Hill Neil E, Murphy Kevin G, Saeed Saima, Phadke Rahul, Chambers Darren, Wilson Duncan R, Brett Stephen J, Singer Mervyn
Section of Investigative Medicine, Imperial College London, London, United Kingdom.
Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom.
PLoS One. 2017 Aug 10;12(8):e0182659. doi: 10.1371/journal.pone.0182659. eCollection 2017.
Patients with multiple injuries or sepsis requiring intensive care treatment invariably develop a catabolic state with resultant loss of lean body mass, for which there are currently no effective treatments. Recovery can take months and mortality is high. We hypothesise that treatment with the orexigenic and anti-inflammatory gastric hormone, ghrelin may attenuate the loss of body mass following critical illness and improve recovery.
Male Wistar rats received an intraperitoneal injection of the fungal cell wall derivative zymosan to induce a prolonged peritonitis and consequent critical illness. Commencing at 48h after zymosan, animals were randomised to receive a continuous infusion of ghrelin or vehicle control using a pre-implanted subcutaneous osmotic mini-pump, and continued for 10 days.
Zymosan peritonitis induced significant weight loss and reduced food intake with a nadir at Day 2 and gradual recovery thereafter. Supra-physiologic plasma ghrelin levels were achieved in the treated animals. Ghrelin-treated rats ate more food and gained more body mass than controls. Ghrelin increased adiposity and promoted carbohydrate over fat metabolism, but did not alter total body protein, muscle strength nor muscle morphology. Muscle mass and strength remained significantly reduced in all zymosan-treated animals, even at ten days post-insult.
Continuous infusion of ghrelin increased body mass and food intake, but did not increase muscle mass nor improve muscle function, in a long-term critical illness recovery model. Further studies with pulsatile ghrelin delivery or additional anabolic stimuli may further clarify the utility of ghrelin in survivors of critical illness.
需要重症监护治疗的多发伤或脓毒症患者不可避免地会出现分解代谢状态，导致瘦体重丧失，目前尚无有效治疗方法。恢复可能需要数月时间，且死亡率很高。我们推测，使用促食欲和抗炎的胃激素胃饥饿素进行治疗，可能会减轻危重症后的体重减轻并改善恢复情况。
雄性Wistar大鼠腹腔注射真菌细胞壁衍生物酵母聚糖，以诱发持续性腹膜炎及随之而来的危重症。从注射酵母聚糖后48小时开始，动物被随机分组，使用预先植入的皮下渗透微型泵持续输注胃饥饿素或赋形剂对照，并持续10天。
酵母聚糖腹膜炎导致显著体重减轻和食物摄入量减少，在第2天达到最低点，此后逐渐恢复。治疗组动物的血浆胃饥饿素水平达到超生理水平。与对照组相比，胃饥饿素治疗的大鼠进食更多食物，体重增加更多。胃饥饿素增加了肥胖程度，促进了碳水化合物而非脂肪的代谢，但未改变全身蛋白质、肌肉力量和肌肉形态。即使在损伤后10天，所有接受酵母聚糖治疗的动物的肌肉质量和力量仍显著降低。
在长期危重症恢复模型中，持续输注胃饥饿素增加了体重和食物摄入量，但未增加肌肉质量，也未改善肌肉功能。对脉冲式胃饥饿素给药或额外合成代谢刺激的进一步研究，可能会进一步阐明胃饥饿素在危重症幸存者中的效用。
