Role of NF-kappa B in endotoxemia-induced alterations of lung neutrophil apoptosis

Acute lung injury is frequently associated with endotoxemia and is characte rized by the accumulation in the lungs of large numbers of neutrophils acti vated to produce proinflammatory mediators. In the setting of acute lung in jury, the percentage of apoptotic cells among lung neutrophils is decreased . The transcriptional regulatory factor NF-kappaB is activated in neutrophi ls and other pulmonary cell populations after endotoxemia and appears to pl ay a central role in the development of the acute inflammatory process that leads to lung injury. Because NF-kappaB can modulate apoptosis through inc reasing expression of anti-apoptotic proteins, activation of NF-kappaB may contribute to the alterations in lung neutrophil apoptosis associated with acute lung injury. In the present experiments, endotoxemia resulted in decr eased apoptosis and increased expression of anti-apoptotic mediators among lung neutrophils. Amounts of A1, A-20, and Bcl-X-L, anti-apoptotic proteins whose transcription is dependent on NF-kappaB, were increased in lung neut rophils after endotoxemia. Inhibition of nuclear translocation of NF-kappaB increased the percentage of apoptotic lung neutrophils after endotoxemia, but not back to the levels found in unmanipulated animals. Although inhibit ion of nuclear translocation of NF-kappaB prevented endotoxemia-induced inc reases in Bcl-x(L), A1, and A20 in lung neutrophils, this intervention did not prevent endotoxemia-associated elevation of Mcl-1, an anti-apoptotic pr otein primarily under the transcriptional regulation of CREB. These results demonstrate that mechanisms independent of NF-kappaB activation play an im portant role in modulating lung neutrophil apoptosis after endotoxemia.