Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1α Release.
Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1α Release.
复制标题
DOI：
10.1016/j.immuni.2015.03.007
复制
发表时间：
2015-04-21
期刊：
影响因子：
32.4
通讯作者：
Arditi, Moshe
中科院分区：
文献类型：
--
作者：
Dagvadorj, Jargalsaikhan;Shimada, Kenichi;Chen, Shuang;Jones, Heather D.;Tumurkhuu, Gantsetseg;Zhang, Wenxuan;Wawrowsky, Kolja A.;Crother, Timothy R.;Arditi, Moshe
急性肺损伤（ALI）仍然是一个严重的健康问题，我们对病理生理学和治疗方法的理解几乎没有改善。我们研究了脂多糖（LPS）诱导早期中性粒细胞向肺募集并增加肺血管通透性的机制。内毒素（LPS）诱导坏死肺泡巨噬细胞（AM）释放白细胞介素1α（IL 1α）前体，激活内皮细胞（EC），通过血管内皮细胞钙粘蛋白（VE-cadherin）的丢失诱导血管渗漏。LPS激活AM嘌呤受体P2 X7（R），引起Ca ~（2+）内流和ATP耗竭，导致坏死。P2 X7 R缺乏可显著减少AM的坏死性死亡和pro-IL-1α向肺内的释放。LPS与P2 X7 R的结合需要CD 14，因为CD 14中和显著减少LPS诱导的AM坏死性死亡和pro-IL-1α释放。这些结果表明，在LPS介导的ALI中，来自坏死肺泡巨噬细胞的pro-IL-1α作为血管通透性增加和早期中性粒细胞浸润的关键起始物发挥关键作用。
Acute lung injury (ALI) remains a serious health issue with little improvement in our understanding of the pathophysiology and therapeutic approaches. We investigated the mechanism that lipopolysaccharide (LPS) induces early neutrophil recruitment to lungs and increases pulmonary vascular permeability during ALI. Intratracheal LPS induced release of pro-interleukin-1α (IL-1α) from necrotic alveolar macrophages (AM), which activated endothelial cells (EC) to induce vascular leakage via loss of vascular endothelial (VE)-cadherin. LPS triggered the AM purinergic receptor P2X7(R) to induce Ca2+ influx and ATP depletion, which led to necrosis. P2X7R deficiency significantly reduced necrotic death of AM and release of pro-IL-1α into the lung. CD14 was required for LPS binding to P2X7R, as CD14 neutralization significantly diminished LPS induced necrotic death of AM and pro-IL-1α release. These results demonstrate a key role for pro-IL-1α from necrotic alveolar macrophages in LPS-mediated ALI, as a critical initiator of increased vascular permeability and early neutrophil infiltration.
登录
查看更多内容
影响因子：
4
作者：
Dejana, Elisabetta;Orsenigo, Fabrizio;Lampugnani, Maria Grazia
通讯作者：
Lampugnani, Maria Grazia
影响因子：
17.1
作者：
London NR;Zhu W;Bozza FA;Smith MC;Greif DM;Sorensen LK;Chen L;Kaminoh Y;Chan AC;Passi SF;Day CW;Barnard DL;Zimmerman GA;Krasnow MA;Li DY
通讯作者：
Li DY
影响因子：
32.4
作者：
Hou, Baidong;Reizis, Boris;DeFranco, Anthony L.
通讯作者：
DeFranco, Anthony L.
影响因子：
4.4
作者：
Denlinger, LC;Fisette, PL;Bertics, PJ
通讯作者：
Bertics, PJ
影响因子：
82.9
作者：
Chen, Chun-Jen;Kono, Hajime;Rock, Kenneth L.
通讯作者：
Rock, Kenneth L.