Novel Signalings and Molecular Targets of Endothelial Regeneration in Aging Lung

描述（由申请人提供）：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富含蛋白质的水肿形成。与年轻患者相比，老年患者败血症导致的ALI/ARDS发生率高达19倍，死亡率高达10倍。然而，人们对其根本原因知之甚少。同样至关重要的是，我们对衰老如何影响脓毒症后内皮细胞再生和血管稳态恢复的机制知之甚少。我们最近发现叉头转录因子FoxM1是内皮细胞再生的关键修复因子。然而，我们在这里提出的新的支持数据显示，在炎症性肺损伤后的老年肺中，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，通过转录控制SDF-1α激活CXCR4受体，导致gpcr依赖的PI3K p110gamma亚型的激活，抑制氧传感器HIF脯氨酰羟化酶（PHDs）重新诱导FoxM1表达并激活老化肺内皮再生程序。因此，我们假设老年肺中继发于PHD2激活的HIF- 1α->FoxM1信号受损是导致这些肺内皮再生严重缺陷的原因，通过抑制PHD2和激活CXCR4激活这一基本修复途径是逆转肺微血管渗漏和提高老年ALI/ARDS患者生存率的潜在新治疗方法。建议的研究涉及以下具体目标。在Aim #1中，我们将研究HIF-1α->FoxM1信号受损在老年肺部中的作用，这是脓毒症挑战后内皮再生和肺血管稳态恢复严重受损的关键因素。在Aim #2中，我们将描述脓毒症挑战后老年肺部严重缺陷的内皮再生的信号机制。在Aim #3中，我们将通过PHD抑制来确定HIF-1α稳定在激活老年肺内皮细胞再生中的作用。我们还将讨论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ALI/ARDS患者中的治疗意义。通过这些综合研究，我们将描述衰老肺部内皮细胞再生受损的基本信号机制，并确定激活这种基本的内在HIF-1α-> foxm1依赖机制来修复肺微血管渗漏的治疗靶点，以治疗老年ALI/ARDS患者。

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.