Hemorrhagic Shock Activation of NLRP3 Inflammasome in Lung Endothelial Cells

被引:128
作者
Xiang, Meng [2 ,3 ]
Shi, Xiaolian [2 ,4 ]
Li, Yuehua [2 ]
Xu, Jia [2 ,5 ]
Yin, Lianhua [3 ]
Xiao, Guozhi [6 ]
Scott, Melanie J. [2 ]
Billiar, Timothy R. [2 ]
Wilson, Mark A. [2 ]
Fan, Jie [1 ,2 ]
机构
[1] Vet Affairs Pittsburgh Healthcare Syst, Dept Surg, Res & Dev, Pittsburgh, PA 15240 USA
[2] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA
[3] Fudan Univ, Shanghai Med Coll, Dept Physiol & Pathophysiol, Shanghai 200032, Peoples R China
[4] Xi An Jiao Tong Univ, Coll Med, Dept Pharmacol, Xian 710061, Peoples R China
[5] So Med Univ, Dept Pathophysiol, Guangzhou 510515, Guangdong, Peoples R China
[6] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA
基金
美国国家卫生研究院;
关键词
MOBILITY GROUP BOX-1; INTERLEUKIN-1 RECEPTOR ANTAGONIST; RESPIRATORY-DISTRESS-SYNDROME; NEUTROPHIL NADPH OXIDASE; MULTIPLE ORGAN FAILURE; SEVERE BLUNT TRAUMA; TLR2; UP-REGULATION; NAD(P)H OXIDASE; ISCHEMIA/REPERFUSION INJURY; ALVEOLAR MACROPHAGES;
D O I
10.4049/jimmunol.1102093
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
071005 [微生物学]; 100108 [医学免疫学];
摘要
Hemorrhagic shock (HS) due to major trauma and surgery predisposes the host to the development of systemic inflammatory response syndrome (SIRS), including acute lung injury (ALI), through activating and exaggerating the innate immune response. IL-1 beta is a crucial proinflammatory cytokine that contributes to the development of SIRS and ALI. Lung endothelial cells (EC) are one important source of IL-1 beta, and the production of active IL-1 beta is controlled by the inflammasome. In this study, we addressed the mechanism underlying HS activation of the inflammasome in lung EC. We show that high mobility group box 1 acting through TLR4, and a synergistic collaboration with TLR2 and receptor for advanced glycation end products signaling, mediates HS-induced activation of EC NAD(P) H oxidase. In turn, reactive oxygen species derived from NAD(P) H oxidase promote the association of thioredoxin-interacting protein with the nucleotide-binding oligomerization domain-like receptor protein NLRP3 and subsequently induce inflammasome activation and IL-1 beta secretion from the EC. We also show that neutrophil-derived reactive oxygen species play a role in enhancing EC NAD(P) H oxidase activation and therefore an amplified inflammasome activation in response to HS. The present study explores a novel mechanism underlying HS activation of EC inflammasome and thus presents a potential therapeutic target for SIRS and ALI induced after HS. The Journal of Immunology, 2011, 187: 4809-4817.
引用
收藏
页码:4809 / 4817
页数:9
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