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

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

Research output: Contribution to journalArticlepeer-review

189 Scopus citations

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 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-κ 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.

Original languageEnglish (US)
Pages (from-to)4995-5005
Number of pages11
JournalJournal of Immunology
Volume176
Issue number8
DOIs
StatePublished - Apr 15 2006
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint

Dive into the research topics of 'Duration and intensity of NF-κB activity determine the severity of endotoxin-induced acute lung injury'. Together they form a unique fingerprint.

Cite this