Role of NF-KB in Endotoxemia-Induced Alterations of Lung Aneutrophil Apoptosis

摘要

Acute lung injury is frequently 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-KB is activated in neutrophils and other pulmonary cell populations after endotoxemia ande appears to play a central role in the develoipment of the actue inflammatory process that leads to lung injury. Because NF-KB can modulate apoptosis through increasing expression of anti-apoptotic proteins, activation of NG-KB 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-x_L, anti-apoptotic proteins whose transcription is dependent on NF-KB, were increased in lung neutrophils after endotoxemia. Inhibition of nuclear translocation of NF-KB 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-KB prevented endotoxemia-induced increases in Bcl-x_L, Al, 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-KB activation play an important role in modulating lung neutrophil apoptosis after endotoxemia.