Role of NF-κB in Endotoxemia-Induced Alterations of Lung Neutrophil Apoptosis

Abstract

Acute lung injury is frequently associated with endotoxemia and is characterized by the accumulation in the lungs of large numbers of neutrophils activated to produce proinflammatory mediators. In the setting of acute lung injury, the percentage of apoptotic cells among lung neutrophils is decreased. The transcriptional regulatory factor NF-κB is activated in neutrophils and other pulmonary cell populations after endotoxemia and appears to play a central role in the development of the acute inflammatory process that leads to lung injury. Because NF-κB can modulate apoptosis through increasing expression of anti-apoptotic proteins, activation of NF-κB may contribute to the alterations in lung neutrophil apoptosis associated with acute lung injury. In the present experiments, endotoxemia resulted in decreased apoptosis and increased expression of anti-apoptotic mediators among lung neutrophils. Amounts of A1, A20, and Bcl-xL, anti-apoptotic proteins whose transcription is dependent on NF-κB, were increased in lung neutrophils after endotoxemia. Inhibition of nuclear translocation of NF-κB increased the percentage of apoptotic lung neutrophils after endotoxemia, but not back to the levels found in unmanipulated animals. Although inhibition of nuclear translocation of NF-κB prevented endotoxemia-induced increases in Bcl-xL, A1, and A20 in lung neutrophils, this intervention did not prevent endotoxemia-associated elevation of Mcl-1, an anti-apoptotic protein primarily under the transcriptional regulation of CREB. These results demonstrate that mechanisms independent of NF-κB activation play an important role in modulating lung neutrophil apoptosis after endotoxemia,

Low Level Laser Therapy (LLLT) Decreases Pulmonary Microvascular Leakage, Neutrophil Influx and IL-1β Levels in Airway and Lung from Rat Subjected to LPS-Induced Inflammation

“…The MPO activity was reduced after LLLT in BAL of rats inflamed with LPS. Although there is a significant participation of macrophages in inflammatory response induced by LPS, these cells suffer lesser anti-apoptotic effects in the presence of cytokines in comparison to neutrophils [33]. High levels of cytokines induce a cellular signaling pathway impairing the apoptosis of neutrophils, which can contribute to perpetuation of inflammatory response [34].…”

The Lupus-Susceptibility Locus, Sle3, Mediates Enhanced Resistance to Bacterial Infections

“…Neutrophil apoptosis is known to be involved in noninflammatory turnover of circulating cells (31) and clearance of cells from inflamed tissues (32)(33)(34)(35). In the context of infection, neutrophils display reduced apoptosis rate and altered apoptotic pathways in response to bacterial products (36), whereas some microorganisms specifically modulate neutrophil apoptosis as a pathogenic mechanism in persisting infections (37)(38)(39).…”

Antibacterial cathelicidin peptide CAP11 inhibits the lipopolysaccharide (LPS)-induced suppression of neutrophil apoptosis by blocking the binding of LPS to target cells

“…The blots were blocked in Block Ace (Dainippon Pharmaceutical, Osaka, Japan), and probed with mouse anti-phosphorylated ERK (1:500 dilution; E-4) mAb or anti-Bcl-XL (1:500; H-5) mAb. The blots were further probed with HRP-conjugated goat antimouse IgG/IgM (1:5000), and phsophorylated ERK-1/-2 and Bcl-XL were finally detected with SuperSignal ® West Pico Chemiluminescent substrate (Pierce, Rockford, IL) [31,32]. Thereafter, the blots were stripped by incubating in the stripping buffer (2% SDS, 62.5 mM Tris-HCl pH 6.8 and 100 mM 2-mercaptoethanol) for 30 min at 60°C, and ERK-1/-2 proteins contained in each sample were detected by reprobing with rabbit anti-ERK polyclonal antibody (1:1000; K-23) and HRP-conjugated goat anti-rabbit IgG (1:5000).…”