Enhanced liver autophagic activity improves survival of septic mice lacking surfactant proteins A and D.
Enhanced liver autophagic activity improves survival of septic mice lacking surfactant proteins A and D.
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DOI：
10.1620/tjem.231.127
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Wang G
中科院分区：
文献类型：
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作者：
Tang Z;Ni L;Javidiparsijani S;Hu F;Gatto LA;Cooney R;Wang G
自噬是一种保护性的细胞机制，可以应对包括败血症在内的各种压力。败血症被定义为感染引起的全身性炎症。表面活性蛋白A和D(SP-A、SP-D)在宿主防御、调节炎症和体内平衡等方面发挥着重要作用。SP-A和SP-D在脓毒症自噬活性及相关基因表达中的作用尚不清楚。在本研究中，SP-A和SP-D双基因敲除(SP-A/D KO)和背景匹配的野生型(WT)C57BL/6小鼠接受盲肠结扎穿孔(CLP)或假手术。结果表明，在CLP脓毒症中，SP-A/D KO小鼠的死亡率低于WT小鼠。CLP治疗24小时后，脓毒症SP-A/D KO和WT小鼠的肝组织均出现明显的病理改变。SP-A/D KO小鼠的基础自噬水平高于WT小鼠(p<；0.05)。在CLP术后6至24小时，脓毒症SP-A/D KO和WT小鼠的自噬活性均显著增加(p<；0.01)。84个自噬相关基因的表达表明，SP-A/D KO和WT小鼠在基础和脓毒症诱导下的基因表达存在差异。与脓毒症SP-A/D KO小鼠相比，脓毒症WT小鼠3个基因(arsa、hgs、fadd)的表达增加，4个基因(Bak-1、NF-κB、P53和Atg12)的表达降低。此外，在与自噬和凋亡相关的6条信号通路中，SP-A/D KO和WT小鼠对脓毒症的反应也不同。因此，SP-A/D KO小鼠自噬活性增强可提高小鼠存活率，代表了SP-A和SP-D功能的一种调节机制。
Autophagy is a protective cellular mechanism in response to various stresses including sepsis. Sepsis is defined as systemic inflammation by infection. Surfactant protein A and D (SP-A, SP-D) play crucial roles in host defense, regulation of inflammation, and homeostasis. The role of SP-A and SP-D on the autophagic activity and relevant gene expression in sepsis are unclear. In this study SP-A and SP-D double knockout (SP-A/D KO) and background-matched wild-type (WT) C57BL/6 mice underwent either cecal ligation and puncture (CLP) or sham surgery. The results showed that SP-A/D KO mice had lower mortality than WT mice in CLP sepsis. Liver tissues showed marked pathological changes in both septic SP-A/D KO and WT mice 24 hrs after CLP treatment. SP-A/D KO mice had higher basal level of autophagy than WT mice (p<0.05). Autophagic activity increased significantly in both septic SP-A/D KO and WT mice from 6 to 24 hrs after CLP surgery (p<0.01). The expression of 84 autophagy-related genes revealed differential basal and sepsis-induced gene expression between SP-A/D KO and WT mice. The expression increased in three genes (Arsa, Hgs, FADD) and decreased in four genes (Bak-1, Nf-κB, p53, and Atg12) in septic WT mice, as compared to septic SP-A/D KO mice (p<0.05). Furthermore, differential responses to sepsis between SP-A/D KO and WT mice were found in six signaling pathways related to autophagy and apoptosis. Therefore, enhanced autophagic activity in SP-A/D KO mice improves mouse survival and represented a regulatory mechanism of SP-A and SP-D function.