-B). The solution phase synthesis of KL4 is a challenging task. The protection and deprotection patterns, the possibility of diastereomer formation in every coupling step, the solubility (or lack of it) of the different fragments and the isolation of intermediates are among the potential problems that face such a synthesis. The process research work resulted in a successful and efficient large scale synthesis of KL4 which will be discussed. 

The solution phase synthesis of the pulmonary surfactant 21-amino acid polypeptide, KL4 was achieved in two different synthesis approaches. The first approach was a linear fragment synthesis that suffered from the low solubility of the larger fragments latter in the synthesis. A convergent approach was developed to minimize these effects and inqirove both yield and purity of the final product. An efficient procedure for the hydrolysis of large polypeptide esters with tetraalkylammonium hydroxides was developed and applied successfully to the synthesis of the key 8-amino acid polypeptide intennediate 25. 

Efficient breathing requires a special lipid mixture known as pulmonary surfactant which contains exceptionally high proportions of dipalmitoyl-phosphatidylcholine. The secretion of pulmonary surfactant is carefully controlled and, when this secretion is impaired, as in premature babies, acute respiratory stress is found. Efforts are now being made to treat such respiratory distress either by hormones to hasten the development of the type II epithelial cells which make surfactant or by replacement therapy with artificial lipid mixtures. 

A liposomal formulation containing a surfactant, which usually coats the mucosa of the bronehi and prevents a collapse of the alveolar vesieles of the lung, has been developed for patients who suffer from infant respiratory distress syndrome (IRDS) or adult-aequired respiratory distress syndrome (ARDS). Premature babies often suffer IRDS before the development of a funetional lung surfaetant and pulmonary gas exehange. ARDS is also a life-threatening failure and loss of the lung function and is usually acquired by illness or accident. Clinieal trials with liposomal surfactant have proved to be effective in prophylaetie treatment of IRDS and ARDS. 

Glucocorticoids have important effects on the development of the fetal lungs. Indeed, the structural and functional changes in the lungs near term, including the production of pulmonary surface-active material required for air breathing (surfactant), are stimulated by glucocorticoids. 

In adults, a severe form of lung injury can develop in association with sepsis, pneumonia, and injury to the lungs due to trauma or surgery. This catastrophic disorder is known as acute respiratory distress syndrome (ARDS) and has a mortality rate of more than 40%. In ARDS, one of the major problems is a massive influx of activated neurophils which damage both vascular endothelium and alveolar epithelium and result in massive pulmonary edema and impairment of surfactant function. Neutrophil proteinases (e.g., elastase) break down surfactant proteins. A potential therapeutic strategy in ARDS involves administration of both surfactant and antiproteinases (e.g., recombinant a I -antitrypsin). 

Fetal lung maturation can be accelerated with antenatal corticosteroids. The National Institutes of Health (NIH) consensus conference in 1994 concluded that all fetuses between 24 and 34 weeks gestation at risk for preterm delivery should receive corticosteroids regardless of gender, race, maternal infection, and availability of surfactant. A report by the National Institutes of Child Health and Development Neonatal Research Network noted that antenatal steroid use was associated with fewer pulmonary problems and mortality. Many women who are appropriate candidates are... 

Premature infants with low levels of lung surfactant (see Chapter 33) require oxygen therapy. The level of oxygen must be closely monitored to prevent retinopathy and subsequent blindness (the retinopathy of prematurity) and to prevent bronchial pulmonary dysplasia. The tendency for these complications to develop is enhanced by the possibility of low levels of SOD and vitamin E in the premature infant. 

Xaylor, M. D. Van Dyke, K. Bowman, L. L. Miles, P. R. Hubbs, A. R Mason, R. J. Shannon, K. Reasor, M. J. A characterization of amiodarone-induced pulmonary toxicity in R344 rats and identification of surfactant protein-D as a potential biomarker for the development of the toxicity. Toxicol. Appl. Pharmacol. 2000,167,182-190. 

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