Novel alveolar mechanisms of hypoxemia in hepatopulmonary syndrome

肝肺综合征低氧血症的新肺泡机制

• 批准号: 10718446
• 负责人: Zhiyu Dai
• 金额: $ 76.28万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718446
• 关键词: Address; Affect; Alveolar; Alveolus; American; Bile Acids; Blood; Blood Vessels; Cells; Cirrhosis; Complication; Defect; Foundations; Functional disorder; Goals; Hepatopulmonary Syndrome; Hypoxemia; Impairment; Knowledge; Lung; Medical; Outcome; Oxygen; Patients; Risk; Role; Severities; System; Vascular remodeling; Work; alveolar epithelium; chronic liver disease; effective therapy; human disease; mortality; new therapeutic target; novel; pulmonary function; surfactant function; surfactant production

Project Summary & Abstract Cirrhosis afflicts more than 4.5 million Americans and hepatopulmonary syndrome (HPS), the most common pulmonary complication of cirrhosis, occurs in up to 30% of patients and significantly increases mortality. No effective therapies exist due to our incomplete understanding of cellular mechanisms. Although classically recognized as alveolar microvascular remodeling causing hypoxemia, the poor correlation between hypoxemia, the degree of microvascular changes, and outcomes in HPS remain unexplained. To address this knowledge gap, we have identified novel abnormalities in the alveolus itself in experimental HPS, along with restrictive ventilatory defects and elevated circulating bile acids in human disease. Our hypothesis is that elevated circulating bile acid levels in cirrhosis, affect alveolar epithelial type 2 cells (AT2 cells), leading to impaired surfactant production and restrictive ventilatory defects which influence the progression and outcome of HPS. To elucidate the role of bile acids and AT2 cells in HPS, we propose to 1) assess the correlation between bile acid levels and the presence and severity of HPS 2) define the role of AT2 cells in HPS and 3) determine the mechanisms and consequences of bile acid medicated AT2 cell loss. Completion of this work will define the mechanisms and significance of AT2 cell dysfunction in HPS, identify novel therapeutic targets and form the foundation for a broader understanding of how chronic liver disease influences lung function.

项目摘要和摘要 肝硬化折磨超过450万美国人和肝肺综合症（HPS），这是最常见的 肝硬化的肺并发症发生在多达30％的患者中，并显着增加死亡率。不 由于我们对细胞机制的了解不完全理解，因此存在有效的疗法。虽然是经典的 被认为是肺泡微血管重塑，导致低氧血症，低氧血症之间的相关性差， 微血管变化的程度和HP的结果仍无法解释。解决这一知识 差距，我们已经确定了实验性HP中肺泡本身的新型异常，并有限 人类疾病中的通气缺陷和循环胆酸升高。我们的假设是 肝硬化中循环胆汁酸水平，影响肺泡上皮2型细胞（AT2细胞），导致受损 表面活性剂的产生和限制性通气缺陷会影响HP的进展和结果。 为了阐明胆汁酸和AT2细胞在HPS中的作用，我们建议1）评估胆汁之间的相关性 酸水平以及HPS的存在和严重程度2）定义AT2细胞在HPS中的作用，3）确定 胆汁酸药物AT2细胞损失的机理和后果。这项工作的完成将定义 AT2细胞功能障碍在HPS中的机理和重要性，鉴定新的治疗靶标并形成 对慢性肝病如何影响肺功能的更广泛理解的基础。