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

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-kappa B 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-kappa B 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-kappa B activation and neutrophilic inflammation that culminated in lung injury at 48 h. To determine whether intervention in the NF-kappa B pathway could prevent progression to lung injury in the LPS pump model, we administered a specific I kappa B kinase inhibitor (BMS-345541) to down-regulate NF-kappa B activation following the onset of inflammation. Treatment with BMS-345541 beginning at 20 h after osmotic pump implantation reduced lung NF-kappa B activation, concentration of KC and NHP-2 in lung lavage, neutrophil influx, and lung edema measured at 48 h. Therefore, sustained NF-kappa B activation correlates with severity of lung injury, and interdiction in the NF-kappa B pathway is beneficial even after the onset of lung inflammation.