Cardiac fibroblasts contribute to myocardial dysfunction in mice with sepsis: the role of NLRP3 inflammasome activation.
Cardiac fibroblasts contribute to myocardial dysfunction in mice with sepsis: the role of NLRP3 inflammasome activation.
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心肌成纤维细胞导致脓毒症小鼠心肌功能障碍：NLRP3 炎性体激活的作用
DOI：
10.1371/journal.pone.0107639
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Rui T
中科院分区：
文献类型：
--
作者：
Zhang W;Xu X;Kao R;Mele T;Kvietys P;Martin CM;Rui T
脓毒症时心肌收缩功能障碍与发病率和死亡率的增加有关。虽然心脏抑制的潜在机制尚未完全阐明，但认为过度的炎症反应是负责的。核巧酸结合寡聚化结构域样受体（Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3，NLRP 3）炎性体是一个细胞内平台，参与白细胞介素（IL）-1β的成熟和释放。本研究的目的是评估脓毒症是否激活心脏成纤维细胞（CF）中的NLRP 3炎性小体/caspase-1/IL-1β通路，以及这种细胞因子是否随后影响心肌细胞的功能（心脏成纤维细胞-心肌细胞串扰）。我们发现，用脂多糖（LPS）处理CFs诱导NLRP 3的上调、caspase-1的活化以及IL-1β的成熟（活化）和释放。此外，CF中NLRP 3炎性体的遗传（小干扰核糖核酸[siRNA]）和药理学（格列本脲）抑制可以阻断该信号传导途径。此外，通过心肌细胞内环磷酸腺苷（cAMP）反应评估，心脏成纤维细胞中NLRP 3炎性体的抑制改善了脂蛋白激发的CF影响心肌细胞功能的能力。在内毒素血症/脓毒症的体内模型中证实了这种NLP 3炎性体/半胱天冬酶-1途径的显著特征。我们发现，抑制NLRP 3炎性体可减轻LPS小鼠的心肌功能障碍，并增加粪便诱导的腹膜炎小鼠的存活率。我们的研究结果表明，在心脏成纤维细胞中的NLRP 3炎性体的激活是在诱导脓毒症心肌功能障碍的关键。
Myocardial contractile dysfunction in sepsis is associated with the increased morbidity and mortality. Although the underlying mechanisms of the cardiac depression have not been fully elucidated, an exaggerated inflammatory response is believed to be responsible. Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome is an intracellular platform that is involved in the maturation and release of interleukin (IL)-1β. The aim of the present study is to evaluate whether sepsis activates NLRP3 inflammasome/caspase-1/IL-1β pathway in cardiac fibroblasts (CFs) and whether this cytokine can subsequently impact the function of cardiomyocytes (cardiac fibroblast-myocyte cross-talk). We show that treatment of CFs with lipopolysaccharide (LPS) induces upregulation of NLRP3, activation of caspase-1, as well as the maturation (activation) and release of IL-1β. In addition, the genetic (small interfering ribonucleic acid [siRNA]) and pharmacological (glyburide) inhibition of the NLRP3 inflammasome in CFs can block this signaling pathway. Furthermore, the inhibition of the NLRP3 inflammasome in cardiac fibroblasts ameliorated the ability of LPS-chalenged CFs to impact cardiomyocyte function as assessed by intracellular cyclic adenosine monophosphate (cAMP) responses in cardiomyocytes. Salient features of this the NLP3 inflammasome/ caspase-1 pathway were confirmed in in vivo models of endotoxemia/sepsis. We found that inhibition of the NLRP3 inflammasome attenuated myocardial dysfunction in mice with LPS and increased the survival rate in mice with feces-induced peritonitis. Our results indicate that the activation of the NLRP3 inflammasome in cardiac fibroblasts is pivotal in the induction of myocardial dysfunction in sepsis.
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影响因子：
120.7
作者：
FISHER, CJ;DHAINAUT, JFA;STABLEIN, D
通讯作者：
STABLEIN, D
影响因子：
8.8
作者：
Cain, BS;Meldrum, DR;Harken, AH
通讯作者：
Harken, AH
影响因子：
10.8
作者：
Rui, T;Feng, QP;Kvietys, PR
通讯作者：
Kvietys, PR
影响因子：
8.8
作者：
Angus, D C;Linde-Zwirble, W T;Pinsky, M R
通讯作者：
Pinsky, M R
DOI：
10.1083/jcb.200903124
发表时间：
2009-10-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lamkanfi M;Mueller JL;Vitari AC;Misaghi S;Fedorova A;Deshayes K;Lee WP;Hoffman HM;Dixit VM
通讯作者：
Dixit VM