PAD4 Deficiency Leads to Decreased Organ Dysfunction and Improved Survival in a Dual Insult Model of Hemorrhagic Shock and Sepsis.
PAD4 Deficiency Leads to Decreased Organ Dysfunction and Improved Survival in a Dual Insult Model of Hemorrhagic Shock and Sepsis.
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DOI：
10.4049/jimmunol.1700639
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发表时间：
2018-03-01
期刊：
影响因子：
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通讯作者：
Ayala A
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文献类型：
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作者：
Biron BM;Chung CS;Chen Y;Wilson Z;Fallon EA;Reichner JS;Ayala A
间接急性呼吸窘迫综合征（iARDS）是由非肺部脓毒症等损伤引起的非肺部炎症过程引起的。中性粒细胞被认为在介导ARDS中起重要作用，iARDS的发展特征在于活化的中性粒细胞失调和募集到肺中。最近，中性粒细胞通过形成中性粒细胞胞外陷阱（NETs）来杀死微生物的一种新机制被确定。NET由从活化的中性粒细胞释放到细胞外空间的大的去浓缩染色质网组成;它们由酶PAD 4通过靶组蛋白的瓜氨酸介导染色质去浓缩来调节。NET的成分与ARDS有关。然而，在非肺损伤间接引起的ARDS中，NET的形成是否有病理学意义尚不清楚。我们使PAD 4-/-小鼠和野生型（WT）小鼠经受低血容量性休克（固定压力出血; Hem）的“2次打击”模型，随后是脓毒性盲肠结扎和穿孔（CLP）损伤（Hem/CLP）。将小鼠处死并复苏; Hem后24小时，然后对小鼠进行CLP。总体而言，与WT小鼠相比，PAD 4缺失导致存活率改善。PAD 4-/-小鼠表现出中性粒细胞流入肺的显著减少，以及促炎介质的存在减少。PAD 4-/-小鼠在Hem/CLP后也能够维持基线肾功能。这些数据综合起来表明，PAD 4介导的NET形成导致了与休克/脓毒症相关的死亡率，并且可能在出血和脓毒症联合引起的终末器官损伤的病理生物学中发挥作用。
Indirect Acute Respiratory Distress Syndrome (iARDS) is caused by a non-pulmonary inflammatory process resulting from insults such as non-pulmonary sepsis. Neutrophils are thought to play a significant role in mediating ARDS, with the development of iARDS being characterized by dysregulation and recruitment of activated neutrophils into the lung. Recently, a novel mechanism of microbial killing by neutrophils was identified through the formation of neutrophil extracellular traps (NETs). NETs are comprised of large webs of decondensed chromatin released from activated neutrophils into the extracellular space; they are regulated by the enzyme PAD4 through mediation of chromatin decondensation via citrullination of target histones. Components of NETs have been implicated in ARDS. However, it is unknown if there is any pathological significance of NET formation in ARDS caused indirectly by non-pulmonary insult. We subjected PAD4-/- mice and wildtype (WT) mice to a “2 hit” model of hypovolemic shock (fixed-pressure hemorrhage; Hem) followed by septic cecal ligation and puncture (CLP) insult (Hem/CLP). Mice were hemorrhaged and resuscitated; 24 hours post-Hem mice were then subjected to CLP. Overall, PAD4 deletion led to an improved survival as compared to WT mice. PAD4-/- mice displayed a marked decrease in neutrophil influx into the lung, as well decreased presence of pro-inflammatory mediators. PAD4-/- mice were also able to maintain baseline kidney function after Hem/CLP. These data taken together suggest PAD4-mediated NET formation contributes to the mortality associated with Shock/Sepsis and may play a role in the pathobiology of end organ injury in response to combined hemorrhage plus sepsis.