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Nuclear Factor-B p50 Limits Inflammation and Prevents Lung Injury during Escherichia coli Pneumonia

Physiology Program, Harvard School of Public Health; Center for Animal Resources and Comparative Medicine, Harvard Medical School; and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Joseph P. Mizgerd, Sc.D., Physiology Program, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115. 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 B sites, and the p50 subunit of nuclear factor-B suppresses the expression of B-associated genes in vitro. We hypothesized that p50 is essential to prevent excessive inflammation and injury during infection. During pulmonary infection with Escherichia coli, the gene-targeted deficiency of p50 did not affect bacterial clearance from mouse lungs, but it resulted in increased expression of proinflammatory cytokines 6 to 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 survive pneumonia.

Key Words: acute lung injury • bacterial pneumonia • cytokines • neutrophil recruitment • transcription factors

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