Mechanisms, consequences, and reversal of abnormalities in lung lymphatics

 描述(由申请人提供)：本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。淋巴管改变对肺功能和炎症反应的影响还知之甚少，并提供了新的治疗策略。该项目将确定肺部炎症中淋巴管异常的发展机制和后果，评估严重程度和对随后炎性损害的易感性的变化，并探索预防、消除或正常化这些异常的新策略。具体目标1建立在淋巴管在持续性炎症中生长和重塑的证据上，通过异常淋巴管的液体和细胞流量受损可以夸大浮肿和改变炎症反应。然而，扩大一个更正常的淋巴网络可以通过改善组织液排出和免疫细胞运输来减少炎症反应。将利用新的鼠标模型和补充技术来解决这些问题。我们将首先测试淋巴生长或重塑可以影响肺部炎症反应的假设。该方法将比较最近发现淋巴管有强烈但非常不同的变化的三种小鼠模型的肺淋巴管重塑的机制和后果。一种新的转基因小鼠模型将与淋巴管生长伴随肺部炎症的模型进行比较，在该模型中，淋巴管在其他正常的呼吸道和肺中的非炎症性生长是由VEGF-C的过度表达驱动的。我们的目标是确定驱动淋巴重塑的因素，并区分淋巴中夸大炎症的异常和减轻炎症的变化。具体目标#2建立在证据的基础上，与新血管不同，新淋巴管在炎症消退时通常不会消退，并影响随后的炎症反应。近年来，促进淋巴管内皮细胞存活的途径已被发现。这些都是消除异常淋巴管的潜在目标。在这里，我们将检验这样一个假设，即肺部炎症消退后持续存在的异常淋巴管可以通过阻断促进内皮细胞存活的途径来消除或正常化。预防淋巴管增长的策略(预防模型)将与消除淋巴管(逆转模型)或使淋巴管正常化(正常化模型)的方法进行比较。阻断VEGFR-2和VEGFR-3信号通路的效果将与阻断mTOR或其他支持内皮细胞存活的通路的效果进行比较。总之，这些结果将为肺淋巴管异常在哮喘、支气管炎、肺炎和其他伴随持续炎症的肺部疾病的严重性中的作用提供机械性见解。

 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.