The inflammasome mediates hyperoxia-induced alveolar cell permeability.
The inflammasome mediates hyperoxia-induced alveolar cell permeability.
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DOI：
10.4049/jimmunol.0902766
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发表时间：
2010-05-15
期刊：
影响因子：
--
通讯作者：
Waxman AB
中科院分区：
文献类型：
--
作者：
Kolliputi N;Shaik RS;Waxman AB
高氧性急性肺损伤的一个标志是炎症细胞涌入肺组织并产生促炎细胞因子，例如 IL-1β；然而，高氧和肺损伤炎症反应之间的联系机制尚不清楚。炎性体蛋白复合物激活caspase-1，促进促炎细胞因子的加工和分泌。我们假设高氧诱导的 K+ 外流通过嘌呤能 P2X7 受体激活炎症小体，引起炎症和高氧急性肺损伤。为了检验这一假设，我们表征了体外暴露于高氧（95％氧气和5％CO2）的原代小鼠肺泡巨噬细胞中以及从暴露于高氧（100％氧气）的小鼠中分离的肺泡巨噬细胞中炎症小体成分的表达和激活。我们的结果表明，高氧会增加 K+ 外流、炎性小体形成、促炎细胞因子的释放以及体外和体内 caspase-1 和 IL-1β 裂解的诱导。 P2X7 激动剂 ATP 增强高氧诱导的炎症小体激活，而 P2X7 拮抗剂氧化 ATP 抑制高氧诱导的炎症小体激活。此外，当用腺苷三磷酸双磷酸酶清除ATP时，高氧诱导的炎症小体激活显着减少。此外，炎症小体成分的短发夹RNA沉默消除了体外高氧诱导的促炎细胞因子的分泌。这些结果表明，高氧诱导 K+ 通过 P2X7 受体流出，导致炎性体激活和促炎细胞因子的分泌。这些事件会影响肺泡上皮的通透性，最终导致上皮屏障功能障碍和细胞死亡。
A hallmark of hyperoxic acute lung injury is the influx of inflammatory cells to lung tissue and the production of proinflammatory cytokines, such as IL-1β; however, the mechanisms connecting hyperoxia and the inflammatory response to lung damage is not clear. The inflammasome protein complex activates caspase-1 to promote the processing and secretion of proinflammatory cytokines. We hypothesized that hyperoxia-induced K+ efflux activates the inflammasome via the purinergic P2X7 receptor to cause inflammation and hyperoxic acute lung injury. To test this hypothesis, we characterized the expression and activation of inflammasome components in primary murine alveolar macrophages exposed to hyperoxia (95% oxygen and 5% CO2) in vitro, and in alveolar macrophages isolated from mice exposed to hyperoxia (100% oxygen). Our results showed that hyperoxia increased K+ efflux, inflammasome formation, release of proinflammatory cytokines, and induction of caspase-1 and IL-1β cleavage both in vitro and in vivo. The P2X7 agonist ATP enhanced hyperoxia-induced inflammasome activation, whereas the P2X7 antagonist, oxidized ATP, inhibited hyperoxia induced inflammasome activation. In addition, when ATP was scavenged with apyrase, hyperoxia-induced inflammasome activation was significantly decreased. Furthermore, short hairpin RNA silencing of inflammasome components abrogated hyperoxia-induced secretion of proinflammatory cytokines in vitro. These results suggest that hyperoxia induces K+ efflux through the P2X7 receptor, leading to inflammasome activation and secretion of proinflammatory cytokines. These events would affect the permeability of the alveolar epithelium and ultimately lead to epithelial barrier dysfunction and cell death.
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影响因子：
12.4
作者：
Petrilli, V.;Papin, S.;Tschopp, J.
通讯作者：
Tschopp, J.
DOI：
10.1165/rcmb.2007-0287oc
发表时间：
2009-03-01
影响因子：
6.4
作者：
Kolliputi, Narasaiah;Waxman, Aaron B.
通讯作者：
Waxman, Aaron B.
影响因子：
11.2
作者：
Ahmad, KA;Iskandar, KB;Pervaiz, S
通讯作者：
Pervaiz, S
影响因子：
6.3
作者：
Abulafia, Denise P.;Vaccari, Juan Pablo de Rivero;Dietrich, W. Dalton
通讯作者：
Dietrich, W. Dalton
影响因子：
3.3
作者：
Hennige, AM;Lembert, N;Ammon, HPT
通讯作者：
Ammon, HPT