Ghrelin-AgRP 肠脑轴对脓毒症急性骨骼肌消耗及早期肠内营养治疗的作用研究

Abdominal sepsis can cause acute skeletal muscle wasting, thus affecting the prognosis. Previous researches revealed enteric and central neuroendocrine system played an important role in the process and early enteral feeding could achieve a good outcome with unknown mechanism. Our preliminary experiments have shown LPS injection could significantly reduced ghrelin level, which also presented good correlation with central neuropeptides and muscle wasting. Therefore, We postulated that in abdominal sepsis, gastrointestinal ghrelin level could be down-regulated, which would impact peripheral skeletal muscle wasting through inhibiting Ghrelin-AgRP gut-brain axis. And early enteral feeding could also ameliorate acute muscle wasting via this pathway in abdominal sepsis. To test this hypothesis, we employ peripheral and central drug administration, gene overexpression, RNA interference, early enteral feeding to study acute skeletal muscle wasting. This research will provide sound information on muscle wasting regulation, and may usher in a new direction in clinical treatment about abdominal sepsis.

腹腔感染所致的脓毒症会导致机体急性骨骼肌消耗，严重影响患者的预后。既往的研究已经逐渐认识到肠道及中枢神经内分泌系统在此代谢过程中的重要作用，并且早期肠内营养是治疗此类疾病的一个有效手段，但具体机制并不明确。预实验结果表明，脓毒症时Ghrelin的含量明显下降，与中枢神经肽及肌肉消耗有较强的相关性。为此，我们推测，腹腔感染时胃肠道Ghrelin激素分泌下降，通过下调Ghrelin-AgRP肠脑轴活性，导致下丘脑关键神经肽分泌改变，进而引起机体急性骨骼肌消耗。而早期肠内营养也可以通过此通路改善脓毒症状态下的急性骨骼肌消耗。为了验证该假说，我们通过对大鼠进行外周及中枢给予Ghrelin类似物，AgRP基因高表达、RNA干扰，早期肠内营养联合调控Ghrelin-AgRP轴等方式研究脓毒症状态下机体的急性骨骼肌消耗情况，为改善此类病人的代谢紊乱和营养支持提供理论依据。

腹腔感染所致的脓毒症会导致机体急性骨骼肌消耗，严重影响患者的预后。但是其调控机制尚不明确。本项目通过对大鼠进行外周及中枢给予Ghrelin类似物，AgRP基因高表达、RNA干扰，早期肠内营养等方式研究脓毒症状态下机体的急性骨骼肌消耗的可能机制。研究结果表明，外周和中枢给以Ghrelin类似物以及使用早期肠内营养均能够改善脓毒症大鼠的急性骨骼肌消耗。并且依赖下丘脑的Ghrelin受体的活化及AgRP的表达。阻断Ghrelin-AgRP肠脑轴的激活，会减弱上述干预措施对急性骨骼肌消耗的改善作用。而下丘脑中NF-κB和JAK2-STAT3信号通路的活化与Ghrelin-AgRP轴的活性降低有密切的关系。因此，调控Ghrelin-AgRP轴有望成为治疗感染所致急性骨骼肌消耗的一个重要靶点。