Duration and intensity of NF-kappaB activity determine the severity of endotoxin-induced acute lung injury.

Everhart MB, Han W, Sherrill TP, Arutiunov M, Polosukhin VV, Burke JR, Sadikot RT, Christman JW, Yull FE, Blackwell TS
J Immunol. 2006 176 (8): 4995-5005

PMID: 16585596 · DOI:10.4049/jimmunol.176.8.4995

Activation of innate immunity in the lungs can lead to a self-limited inflammatory response or progress to severe lung injury. We investigated whether specific parameters of NF-kappaB pathway activation determine the outcome of acute lung inflammation using a novel line of transgenic reporter mice. Following a single i.p. injection of Escherichia coli LPS, transient NF-kappaB activation was identified in a variety of lung cell types, and neutrophilic inflammation resolved without substantial tissue injury. However, administration of LPS over 24 h by osmotic pump (LPS pump) implanted into the peritoneum resulted in sustained, widespread NF-kappaB activation and neutrophilic inflammation that culminated in lung injury at 48 h. To determine whether intervention in the NF-kappaB pathway could prevent progression to lung injury in the LPS pump model, we administered a specific IkappaB kinase inhibitor (BMS-345541) to down-regulate NF-kappaB activation following the onset of inflammation. Treatment with BMS-345541 beginning at 20 h after osmotic pump implantation reduced lung NF-kappaB activation, concentration of KC and MIP-2 in lung lavage, neutrophil influx, and lung edema measured at 48 h. Therefore, sustained NF-kappaB activation correlates with severity of lung injury, and interdiction in the NF-kappaB pathway is beneficial even after the onset of lung inflammation.

MeSH Terms (17)

Animals Female I-kappa B Kinase Imidazoles Immunity, Innate Inflammation Lipopolysaccharides Lung Lung Injury Male Mice Mice, Inbred C57BL Mice, Inbred DBA Mice, Transgenic NF-kappa B Protein Kinase Inhibitors Quinoxalines

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