PT  - JOURNAL ARTICLE
AU  - Everhart, M. Brett
AU  - Han, Wei
AU  - Sherrill, Taylor P.
AU  - Arutiunov, Melissa
AU  - Polosukhin, Vasiliy V.
AU  - Burke, James R.
AU  - Sadikot, Ruxana T.
AU  - Christman, John W.
AU  - Yull, Fiona E.
AU  - Blackwell, Timothy S.
TI  - Duration and Intensity of NF-κB Activity Determine the Severity of Endotoxin-Induced Acute Lung Injury
AID  - 10.4049/jimmunol.176.8.4995
DP  - 2006 Apr 15
TA  - The Journal of Immunology
PG  - 4995--5005
VI  - 176
IP  - 8
4099  - http://www.jimmunol.org/content/176/8/4995.short
4100  - http://www.jimmunol.org/content/176/8/4995.full
SO  - J. Immunol.2006 Apr 15; 176
AB  - 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-κB 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-κB 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-κB activation and neutrophilic inflammation that culminated in lung injury at 48 h. To determine whether intervention in the NF-κB pathway could prevent progression to lung injury in the LPS pump model, we administered a specific IκB kinase inhibitor (BMS-345541) to down-regulate NF-κB activation following the onset of inflammation. Treatment with BMS-345541 beginning at 20 h after osmotic pump implantation reduced lung NF-κB activation, concentration of KC and MIP-2 in lung lavage, neutrophil influx, and lung edema measured at 48 h. Therefore, sustained NF-κB activation correlates with severity of lung injury, and interdiction in the NF-κB pathway is beneficial even after the onset of lung inflammation.