Genetic deficiency of NADPH oxidase does not diminish, but rather enhances, LPS-induced acute inflammatory responses in vivo

Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
Free Radical Biology and Medicine (Impact Factor: 5.71). 03/2009; 46(6):791-798. DOI: 10.1016/j.freeradbiomed.2008.12.003

ABSTRACT Reactive oxygen species (ROS) and oxidative stress are thought to play a central role in the etiology of cell dysfunction and tissue damage in sepsis. However, there is limited and controversial evidence from in vivo studies that ROS mediate cell signaling processes that elicit acute inflammatory responses during sepsis. Because NADPH oxidase is one of the main cellular sources of ROS, we investigated the role of this enzyme in lipopolysaccharide (LPS)-induced acute inflammation in vivo, utilizing mice deficient in the gp91phox or p47phox subunits of NADPH oxidase. Age-and body weight-matched C57BL/6J wild-type (WT) and gp91phox−/− and p47phox−/− mice were injected ip with 50 μg LPS or saline vehicle and sacrificed at various time points up to 24 h. We found that LPS-induced acute inflammatory responses in serum and tissues were not significantly diminished in gp91phox−/− and p47phox−/− mice compared to WT mice. Rather, genetic deficiency of NADPH oxidase was associated with enhanced gene expression of inflammatory mediators and increased neutrophil recruitment to lung and heart. Furthermore, no protection from LPS-induced septic death was observed in either knockout strain. Our findings suggest that NADPH oxidase-mediated ROS production and cellular redox signaling do not promote, but instead limit, LPS-induced acute inflammatory responses in vivo.

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Available from: Hao Wei, Mar 20, 2015
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    • "Sadikot et al. (2004) have demonstrated that the activation of RelA subunit of NF-jB was decreased in the lungs of p47 phox-/-and gp91 phox-/-mice compared with wild-type (WT) mice in response to CS exposure. In contrast, other report demonstrated that NADPH deficiency enhances LPS-induced acute inflammatory responses in vivo (Zhang et al. 2009). Furthermore, a low i.p. dose of LPS [5 lg/g body weight (bw)], equally induced pulmonary NF-jB activation in p47 phox-/-and WT mice, however, 20 lg/g bw, i.p. dose of LPS-mediated NF-jB activation was lower in p47 phox-/mice (Koay et al. 2001). "
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    • "These results might also be related to clinical observations in patients with the X-linked form of chronic granulomatous disease (gp91 phox deficiency), who are more prone to infection and present with hyperinflammatory conditions [45] [46] [47]. However, in this study we showed that reduced phagocytic NOX- ROS diminished TNFα-induced acute lung inflammatory responses and lung injury, which is opposite to our observations in mice exposed to LPS instead of TNFα [21]. These apparently discrepant results highlight the above notion that the role of ROS in cell signaling and inflammatory gene expression can vary widely depending on, e.g., the proinflammatory cytokine or bacterial agent used and the affected tissue or cell type. "
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