Mechanisms, consequences, and reversal of abnormalities in lung lymphatics

肺淋巴管异常的机制、后果和逆转

• 批准号: 9035306
• 负责人: Donald M McDonald
• 金额: $ 55.46万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035306
• 关键词: Address; Asthma; Blood Vessels; Bronchitis; Cell Survival; Cells; Clinical; Development; Drainage procedure; Edema; Effectiveness; Endothelial Cells; FRAP1 gene; Goals; Growth; Health; Immune; Inflammation; Inflammatory; Inflammatory Response; KDR gene; Liquid substance; Location; Lung; Lung Inflammation; Lung diseases; Lymphatic; Lymphatic Abnormalities; Lymphatic Endothelial Cells; Lymphatic vessel; Modeling; Nature; Pathway interactions; Pneumonia; Predisposition; Prevention; Property; Resolution; Respiratory physiology; Severities; Signal Pathway; Signal Transduction; Stimulus; Technology; Testing; Tissues; Transgenic Mice; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3; cell growth; experience; improved; inflammatory lung disease; insight; mouse model; novel strategies; novel therapeutic intervention; overexpression; preclinical study; prevent; research study; trafficking

 DESCRIPTION (provided by applicant): This project will examine the effects of lymphatic vessel growth and remodeling on the severity of lung inflammation. Effects of changes in lymphatics on lung function and inflammatory responses are poorly understood and offer new therapeutic strategies. The project will determine the mechanisms of development and consequences of lymphatic vessel abnormalities in lung inflammation, assess changes in severity and susceptibility to subsequent inflammatory insults, and explore novel strategies for preventing, eliminating, or normalizing the abnormalities. Specific Aim #1 builds on evidence that lymphatics grow and undergo remodeling in sustained inflammation, and impaired fluid and cell flux through abnormal lymphatics can exaggerate edema and alter inflammatory responses. Yet, expansion of a more normal lymphatic network can reduce inflammatory responses by improving tissue fluid drainage and immune cell traffic. New mouse models and complementary technologies will be exploited to address these issues. We will first test the hypothesis that lymphatic growth or remodeling can influence inflammatory responses in the lung. The approach will be to compare the mechanisms and consequences of remodeling of lung lymphatics in three mouse models recently found to have robust but very different changes in lymphatics. A new transgenic mouse model, where non- inflammatory growth of lymphatics in otherwise normal airways and lung is driven by overexpression of VEGF- C, will be compared to models where lymphatic growth accompanies lung inflammation. The goals are to identify factors that drive lymphatic remodeling and distinguish abnormalities in lymphatics that exaggerate inflammation from changes that reduce inflammation. Specific Aim #2 builds on evidence that, unlike new blood vessels, new lymphatics usually do not regress when inflammation resolves and influence subsequence inflammatory responses. Pathways that promote lymphatic endothelial cell survival have been identified in recent years. These are potential targets for eliminating abnormal lymphatics. Here, we will test the hypothesis that abnormal lymphatics that persist after lung inflammation resolves can be eliminated or normalized by blocking pathways that promote endothelial cell survival. Strategies that prevent lymphatic growth (prevention models) will be compared to approaches that eliminate lymphatics (reversal models) or normalize lymphatics (normalization models). The effectiveness of blocking VEGFR-2 and VEGFR-3 signaling will be compared to effects of blocking mTOR or other pathways that support endothelial cell survival. Together, the results will provide mechanistic insights into the contribution of abnormalities in lung lymphatics to the severity of asthma, bronchitis, pneumonia, and other lung disease accompanied by sustained inflammation.

 描述（由申请人提供）：该项目将研究淋巴管生长和重塑对肺部炎症严重程度的影响。目前人们对淋巴管变化对肺功能和炎症反应的影响知之甚少，并将提供新的治疗策略。肺部炎症中淋巴管异常的发展机制和后果，评估随后炎症损伤的严重程度和易感性的变化，并探索基于特定目标#1的预防、消除或正常化异常的新策略。有证据表明，淋巴管在持续炎症中生长并经历重塑，通过异常淋巴管的液体和细胞流量受损会加剧水肿并改变炎症反应，然而，更正常的淋巴网络的扩张可以通过改善组织液引流和免疫细胞交通来减少炎症反应。我们将利用新的小鼠模型和补充技术来解决这些问题，我们将首先测试淋巴管生长或重塑可以影响肺部炎症反应的假设，该方法将比较肺淋巴管重塑的机制和后果。最近发现三种小鼠模型的淋巴管有明显但非常不同的变化，其中正常气道和肺部的淋巴管非炎症性生长是由 VEGF-C 过度表达驱动的，将与其他模型进行比较。淋巴管生长伴随肺部炎症，其目标是确定促进淋巴管重塑的因素，并区分加剧炎症的淋巴管异常和减少炎症的变化。当炎症消退时，新的淋巴管通常不会消退，并影响随后的炎症反应。近年来，我们已经确定了促进淋巴管内皮细胞存活的途径，这些是消除异常淋巴管的潜在目标。肺部炎症消退后，可以通过阻断促进内皮细胞存活的途径来消除或使其正常化，将阻止淋巴管生长的策略（预防模型）与消除淋巴管的方法（逆转）进行比较。阻断 VEGFR-2 和 VEGFR-3 信号传导的有效性将与阻断 mTOR 或支持内皮细胞存活的其他途径的效果进行比较，结果将提供有关其贡献的机制见解。肺淋巴管异常导致哮喘、支气管炎、肺炎和其他伴有持续炎症的肺部疾病的严重程度。