Hemorrhagic shock activates lung endothelial reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase via neutrophil NADPH oxidase

Meng Xiang, Lianhua Yin, Yuehua Li, Guozhi Xiao, Yoram Vodovotz, Timothy R. Billiar, Mark A. Wilson, Jie Fan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


The vascular endothelium plays an important role in the regulation of inflammatory responses after trauma and hemorrhage. Interactions of neutrophils with endothelial cells (ECs) contribute to the activation of specific EC responses involved in innate immunity.We have previously reported that oxidants derived from the neutrophil reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a critical regulator to EC activation. Our objective was to test the role of neutrophil NADPH oxidase-derived oxidants in mediating and enhancing hemorrhagic shock (HS)-induced activation of lung endothelial NADPH oxidase. Mice were subjected to HS and neutrophil depletion. The mice were also replenished with the neutrophil from NADPH oxidase-deficient mice. The resultant activation of lung NADPH oxidase was analyzed. The in vivo studies were also recapitulated with in vitro neutrophil-EC coculture system. HS induces NADPH oxidase activation in neutrophils and lung through high-mobility group box 1/Toll-like receptor 4-dependent signaling. In neutropenic mice, shock-induced NADPH oxidase activation in the lung was reduced significantly, but was restored upon repletion with neutrophils obtained from wild-type mice subjected to shock, but not with neutrophils from shock mice lacking the gp91phox subunit of NADPH oxidase. The findings were recapitulated in mouse lung vascular ECs cocultured with neutrophils. The data further demonstrate that neutrophil-derived oxidants are key factors mediating augmented High mobility group box 1 (HMGB1)-induced endothelial NADPH oxidase activation through a Rac1-dependent, but p38 mitogen-activated protein kinase-independent, pathway. Oxidant signaling by neutrophil NADPH oxidase is an important determinant of activation of endothelial NADPH oxidase after HS.

Original languageEnglish
Pages (from-to)333-340
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Issue number3
StatePublished - 1 Mar 2011
Externally publishedYes


  • High mobility group box 1 (HMGB1)
  • Inflammation
  • Lung
  • Oxidants
  • Toll-like receptor


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