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首页> 美国卫生研究院文献>PLoS Clinical Trials >Hemorrhage enhances cytokine, complement component 3, and caspase-3, and regulates microRNAs associated with intestinal damage after whole-body gamma-irradiation in combined injury
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Hemorrhage enhances cytokine, complement component 3, and caspase-3, and regulates microRNAs associated with intestinal damage after whole-body gamma-irradiation in combined injury

机译：出血增强了全身γ射线对合并损伤的肠道损伤后细胞因子，补体成分3和caspase-3的表达，并调节microRNA。

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Hemorrhage following whole-body γ-irradiation in a combined injury (CI) model increases mortality compared to whole-body γ-irradiation alone (RI). The decreased survival in CI is accompanied by increased bone marrow injury, decreased hematocrit, and alterations of miRNA in the kidney. In this study, our aim was to examine cytokine homeostasis, susceptibility to systemic bacterial infection, and intestinal injury. More specifically, we evaluated the interleukin-6 (IL-6)-induced stress proteins including C-reactive protein (CRP), complement 3 (C3), Flt-3 ligand, and corticosterone. CD2F1 male mice received 8.75 Gy 60Co gamma photons (0.6 Gy/min, bilateral) which was followed by a hemorrhage of 20% of the blood volume. In serum, RI caused an increase of IL-1, IL-2, IL-3, IL-5, IL-6, IL-12, IL-13, IL-15, IL-17A, IL-18, G-CSF, CM-CSF, eotaxin, IFN-γ, MCP-1, MIP, RANTES, and TNF-α, which were all increased by hemorrhage alone, except IL-9, IL-17A, and MCP-1. Nevertheless, CI further elevated RI-induced increases of these cytokines except for G-CSF, IFN- γ and RANTES in serum. In the ileum, hemorrhage in the CI model significantly enhanced RI-induced IL-1β, IL-3, IL-6, IL-10, IL-12p70, IL-13, IL-18, and TNF-α concentrations. In addition, Proteus mirabilis Gram(-) was found in only 1 of 6 surviving RI mice on Day 15, whereas Streptococcus sanguinis Gram(+) and Sphingomonas paucimobilis Gram(-) were detected in 2 of 3 surviving CI mice (with 3 CI mice diseased due to inflammation and infection before day 15) at the same time point. Hemorrhage in the CI model enhanced the RI-induced increases in C3 and decreases in CRP concentrations. However, hemorrhage alone did not alter the basal levels, but hemorrhage in the CI model displayed similar increases in Flt-3 ligand levels as RI did. Hemorrhage alone altered the basal levels of corticosterone early after injury, which then returned to the baseline, but in RI mice and CI mice the increased corticosterone concentration remained elevated throughout the 15 day study. CI increased 8 miRNAs and decreased 10 miRNAs in serum, and increased 16 miRNA and decreased 6 miRNAs in ileum tissue. Among the altered miRNAs, CI increased miR-34 in the serum and ileum which targeted an increased phosphorylation of ERK, p38, and increased NF-κB, thereby leading to increased iNOS expression and activation of caspase-3 in the ileum. Further, let-7g/miR-98 targeted the increased phosphorylation of STAT3 in the ileum, which is known to bind to the iNOS gene. These changes may correlate with cell death in the ileum of CI mice. The histopathology displayed blunted villi and villus edema in RI and CI mice. Based on the in silico analysis, miR-15, miR-99, and miR-100 were predicted to regulate IL-6 and TNF. These results suggest that CI-induced alterations of cytokines/chemokines, CRP, and C3 cause a homeostatic imbalance and may contribute to the pathophysiology of the gastrointestinal injury. Inhibitory intervention in these responses may prove therapeutic for CI and improve recovery of the ileal morphologic damage.
机译：与单独进行全身γ射线照射（RI）相比，在综合伤害（CI）模型中进行全身γ射线照射后的出血会增加死亡率。 CI生存率的降低伴随着骨髓损伤的增加，血细胞比容的降低以及肾脏中miRNA的改变。在这项研究中，我们的目的是检查细胞因子的稳态，对系统性细菌感染的敏感性以及肠道损伤。更具体地说，我们评估了白介素6（IL-6）诱导的应激蛋白，包括C反应蛋白（CRP），补体3（C3），Flt-3配体和皮质酮。 CD2F1雄性小鼠接受8.75 Gy 60 Coγ光子（0.6 Gy / min，双侧），随后出血量为血液的20％。血清中RI导致IL-1，IL-2，IL-3，IL-5，IL-6，IL-12，IL-13，IL-15，IL-17A，IL-18，G- CSF，CM-CSF，嗜酸性粒细胞趋化因子，IFN-γ，MCP-1，MIP，RANTES和TNF-α都仅因出血而增加，但IL-9，IL-17A和MCP-1除外。尽管如此，CI进一步升高了RI诱导的这些细胞因子的升高，除了血清中的G-CSF，IFN-γ和RANTES。在回肠中，CI模型中的出血显着增强了RI诱导的IL-1β，IL-3，IL-6，IL-10，IL-12p70，IL-13，IL-18和TNF-α的浓度。此外，在第15天，仅在6只存活的RI小鼠中发现1只奇异变形杆菌Gram（-），而在3只存活的CI小鼠中有2只（其中3只CI被发现）血红链球菌Gram（+）和Sphingomonas paucimobilis Gram（-）。在第15天之前）在同一时间点因炎症和感染而患病的小鼠。 CI模型中的出血增强了RI诱导的C3升高和CRP浓度降低。然而，仅出血并不能改变基础水平，但是CI模型中的出血显示出与RI相似的Flt-3配体水平增加。单独的出血会在损伤后早期改变皮质酮的基础水平，然后恢复到基线，但是在RI小鼠和CI小鼠中，皮质酮的增加浓度在整个15天的研究中均保持升高。 CI在血清中增加了8个miRNA，减少了10个miRNA，在回肠组织中增加了16个miRNA，减少了6个miRNA。在改变的miRNA中，CI可增加血清和回肠中的miR-34，从而靶向增加ERK，p38的磷酸化并增加NF-κB，从而导致回肠中iNOS表达增加和caspase-3活化。此外，let-7g / miR-98靶向回肠中STAT3磷酸化的增加，已知该磷酸化与iNOS基因结合。这些变化可能与CI小鼠回肠中的细胞死亡有关。组织病理学在RI和CI小鼠中显示出钝的绒毛和绒毛水肿。根据计算机分析，预测miR-15，miR-99和miR-100可以调节IL-6和TNF。这些结果表明CI诱导的细胞因子/趋化因子，CRP和C3的改变会引起体内平衡失衡，并可能有助于胃肠道损伤的病理生理。在这些反应中的抑制性干预可能证明对CI具有治疗作用，并改善了回肠形态损伤的恢复。

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