Karpurapu Manjula, Lee Yong Gyu, Qian Ziqing, Wen Jin, Ballinger Megan N, Rusu Luiza, Chung Sangwoon, Deng Jing, Qian Feng, Reader Brenda F, Nirujogi Teja Srinivas, Park Gye Young, Pei Dehua, Christman John W
Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH 43210, USA.
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
Oncotarget. 2018 Jan 25;9(12):10606-10620. doi: 10.18632/oncotarget.24320. eCollection 2018 Feb 13.
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.
目前缺乏针对脓毒症诱导的急性肺损伤（ALI）发病机制中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（NFATc3）在脓毒症诱导的ALI过程中调节巨噬细胞表型方面的关键作用，随后的研究表明NFATc3在转录水平上调节巨噬细胞CCR2和TNFα基因的表达。当与脂多糖（LPS）刺激的NFATc3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，而野生型巨噬细胞则导致单层屏障渗漏。更重要的是，在致死性盲肠结扎穿孔（CLP）脓毒症小鼠模型中，NFATc3缺陷型小鼠的中性粒细胞性肺部炎症减轻，肺泡毛细血管屏障功能改善，动脉血氧饱和度提高，且具有生存优势。此外，接受致死性CLP脓毒症的野生型小鼠使用广谱抗生素后生存率并未提高，而NFATc3缺陷型小鼠用亚胺培南治疗后生存率提高到40%-60%。被动过继转移NFATc3缺陷型巨噬细胞可使野生型小鼠免受LPS诱导的ALI。此外，CP9-ZIZIT是一种高效、可穿透细胞的钙调神经磷酸酶肽抑制剂，可抑制NFATc3的激活。CP9-ZIZIT有效降低了小鼠脓毒症诱导的炎性细胞因子和肺水肿。因此，本研究表明CP9-ZIZIT抑制NFATc3激活为减轻脓毒症诱导的ALI/肺水肿提供了一种潜在的治疗选择。
