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

Abstract

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.

• Authors: M Brett Everhart, Wei Han, Taylor P Sherrill, Melissa Arutiunov, Vasiliy V Polosukhin, James R Burke, Ruxana T Sadikot, John W Christman, Fiona E Yull, Timothy S Blackwell
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 176 Issue 8 Pg. 4995-5005 (Apr 15 2006) ISSN: 0022-1767 [Print] United States
• PMID: 16585596 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
• Imidazoles
• Lipopolysaccharides
• NF-kappa B
• Protein Kinase Inhibitors
• Quinoxalines
• I-kappa B Kinase

Topics

• Animals
• Female
• I-kappa B Kinase (antagonists & inhibitors)
• Imidazoles (pharmacology)
• Immunity, Innate
• Inflammation (chemically induced, immunology, metabolism, pathology)
• Lipopolysaccharides (toxicity)
• Lung (drug effects, immunology, metabolism)
• Lung Injury
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Transgenic
• NF-kappa B (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Quinoxalines (pharmacology)