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Published ahead of print on July 11, 2003, doi:10.1164/rccm.200303-412OC

Am. J. Respir. Crit. Care Med., Volume 168, Number 7, October 2003, 810-817

A more recent version of this article appeared on October 1, 2003
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Submitted on March 24, 2003
Accepted on July 2, 2003

NF-{kappa}B p50 limits inflammation and prevents lung injury during E. coli pneumonia

Joseph P Mizgerd1*, Michal M Lupa1, Mariya S Kogan1, Henry B Warren2, Lester Kobzik1, and George P Topulos3

1 Physiology Program, Harvard School of Public Health, Boston, MA, USA, 2 Center for Animal Resources and Comparative Medicine, Harvard Medical School, Boston, MA, USA, 3 Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: jmizgerd{at}hsph.harvard.edu.

Inflammatory responses to infection must be precisely regulated to facilitate microbial killing while limiting host tissue damage. Many inflammatory genes are regulated by {kappa}B sites, and the p50 subunit of NF-{kappa}B suppresses the expression of {kappa}B-associated genes in vitro. We hypothesized that p50 is essential to preventing excessive inflammation and injury during infection. During pulmonary infection with E. coli, the gene-targeted deficiency of p50 did not affect bacterial clearance from mouse lungs, but it resulted in increased expression of pro-inflammatory cytokines 6-24 hours after infection. This dysregulation exacerbated inflammation (neutrophil recruitment), respiratory distress (pulmonary edema and blood-gas exchange impairment), and decompartmentalization (transit of protein and bacteria from the air spaces to the blood). We interpret these studies to indicate that endogenous p50 protects the host by curbing inflammatory responses to prevent injury, essential to surviving pneumonia.
Key words: Acute Lung Injury, Bacterial Pneumonia, Cytokines, Neutrophil Recruitment, Transcription Factors




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