Mascarenhas Desmond D, Elayadi Amina, Singh Baljit K, Prasai Anesh, Hegde Sachin D, Herndon David N, Finnerty Celeste C
Mayflower Organization for Research & Education Sunnyvale, CA 94085, USA ; Protigen Inc. Sunnyvale, CA 94085, USA.
Int J Burns Trauma. 2013 Nov 1;3(4):190-200. eCollection 2013.
Sepsis occurs three times more often in burns than in other types of trauma, suggesting an overlap or synergy between underlying immune mechanisms in burn trauma and sepsis. Nephrilin peptide, a designed inhibitor of mTORC2, has previously been shown to modulate a neuroimmune stress response in rodent models of xenobiotic and metabolic stress. Here we investigate the effect of nephrilin peptide administration in different rodent models of burn trauma and sepsis. In a rat scald burn model, daily subcutaneous bolus injection of 4 mg/kg nephrilin significantly reduced the elevation of kidney tissue substance P, S100A9 gene expression, PMN infiltration and plasma inflammatory markers in the acute phase, while suppressing plasma CCL2 and insulin C-peptide, kidney p66shc-S36 phosphorylation and PKC-beta and CGRP in dorsal root ganglia at 14 days (chronic phase). In the mouse cecal ligation and puncture model of sepsis, nephrilin fully protected mice from mortality between surgery and day 7, compared to 67% mortality in saline-treated animals, while significantly reducing elevated CCL2 in plasma. mTORC2 may modulate important neuroimmune responses in both burn trauma and sepsis.
脓毒症在烧伤患者中的发生率是其他类型创伤的三倍，这表明烧伤创伤和脓毒症潜在的免疫机制之间存在重叠或协同作用。Nephrilin肽是一种设计的mTORC2抑制剂，先前已被证明可调节异种生物和代谢应激的啮齿动物模型中的神经免疫应激反应。在这里，我们研究了在不同的烧伤创伤和脓毒症啮齿动物模型中给予Nephrilin肽的效果。在大鼠烫伤模型中，每天皮下注射4mg/kg Nephrilin肽可显著降低急性期肾组织P物质、S100A9基因表达、PMN浸润和血浆炎症标志物的升高，同时在14天（慢性期）抑制血浆CCL2和胰岛素C肽、肾p66shc-S36磷酸化以及背根神经节中的PKC-β和CGRP。在脓毒症的小鼠盲肠结扎和穿刺模型中，与盐水处理动物67%的死亡率相比，Nephrilin肽可使小鼠在手术至第7天期间完全免受死亡，同时显著降低血浆中升高的CCL2。mTORC2可能在烧伤创伤和脓毒症中调节重要的神经免疫反应。
