SEPSIS INDUCED HYPOTHYROIDISM AND SURFACTANT DYSFUNCTION

脓毒症引起的甲状腺功能减退症和表面活性剂功能障碍

• 批准号: 2186859
• 负责人: Scott Alexander Dulchavsky
• 金额: $ 9.61万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2186859
• 关键词: acyltransferase; apolipoproteins; blood toxicology; cellular pathology; enzyme activity; genetic transcription; homeostasis; hormone receptor; hormone regulation /control mechanism; hormone therapy; hypothyroidism; laboratory rat; lipid biosynthesis; lipid metabolism; molecular pathology; northern blottings; phosphatidate phosphatase; protein biosynthesis; pulmonary surfactants; respiratory disorder; respiratory epithelium; respiratory function; thyroid hormones; tissue /cell culture

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.

败血症引起的呼吸衰竭是晚期死亡的主要原因， 危重病人。 脓毒症也会导致 甲状腺激素水平低T3综合征 肺磷脂和 表面活性剂脱辅基蛋白合成已经显示出 反应;脓毒性甲状腺功能减退症对这些重要 肺功能的测定方法尚不清楚。 该提案调查 脓毒症、甲状腺功能减退症与肺功能的关系 与表面活性剂功能障碍有关的生化完整性。 具体而言，本提案将解决以下问题： 1)脓毒症引起的肺生理后遗症是什么 甲状腺功能减退症？ 2)甲状腺状态对肺表面活性物质稳态的作用是什么 败血症 3)什么是细胞和分子机制，其基础是什么？ 脓毒症期间T3替代增加表面活性剂可用性？ 该提案将首先确定生物响应，生物物理 脓毒症诱导的甲状腺功能减退症在离体离体肺中的作用 模型 表面活性剂磷脂组成、功能和 载脂蛋白的量和调节将随后进行研究。 最后 脓毒症期间调节表面活性剂代谢的机制将 阐明包括关键磷脂调节活性 内切酶 关键磷脂酶的基因转录和 脱辅基蛋白将提供进一步的监管澄清。 对表面活性剂激素调节的基本认识 代谢处于婴儿期;表面活性剂的药理学改进 异常或缺陷将具有相当大的临床价值。 这 建议将提供必要的基础工作，以指导以后的临床 审判