Genetic ablation of phagocytic NADPH oxidase in mice limits TNFα-induced inflammation in the lungs but not other tissues.

Abstract

In vitro and limited in vivo evidence suggests that reactive oxygen species derived from NADPH oxidases (NOX-ROS) play an important role in inflammatory responses by enhancing the activity of redox-sensitive cell signaling pathways and transcription factors. Here, we investigated the role of NOX-ROS in TNFα-induced acute inflammatory responses in vivo, using mice deficient in the gp91(phox) (NOX2) or p47(phox) subunits of NADPH oxidase. Age- and body weight-matched C57BL/6J wild-type (WT) and gp91(phox) or p47(phox) knockout mice were injected intraperitoneally with 50 μg TNFα/kg bw or saline vehicle control and sacrificed at various time points up to 24 h. Compared to WT mice, gp91(phox -/-) mice exhibited significantly diminished (P<0.05) TNFα-induced acute inflammatory responses in the lungs but not other tissues, including heart, liver, and kidney, as evidenced by decreased activation of the redox-sensitive transcription factor NF-κB, and decreased gene expression of interleukin (IL)-1β, IL-6, TNFα, E-selectin, and other cellular adhesion molecules. Similar results were observed in p47(phox -/-) mice. Interestingly, decreased lung inflammation in knockout mice was accompanied by increased leukocyte infiltration into the lungs compared to other tissues. Our data suggest that phagocytic NOX-ROS signaling plays a critical role in promoting TNFα-induced, NF-κB-dependent acute inflammatory responses and tissue injury specifically in the lungs, which is effected by preferential leukocyte infiltration.

• Authors: Wei-Jian Zhang, Hao Wei, Ying-Tzang Tien, Balz Frei
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 50 Issue 11 Pg. 1517-25 (Jun 01 2011) ISSN: 1873-4596 [Electronic] United States
• PMID: 21376114 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• E-Selectin
• Inflammation Mediators
• Membrane Glycoproteins
• NF-kappa B
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• Cybb protein, mouse
• NADPH Oxidase 2
• NADPH Oxidases
• neutrophil cytosolic factor 1

Topics

• Animals
• Cell Movement (drug effects)
• Cytokines (genetics, metabolism)
• E-Selectin (genetics, metabolism)
• Inflammation Mediators (metabolism)
• Leukocytes, Mononuclear (immunology, metabolism, pathology)
• Membrane Glycoproteins (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NADPH Oxidase 2
• NADPH Oxidases (genetics)
• NF-kappa B (genetics, metabolism)
• Phagocytes (immunology, metabolism, pathology)
• Pneumonia (chemically induced, genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Transcriptional Activation (drug effects)
• Tumor Necrosis Factor-alpha (administration & dosage)