Mechanisms, consequences, and reversal of abnormalities in lung lymphatics

 描述（由申请人提供）：本项目将检查淋巴管生长和重塑对肺部炎症严重程度的影响。代谢物的变化对肺功能和炎症反应的影响知之甚少，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和后果的机制，评估严重程度和对后续炎症损伤的易感性的变化，并探索预防，消除或正常化异常的新策略。具体目标#1建立在以下证据的基础上：在持续的炎症中，炎性细胞生长并经历重塑，并且通过异常炎性细胞的受损的液体和细胞流量可以加重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运输来减少炎症反应。新的小鼠模型和补充技术将被用来解决这些问题。我们将首先检验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的三种小鼠模型中肺动脉重塑的机制和后果，这些小鼠模型具有稳健但非常不同的动脉改变。将比较一种新的转基因小鼠模型与淋巴生长伴随肺部炎症的模型，其中在其他正常气道和肺部中淋巴细胞的非炎性生长是由VEGF-C的过表达驱动的.目标是确定驱动淋巴重塑的因素，并区分炎症加剧的淋巴系统异常和减轻炎症的变化。具体目标#2基于以下证据：与新血管不同，当炎症消退并影响后续炎症反应时，新血管通常不会消退。近年来，已经确定了促进淋巴管内皮细胞存活的途径。这些是消除异常代谢物的潜在目标。在这里，我们将检验一个假设，即肺部炎症消退后持续存在的异常内皮细胞可以通过阻断促进内皮细胞存活的途径来消除或正常化。预防淋巴生长的策略（预防模型）将与消除淋巴细胞（逆转模型）或使淋巴细胞正常化（正常化模型）的方法进行比较。将阻断VEGFR-2和VEGFR-3信号传导的有效性与阻断mTOR或支持内皮细胞存活的其他途径的效果进行比较。总之，这些结果将为肺部炎症异常对哮喘、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的贡献提供机理上的见解。

 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.