title: Role of NF-kappaB 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-kappaB 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-kappaB can modulate apoptosis through increasing 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 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-kappaB, were increased in lung neutrophils 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 inhibition of nuclear translocation of NF-kappaB prevented endotoxemia-induced increases in Bcl-x(L), 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-kappaB activation play an important role in modulating lung neutrophil apoptosis after endotoxemia.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80220, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Kupfner
authors.forename: J J
authors.initials: JJ
authors.lastname: Arcaroli
authors.forename: H K
authors.initials: HK
authors.lastname: Yum
authors.forename: S G
authors.initials: SG
authors.lastname: Nadler
authors.forename: K Y
authors.initials: KY
authors.lastname: Yang
authors.forename: E
authors.initials: E
authors.lastname: Abraham
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D019446:Endotoxemia / Q000276:immunology* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008171:Lung Diseases / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000494:pharmacology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051818:Replication Protein C; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D051020:bcl-X Protein
chemical_list: C411484:BMS 205820; C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse; D051818:Replication Protein C