Combined zinc supplementation with proinsulin C-peptide treatment decreases the inflammatory response and mortality in murine polymicrobial sepsis.
Combined zinc supplementation with proinsulin C-peptide treatment decreases the inflammatory response and mortality in murine polymicrobial sepsis.
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DOI：
10.1097/shk.0000000000000127
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发表时间：
2014-04
期刊：
影响因子：
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通讯作者：
Zingarelli B
中科院分区：
文献类型：
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作者：
Slinko S;Piraino G;Hake PW;Ledford JR;O'Connor M;Lahni P;Solan PD;Wong HR;Zingarelli B
锌是在宿主对感染的反应期间对免疫功能至关重要的微量元素。已证明胰岛素原C肽通过激活实验性内毒素血症中的抗炎过氧化物酶体增殖物激活受体-γ（PPARγ）发挥有益作用。C肽的某些体外活性似乎依赖于锌的存在。我们研究了脓毒症发作前补锌对C肽抗炎特性的影响。通过盲肠结扎和穿孔（CLP）使雄性C57 BL/6小鼠经受多微生物脓毒症。小鼠在CLP前腹膜内（IP）接受葡萄糖酸锌（1.3mg/kg）三天。CLP后1小时，动物接受C肽（280 nmol/kg IP）或抗微生物剂亚胺培南（25 mg/kg IP）。CLP与11%的存活率、肺白细胞隔离和肝损伤相关。脓毒症小鼠肺中的分子分析显示，与假手术动物相比，促炎细胞外信号调节激酶（ERK）1/2和核因子-κB（NF-κB）的核活化增加，但PPARγ表达降低。与单独的媒介物、C-肽或锌治疗相比，锌补充与C-肽治疗后的组合显著改善了存活率（61%），与抗生素治疗（60%）类似，改善了肺结构和肝功能，减少了组织中性粒细胞浸润，并增加了细菌清除率。与溶媒或单一治疗方案相比，这些有益作用与肺细胞核的PPARγ表达恢复以及pERK 1/2和NF-κB活性降低相关。我们的数据表明，短期锌预防感染性损伤前是一个必要的抗炎特性的C肽，促进炎症途径的调制。
Zinc is a trace element vital for immune function during host response to infection. The proinsulin C-peptide has been shown to exert beneficial effects through activation of the anti-inflammatory peroxisome proliferator activated receptor-γ (PPARγ) in experimental endotoxemia. Some in vitro activities of C-peptide appear dependent upon the presence of zinc. We investigated the effect of zinc supplementation before onset of sepsis on the anti-inflammatory properties of C-peptide. Male C57BL/6 mice were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). Mice received zinc gluconate (1.3 mg/kg) intraperitonally (IP) for three days before CLP. One hour after CLP, animals received C-peptide (280 nmol/kg IP) or the anti-microbial agent imipenem (25 mg/kg IP). CLP was associated with an 11% survival rate, pulmonary leukosequestration and liver injury. Molecular analysis in lungs of septic mice showed increased nuclear activation of the pro-inflammatory extracellular signal regulated kinases (ERK)1/2 and nuclear factor-κB (NF-κB), but decreased PPARγ expression, when compared to sham animals. Combination of zinc supplementation with C-peptide post-treatment significantly improved survival rate (61%) similarly to antibiotic treatment (60%), ameliorated lung architecture and liver function, reduced tissue neutrophil infiltration, and increased bacterial clearance when compared with vehicle, C-peptide, or zinc treatment alone. These beneficial effects were associated with restored lung nuclear expression of PPARγ, and reduction of pERK1/2 and NF-κB activities in comparison to vehicle or single treatment protocols. Our data demonstrate that short-term zinc prophylaxis prior the infectious insult is a requisite for the anti-inflammatory properties of C-peptide by facilitating modulation of inflammatory pathways.