The influence of hyperoxia and dexamethasone on pulmonary protein synthesis

Fussell, Julia Claire (1990) The influence of hyperoxia and dexamethasone on pulmonary protein synthesis. University of Southampton, Doctoral Thesis.

Abstract

The structural and biochemical components of the human lung, which are vital for normal respiration, develop during the latter part of gestation. Before approximately 32 weeks gestation (full term is 40 weeks) the extent of pulmonary immaturity is such, that an infant born at this stage of development will succumb to life threatening disorders. The survival of preterm babies is dependent upon the provision of supplementary oxygen, while steroid therapy is employed pre- and postnatally to alleviate the acute and chronic conditions associated with prematurity. This thesis has utilized animal models to study the effects of hyperoxia and dexamethasone on lung growth, and thereby has assessed their potential in contributing towards the poor pulmonary growth experienced by infants with chronic respiratory problems. Following a 24 hour exposure to ≥95% oxygen, the rate of protein synthesis and breakdown were depressed (12-15%) in the lung of neonatal guinea pigs. As a consequence, pulmonary growth was unaffected. Extending the period of hyperoxia to 72 hours had no greater inhibitory effect. Adolescent guinea pigs did not show any difference in lung protein turnover following hyperoxia. The overall reduction in ribosomal efficiency in the lungs of oxygen exposed animals was not defined to a specific translational step, however the unchanged polysome and monomer pools would suggest a block occurring at both peptide chain initiation and elongation. Further investigations were conflicting in their support that oxidized glutathione (GSSG) was involved in the inhibitory activity of hyperoxia on pulmonary protein synthesis. Although GSSG inhibited peptide chain initiation in a cell-free system derived from the mammalian lung, the concentration (0.2-0.5mM) required to produce such an effect could not be detected in the lung of animals following hyperoxia. The potential benefits and risks associated with antenatal glucocorticoid therapy were investigated by assessing indices of biochemical maturation and growth in the lung of the fetal guinea pig. The administration of dexamethasone (2.0mg/Kg/day) from day 55 to day 60 of gestation had no effect on protein metabolism in the lung of the 61 day fetus. Furthermore, fetal pulmonary antioxidant and surfactant systems were unresponsive to maternal steroid treatment. Possible explanations regarding the insensitivity of the fetal guinea pig lung to the steroid regime employed are discussed. The influence of postnatal glucocorticoid treatment on pulmonary protein turnover was examined in young rats. Within 24 hours, dexamethasone (2.5mg/KG/day) completely inhibited lung growth. This rapid response was due to a 38% fall in the pulmonary protein synthesis which was associated with a reduced (44%) ribosomal efficiency. Extending dexamethasone treatment to 5 days resulted in decreases in both ribosomal efficiency (35%) and capacity (28%) explaining the greater inhibition (53%) of lung protein synthesis at this time. Following both the acute and chronic steroid regimes, the decreased rates of pulmonary protein synthesis were accompanied by a loss of polysomes and an elevated ribosomal monomer pool, indicating that dexamethasone blocked translation at the site of peptide chain initiation.

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