Sepsis induced respiratory failure is the leading cause of late death in critically ill patients. Sepsis also causes a profound decrease in thyroid hormone levels, the low T3 syndrome. Lung phospholipid and surfactant apoprotein synthesis have been show to be hormonally responsive; the effect of septic hypothyroidism on these important determinates of lung function is not known. This proposal investigates the relationship between sepsis, hypothyroidism, and lung functional and biochemical integrity as related to surfactant dysfunction. Specifically, this proposal will address the following questions; 1) What are the lung physiologic sequelae of sepsis induced hypothyroidism? 2) What is the role of thyroid status on surfactant homeostasis during sepsis? 3)What are the cellular and molecular mechanisms that underlie the increase in surfactant availability with T3 replacement during sepsis? The proposal will first determine the hormonally responsive, biophysical effects of sepsis induced hypothyroidism in an ex-vivo, isolated lung model. Alterations in surfactant phospholipid composition, function, and apoprotein amount and regulation will be investigated next. Finally, the mechanisms that regulate the metabolism of surfactant during sepsis will be clarified including the activity of key phospholipid regulatory enzymes. Genetic transcription of key phospholipid enzymes and apoproteins will provide further regulatory clarification. Fundamental understanding of the hormonal regulation of surfactant metabolism is in its infancy; pharmacologic improvement of surfactant abnormalities or deficits would be of considerable clinical value. This proposal will provide the necessary ground work to guide later clinical trials.
| Compton, C N; Franko, A P; Murray, M T et al. (1998) Signaling of apoptotic lung injury by lipid hydroperoxides. J Trauma 44:783-8 |
| Raafat, A M; Franko, A P; Zafar, R et al. (1997) Effect of thyroid hormone (T3)-responsive changes in surfactant apoproteins on surfactant function during sepsis. J Trauma 42:803-8; discussion 808-9 |
