Inhibition of nuclear factor of activated T cells (NFAT) c3 activation attenuates acute lung injury and pulmonary edema in murine models of sepsis.
Inhibition of nuclear factor of activated T cells (NFAT) c3 activation attenuates acute lung injury and pulmonary edema in murine models of sepsis.
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DOI：
10.18632/oncotarget.24320
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发表时间：
2018-02-13
期刊：
影响因子：
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通讯作者：
Christman JW
中科院分区：
文献类型：
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作者：
Karpurapu M;Lee YG;Qian Z;Wen J;Ballinger MN;Rusu L;Chung S;Deng J;Qian F;Reader BF;Nirujogi TS;Park GY;Pei D;Christman JW
缺乏针对脓毒症诱导的急性肺损伤（ALI）发病机制的细胞和分子事件的特异性疗法。我们已经报道了活化T细胞核因子（NFATc 3）在脓毒症诱导的ALI中调节巨噬细胞表型的关键作用，随后的研究表明NFATc 3转录调节巨噬细胞CCR 2和TNFα基因表达。当与LPS刺激的NFATc 3缺陷型巨噬细胞共培养时，小鼠肺微血管内皮细胞单层保持更紧密的屏障功能，而野生型巨噬细胞导致单层屏障渗漏。更重要的是，NFATc 3缺陷小鼠在致死性CLP脓毒症小鼠模型中表现出嗜酸性肺部炎症减少，肺泡毛细血管屏障功能改善，动脉血氧饱和度和生存益处。此外，遭受致死性CLP脓毒症的野生型小鼠的存活率没有用广谱抗生素改善，而NFATc 3缺陷型小鼠的存活率在用亚胺培南治疗时改善至40-60%。NFATc 3缺陷型巨噬细胞的被动过继转移在野生型小鼠中赋予针对LPS诱导的ALI的保护。此外，CP 9-ZIZIT，一种钙调磷酸酶的高效细胞渗透性肽抑制剂，抑制NFATc 3活化。CP 9-ZIZIT有效地减少脓毒症诱导的小鼠炎性细胞因子和肺水肿。因此，该研究表明，通过CP 9-ZIZIT抑制NFATc 3活化为减弱脓毒症诱导的ALI/肺水肿提供了潜在的治疗选择。
Specific therapies targeting cellular and molecular events of sepsis induced Acute Lung Injury (ALI) pathogenesis are lacking. We have reported a pivotal role for Nuclear Factors of Activated T cells (NFATc3) in regulating macrophage phenotype during sepsis induced ALI and subsequent studies demonstrate that NFATc3 transcriptionally regulates macrophage CCR2 and TNFα gene expression. Mouse pulmonary microvascular endothelial cell monolayer maintained a tighter barrier function when co-cultured with LPS stimulated NFATc3 deficient macrophages whereas wild type macrophages caused leaky monolayer barrier. More importantly, NFATc3 deficient mice showed decreased neutrophilic lung inflammation, improved alveolar capillary barrier function, arterial oxygen saturation and survival benefit in lethal CLP sepsis mouse models. In addition, survival of wild type mice subjected to the lethal CLP sepsis was not improved with broad-spectrum antibiotics, whereas the survival of NFATc3 deficient mice was improved to 40–60% when treated with imipenem. Passive adoptive transfer of NFATc3 deficient macrophages conferred protection against LPS induced ALI in wild type mice. Furthermore, CP9-ZIZIT, a highly potent, cell-permeable peptide inhibitor of Calcineurin inhibited NFATc3 activation. CP9-ZIZIT effectively reduced sepsis induced inflammatory cytokines and pulmonary edema in mice. Thus, this study demonstrates that inhibition of NFATc3 activation by CP9-ZIZIT provides a potential therapeutic option for attenuating sepsis induced ALI/pulmonary edema.