Lipopolysaccharide-induced lung injury does not require production of reactive oxygen species by NAD(P)H oxidase

Abstract

We examined toll-like receptor 4 (TLR4) protein signaling in the innate immune response to the invasion of the body by gram negative bacteria. When humans are exposed to lipopolysaccharide (LPS or endotoxin), neutrophils attach to the endothelium and infiltrate the lung. This involves activation of TLR4 on the endothelium and on neutrophils and the subsequent activation of cell signaling pathways, such as NF-kB and other transcription factors that stimulate reactive oxygen species (ROS) production, to promote the inflammation process. The activation of endothelial TLR4 produces a generalized inflammatory response that includes activation of adhesion molecules which results in the accumulation of neutrophils on the endothelial side of the inflamed tissue. To test the role of ROS production by NAD(P)H oxidase in this process, wild type (WT) mice and mice deficient in the p47phox component of NAD(P)H oxidase enzyme (KO) were challenged with LPS and the degree of pulmonary injury was assessed. In both WT and KO mice maximal lung injury was observed 4 hours after challenge with LPS. In contrast to WT mice, lung injury in KO mice was more severe and persisted for 8 hours