Nuclear factor-kappaB p50 limits inflammation and prevents lung injury during Escherichia coli pneumonia.
Inflammatory responses to infection must be precisely regulated to facilitate microbial killing while limiting host tissue damage. Many inflammatory genes are regulated by kappaB sites, and the p50 subunit of nuclear factor-kappaB suppresses the expression of kappaB-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.
Mizgerd
Joseph P
JP
Physiology Program, Harvard School of Public Health, Boston, MA 02115, USA. jmizgerd@hsph.harvard.edu
Lupa
Michal M
MM
Kogan
Mariya S
MS
Warren
Henry B
HB
Kobzik
Lester
L
Topulos
George P
GP
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004927:Escherichia coli Infections / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000502:physiology*; D020556:Neutrophil Infiltration / Q000502:physiology; D018410:Pneumonia, Bacterial / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000517:prevention & control; D015657:Respiratory Transport / Q000502:physiology; D013997:Time Factors
D016207:Cytokines; D052002:NF-kappa B p50 Subunit