Title | Genetic ablation of phagocytic NADPH oxidase in mice limits TNFα-induced inflammation in the lungs but not other tissues. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Zhang W-J, Wei H, Tien Y-T, Frei B |
Journal | Free Radic Biol Med |
Volume | 50 |
Issue | 11 |
Pagination | 1517-25 |
Date Published | 2011 Jun 01 |
ISSN | 1873-4596 |
Keywords | Animals, Cell Movement, Cytokines, E-Selectin, Inflammation Mediators, Leukocytes, Mononuclear, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, NADPH Oxidase 2, NADPH Oxidases, NF-kappa B, Phagocytes, Pneumonia, Reactive Oxygen Species, Transcriptional Activation, Tumor Necrosis Factor-alpha |
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. |
DOI | 10.1016/j.freeradbiomed.2011.02.027 |
Alternate Journal | Free Radic. Biol. Med. |
PubMed ID | 21376114 |
PubMed Central ID | PMC3090478 |
Grant List | P01 AT002034-04 / AT / NCCIH NIH HHS / United States P01 AT002034-02 / AT / NCCIH NIH HHS / United States P01 AT002034-03 / AT / NCCIH NIH HHS / United States P01 AT002034-09 / AT / NCCIH NIH HHS / United States P01 AT002034-08 / AT / NCCIH NIH HHS / United States P01 AT002034-06 / AT / NCCIH NIH HHS / United States P01 AT002034-07 / AT / NCCIH NIH HHS / United States P01 AT002034-05 / AT / NCCIH NIH HHS / United States P01 AT002034 / AT / NCCIH NIH HHS / United States P01 AT002034-01 / AT / NCCIH NIH HHS / United States |