Extracellular ATP drives systemic inflammation, tissue damage and mortality.
Extracellular ATP drives systemic inflammation, tissue damage and mortality.
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DOI：
10.1038/cddis.2014.70
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发表时间：
2014-03-06
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
全身炎症反应综合征(SIRS)可由感染性和无菌损伤引起，如创伤、缺血再灌注或烧伤。它们的特点是早期过度产生炎性细胞因子和内源性释放几种有毒和破坏性的分子。这些对于抗击和解决SIRS的原因是必要的，但往往最终会逐渐损害细胞和组织，导致威胁生命的多器官功能障碍综合征(MODS)。由于炎症体依赖的细胞因子如白介素1β在全身炎症反应综合征的发展和死亡中起关键作用，而三磷酸腺苷是体外炎症体的重要激活剂，我们决定在内毒素诱导的小鼠炎症模型中分析三磷酸腺苷的去除对防止过度的组织损伤和死亡的能力。我们的结果确实表明细胞外ATP具有重要的促炎作用。然而，三磷酸腺苷的作用并不局限于炎症小体的激活。用全身性apyrase去除细胞外的三磷酸腺苷不仅可以防止IL-1β的积聚，还可以防止非炎症体细胞因子的产生，如肿瘤坏死因子和IL-10。此外，去除ATP还可以防止全身证据表明细胞解体、线粒体损伤、细胞凋亡、肠道屏障破坏，甚至死亡。用广谱的P2嘌呤能受体拮抗剂苏拉明阻断ATP受体，虽然能模拟apyrase治疗的某些有益作用，但根本不能预防发病率或死亡率。我们的结论是，清除全身细胞外的ATP可能是减轻全身炎症损伤和SIRS毒性的一种有价值的策略。
Systemic inflammatory response syndromes (SIRS) may be caused by both infectious and sterile insults, such as trauma, ischemia-reperfusion or burns. They are characterized by early excessive inflammatory cytokine production and the endogenous release of several toxic and damaging molecules. These are necessary to fight and resolve the cause of SIRS, but often end up progressively damaging cells and tissues, leading to life-threatening multiple organ dysfunction syndrome (MODS). As inflammasome-dependent cytokines such as interleukin-1β are critically involved in the development of MODS and death in SIRS, and ATP is an essential activator of inflammasomes in vitro, we decided to analyze the ability of ATP removal to prevent excessive tissue damage and mortality in a murine LPS-induced inflammation model. Our results indeed indicate an important pro-inflammatory role for extracellular ATP. However, the effect of ATP is not restricted to inflammasome activation at all. Removing extracellular ATP with systemic apyrase treatment not only prevented IL-1β accumulation but also the production of inflammasome-independent cytokines such as TNF and IL-10. In addition, ATP removal also prevented systemic evidence of cellular disintegration, mitochondrial damage, apoptosis, intestinal barrier disruption and even mortality. Although blocking ATP receptors with the broad-spectrum P2 purinergic receptor antagonist suramin imitated certain beneficial effects of apyrase treatment, it could not prevent morbidity or mortality at all. We conclude that removal of systemic extracellular ATP could be a valuable strategy to dampen systemic inflammatory damage and toxicity in SIRS.
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影响因子：
3.8
作者：
Bultinck, Jennyfer;Brouckaert, Peter;Cauwels, Anje
通讯作者：
Cauwels, Anje
影响因子：
30.5
作者：
Cauwels, A;Janssen, B;Brouckaert, P
通讯作者：
Brouckaert, P
影响因子：
8.8
作者：
Levy, MM;Fink, MP;Ramsay, G
通讯作者：
Ramsay, G
影响因子：
4.4
作者：
Pelegrin, Pablo;Barroso-Gutierrez, Consuelo;Surprenant, Annmarie
通讯作者：
Surprenant, Annmarie
DOI：
10.4049/jimmunol.1202737
发表时间：
2013-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
He Y;Franchi L;Núñez G
通讯作者：
Núñez G