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: 2459486
• 负责人: Scott Alexander Dulchavsky
• 金额: $ 11.04万
• 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/2459486
• 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#年晚期死亡的主要原因。 危重病人。脓毒症还会导致 甲状腺激素水平降低，出现低T_3综合征。肺磷脂和 表面活性物质载脂蛋白的合成已被证明是激素 感染性甲状腺功能减退症对这些重要因素的影响 肺功能的确定尚不清楚。这份提案调查了 脓毒症、甲状腺功能减退症与肺功能和甲状腺功能的关系 与表面活性物质功能障碍相关的生化完整性。 具体地说，这项提案将解决以下问题； 1)脓毒症的肺生理后遗症是什么？ 甲状腺功能减退症？ 2)甲状腺状况对肺表面活性物质动态平衡的影响是什么 败血症？ 3)细胞和分子机制是什么 脓毒症期间T3替代治疗可增加肺表面活性物质的利用率？ 该提案将首先确定荷尔蒙反应、生物物理 脓毒症所致甲状腺功能减退对体外培养肺的影响 模特。表面活性物质磷脂组成、功能和功能的改变 接下来将研究载脂蛋白的数量和调节。最后， 脓毒症时调节表面活性物质代谢的机制将 包括关键磷脂调节活性的阐明 酵素。关键磷脂酶的基因转录和 载脂蛋白将提供进一步的调节澄清。 对表面活性物质激素调节的基本认识 新陈代谢处于初级阶段；表面活性物质的药理改进 异常或缺陷将具有相当大的临床价值。这 提案将为指导以后的临床工作提供必要的基础工作 审判。