Novel Signalings and Molecular Targets of Endothelial Regeneration in Aging Lung

描述(申请人提供)：急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)的一个重要组成部分是肺微血管内皮细胞屏障的损伤导致肺血管对蛋白质的通透性持续增加和难治性的富含蛋白质的水肿形成。与年轻患者相比，老年患者因脓毒症而导致的ALI/ARDS的发生率高出19倍，死亡率高达10倍。然而，人们对其根本原因知之甚少。同样重要的是，在脓毒症挑战后，衰老如何影响血管内皮细胞再生和血管内稳态的恢复机制还知之甚少。我们最近发现，Forkhead转录因子FOXM1是负责内皮再生的关键修复因子。然而，我们提供的新的支持数据显示，在炎症性肺损伤后的老年肺组织中，FOXM1的表达和内源性内皮再生程序严重受损。我们观察到，内皮缺氧诱导因子HIF-1α是FOXM1表达的关键介质，通过转录调控SDF-1α激活CXCR4受体，从而激活依赖于GPCRPI3K的p110伽马亚型；抑制氧感受器HIF Pro-1羟基酶(PhDS)重新诱导FOXM1表达，并激活老年肺内皮细胞再生程序。因此，我们推测老年肺组织中继发于PHD2活化的HIF-1FXM1信号通路受损是导致这些肺内皮细胞再生严重缺陷的原因，而通过抑制PHD2和激活α激活这一基本修复途径是逆转老年ALI/ARDS患者肺微血管渗漏、提高患者存活率的潜在治疗途径。拟议的研究涉及以下具体目标。在目标1中，我们将阐述老年肺中受损的HIF-1α-&FOXM1信号的作用，它是导致败血症后严重受损的内皮再生和肺血管动态平衡恢复的关键因素。在目标2中，我们将描述脓毒症后老年肺内皮细胞再生严重缺陷的信号机制。在目标3中，我们将通过抑制PHD来确定HIF-1α稳定在激活老年肺内皮细胞再生中的作用。我们还将探讨我们在动物模型中的发现与人类的潜在临床相关性，从而确定抑制PHD2和激活CXCR4在治疗老年患者ALI/ARDS中的治疗意义。通过这些综合研究，我们将勾勒出老年肺内皮细胞再生受损的基本信号机制，并确定治疗靶点，以激活这种基本的内在HIF-1α-&FOXM1依赖的机制来修复渗漏的肺微血管，用于治疗老年患者的ALI/ARDS。

DESCRIPTION (provided by applicant): An essential component of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is that injury of the endothelial barrier of pulmonary microvessels results in persistent increase in lung vascular permeability to protein and intractable protein-rich edema formation. Compared to young patients, the incidence of ALI/ARDS resulting from sepsis in elderly patients is as much as 19-fold greater and the mortality rate is up to 10-fold greater. However, the underlying causes are poorly understood. Also crucially little is known how aging influences mechanisms of endothelial regeneration and restoration of vascular homeostasis following sepsis challenge. We have recently shown that the Forkhead transcription factor FoxM1 is a key reparative factor responsible for endothelial regeneration. However, our new Supporting Data presented here show that FoxM1 expression and the endogenous endothelial regeneration program were severely impaired in aged lungs following inflammatory lung injury. We observed that endothelial hypoxia-inducible factor HIF-1α is the critical mediator of FoxM1 expression through transcriptional control of SDF-1α which activates CXCR4 receptor leading to activation of the GPCR-dependent p110gamma isoform of PI3K, and that inhibition of the oxygen sensors HIF prolyl hydroxylase (PHDs) re-induced FoxM1 expression and activated the endothelial regeneration program in aged lungs. Thus, we hypothesize that impaired HIF- 1α->FoxM1 signaling secondary to activation of PHD2 in aged lungs is responsible for the severely defective endothelial regeneration in these lungs, and activation of this fundamental reparative pathway through PHD2 inhibition and CXCR4 activation is a potential novel therapeutic approach for reversing lung microvessel leakiness and improving survival of elderly ALI/ARDS patients. The proposed studies address the following Specific Aims. In Aim #1, we will address the role of impaired HIF-1α->FoxM1 signaling in aged lungs as a crucial factor responsible for severely impaired endothelial regeneration and restoration of lung vascular homeostasis following sepsis challenge. In Aim #2, we will delineate the signaling mechanisms underlying severely defective endothelial regeneration in aged lungs following sepsis challenge. In Aim #3, we will determine the role of HIF-1α stabilization through PHD inhibition in activating endothelial regeneration in aged lungs. We will also address the potential clinical relevance of our findings in animal models to humans; thereby determine the therapeutic implications of inhibition of PHD2 and activation of CXCR4 in treatment of ALI/ARDS of elderly patients. With these comprehensive studies, we will delineate the fundamental signaling mechanisms of impaired endothelial regeneration in aged lungs, and identify therapeutic targets to activate this fundamental intrinsic HIF-1α->FoxM1-dependent mechanisms to repair leaky lung microvessels for the treatment of ALI/ARDS in elderly patients.