Regulation and functional relevance of GLP-2 in sepsis

全身感染和败血症是危重病患者常见的并发症。在许多情况下，没有发现感染源，这表明生理微生物区系在应激有机体中扮演着感染源的角色。危重疾病会损害肠道屏障功能，并允许微生物向机体移位。肠屏障功能的改善可能为防止危重病人细菌易位和通过封闭细菌进入部位减少感染负担提供有价值的策略。在这项研究中，我们旨在评估GLP-2作为一种从肠道和胰腺释放的前胰高血糖素裂解产物，在炎症条件下改善肠道屏障功能的调节和机制相关性。在初步结果中，我们发现危重病患者的GLP-2水平显著升高，而小鼠对炎症刺激的反应是以IL6依赖的方式增加GLP-2的水平。使用组织特异性前胰高血糖素原表达的小鼠，我们发现炎症GLP-2分泌来自胰腺，而不是肠道。在功能上，应用GLP-2可显著改善结扎结扎(CLP)或内毒素诱导的脓毒症小鼠的炎症反应，而缺乏GLP-2的前胰高血糖素基因敲除小鼠则相反。这项建议的目的是描述内源性GLP-2分泌与脓毒症的炎症反应和预后的相关性。在第一步中，我们将通过使用前胰高血糖素原报告小鼠(目标1)来表征导致内毒素依赖性GLP-2分泌的炎症级联反应。然后，我们将利用获得和丧失功能模型(目标2)研究GLP-2在小鼠脓毒症中的抗炎能力，研究胰腺和肠道GLP-2产生的相关性(目标3)，并研究IL6作为GLP-2诱导刺激在小鼠脓毒症中的功能相关性(目标4)。

Systemic infection and sepsis are frequent complications of critical ill patients. In many cases no infectious focus can be found, suggesting the physiological microflora to act as an infectious source in the stressed organism. Critical illness impairs intestinal barrier function and allows translocation of microorganisms to the organism. Improvement of gut barrier function might provide a valuable strategy to prevent bacterial translocation of critical ill patients and to reduce infectious burden by sealing bacterial entry sites. In this study we are aiming to evaluate the regulation and mechanistic relevance of GLP-2 as a preproglucagon cleavage product released from the gut and the pancreas to improve gut barrier function under inflammatory conditions. In preliminary results we demonstrate marked elevation of GLP-2 levels in critical ill patients, while GLP-2 was increased in response to inflammatory stimuli in an IL6 dependent manner in mice. Using tissue specific preproglucagon expressing mice we found inflammatory GLP-2 secretion to originate from the pancreas but not from the gut. Functionally, GLP-2 application strongly modified the inflammatory response of mice challenged by colon ligation puncture (CLP) or endotoxin induced sepsis, while absence of GLP-2 in preproglucagon knockout mice caused the opposite. It is the aim of this proposal to characterise the relevance of endogenous GLP-2 secretion for inflammatory response and outcome in sepsis. In the first step we will characterize the inflammatory cascade leading to endotoxin dependent GLP-2 secretion in mice by employing preproglucagon reporter mice (Aim 1). We will then study the anti-inflammatory capacities of GLP-2 in murine sepsis by use of gain and loss of function models (Aim 2), investigate the relevance of pancreatic vs. intestinal GLP-2 production (Aim 3) and study the functional relevance of IL6 as a GLP-2 inducing stimulus in murine sepsis (Aim 4).