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

MB Everhart, W Han, TP Sherrill… - The Journal of …, 2006 - journals.aai.org
MB Everhart, W Han, TP Sherrill, M Arutiunov, VV Polosukhin, JR Burke, RT Sadikot
The Journal of Immunology, 2006journals.aai.org
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 ip 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 …
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-κB pathway activation determine the outcome of acute lung inflammation using a novel line of transgenic reporter mice. Following a single ip 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.
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