Nuclear Factor-κB p50 Limits Inflammation and Prevents Lung Injury duringEscherichia coliPneumonia

Abstract

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.

Neutrophil Recruitment to the Lungs during Bacterial Pneumonia

“…Extended observations using RelA and tumor necrosis factor receptor 1 (TNF-R1) or RelA and TNF-␣ double-gene-deficient mice lead to the attenuation of neutrophil accumulation in the lungs in response to LPS challenge or viable E. coli challenge compared with the neutrophil accumulation of either TNF-R1 or TNF-␣ single-gene-deficient mice, demonstrating that NF-B is an important mediator of neutrophil recruitment into the lungs (5). A further advancement in our understanding of transcriptional factors is the finding that RelA deficiency (in the TNF-R1 knockout background) resulted in the attenuation of neutrophil influx during E. coli (58) and pneumococcal (42,72) pneumonia.…”

Mechanisms of Neutrophil Accumulation in the Lungs Against Bacteria

“…Activation of NF-kB contributes to neutrophil accumulation elicited in the lungs by LPS, which is largely in part through the up-regulation of several neutrophil chemokines (keratinocyte-derived chemokine [KC], macrophage inflammatory protein [MIP]-2, and CXCL5). Studies demonstrate that endogenous NF-kB protects the mice during E. coli (46,47) and pneumococcal pneumonia, and is essential for the survival during these infections (48). Neutrophil emigration to the alveoli during LPS-induced inflammation was severely reduced in TNF Receptor 1/RelA-double knockout mice, when compared with their control (TNFR1-deficient) mice (49).…”

Toll-IL-1 Receptor Domain-Containing Adaptor Protein Is Critical for Early Lung Immune Responses againstEscherichia coliLipopolysaccharide and ViableEscherichia coli

“…In a separate set of experiments, BAL fluid was harvested from the mice after E. coli infection for total WBC and neutrophil counts, and cytokine and chemokine measurements, and the lungs were harvested for NF-B translocation and chemokine and cytokine expression. At 24 h after E. coli LPS or E. coli administration, 5-m lung sections were prepared and stained with H&E for histopathology, as previously described (36). Descriptive histopathology was performed by a pulmonologist/pathologist in a blinded fashion.…”