title: NF-kappaB regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome.
abstract: Activation of the nuclear regulatory factor NF-kappaB occurs in the lungs of patients with the acute respiratory distress syndrome (ARDS) and may contribute to the increased expression of immunoregulatory cytokines and other proinflammatory mediators in this setting. Because of the important role that NF-kappaB activation appears to play in the development of acute lung injury, we examined cytoplasmic and nuclear NF-kapppaB counterregulatory mechanisms, involving IkappaB proteins, in alveolar macrophages obtained from 7 control patients without lung injury and 11 patients with established ARDS. Cytoplasmic levels of the NF-kappaB subunits p50, p65, and c-Rel were significantly decreased in alveolar macrophages from patients with ARDS, consistent with enhanced migration of liberated NF-kappaB dimers from the cytoplasm to the nucleus. Cytoplasmic and nuclear levels of IkappaBalpha were not significantly altered in alveolar macrophages from patients with established ARDS, compared with controls. In contrast, nuclear levels of Bcl-3 were significantly decreased in patients with ARDS compared with controls (P = 0.02). No IkappaBgamma, IkappaBbeta, or p105 proteins were detected in the cytoplasm of alveolar macrophages from control patients or patients with ARDS. The presence of activated NF-kappaB in alveolar macrophages from patients with established ARDS implies the presence of an ongoing stimulus for NF-kappaB activation. In this setting, appropriate counterregulatory mechanisms to normalize nuclear levels of NF-kappaB and to suppress NF-kappaB-mediated transcription, such as increased cytoplasmic and nuclear IkappaBalpha levels or decreased Bcl-3 levels, appeared to be induced. Nevertheless, even though counterregulatory mechanisms to NF-kappaB activation are activated in lung macrophages of patients with ARDS, NF-kappaB remains activated. These results suggest that fundamental abnormalities in transcriptional mechanisms involving NF-kappaB and important in the inflammatory response occur in the lungs of patients with ARDS.
authors.affiliation: Département d'Anesthésie Réanimation Chirurgicale, CHU de Bicêtre, Université Paris Sud, France.
authors.forename: P
authors.initials: P
authors.lastname: Moine
authors.forename: R
authors.initials: R
authors.lastname: McIntyre
authors.forename: M D
authors.initials: MD
authors.lastname: Schwartz
authors.forename: D
authors.initials: D
authors.lastname: Kaneko
authors.forename: R
authors.initials: R
authors.lastname: Shenkar
authors.forename: Y
authors.initials: Y
authors.lastname: Le Tulzo
authors.forename: E E
authors.initials: EE
authors.lastname: Moore
authors.forename: E
authors.initials: E
authors.lastname: Abraham
mesh_terms: D000081242:B-Cell Lymphoma 3 Protein; D018893:Bronchoalveolar Lavage; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D011498:Protein Precursors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000276:immunology / Q000378:metabolism*; D012720:Severity of Illness Index; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C000606204:NFKBIA protein, human; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha; C072386:p50B-p97 protein, human