Differential NF-kappaB activation after intratracheal endotoxin.

Abstract

We examined the relationship between nuclear factor (NF)-kappaB DNA binding activity, cytokine gene expression, and neutrophilic alveolitis in rats after intratracheal (IT) instillation of endotoxin [lipopolysaccharide (LPS)]. NF-kappaB activation in lung tissue mirrored neutrophilic alveolitis after IT LPS instillation, with NF-kappaB activation and neutrophilic influx beginning 2 h after IT LPS doses of 0.01 mg/kg or greater. In lung lavage fluid cells, however, transient NF-kappaB activation was present in alveolar macrophages by 15 min after IT LPS instillation, followed by a second peak of NF-kappaB activation corresponding to the onset on neutrophilic alveolitis. For cytokines thought to be NF-kappaB dependent, two different patterns of mRNA expression were found. Interleukin (IL)-1alpha, IL-1beta, and tumor necrosis factor-alpha showed increased mRNA by 30 min after IT LPS instillation, but IL-6- and cytokine-induced neutrophil chemoattractant mRNAs were not substantially increased until 2 h after IT LPS instillation. Therefore, IT LPS causes differential NF-kappaB activation in air space cells and lung tissue, which likely determines production of key cytokines and directs the evolution of neutrophilic alveolitis.