NF-κB REGULATORY MECHANISMS IN ALVEOLAR MACROPHAGES FROM... : Shock (original) (raw)

NF-?B REGULATORY MECHANISMS IN ALVEOLAR MACROPHAGES FROM PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME: PDF Only

NF-κB REGULATORY MECHANISMS IN ALVEOLAR MACROPHAGES FROM PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME

Moine, Pierre*†; McIntyre, Robert‡; Schwartz, Michael D.†; Kaneko, Debra†; Shenkar, Robert†; Tulzo, Yves Le†; Moore, Ernest E.§; Abraham, Edward†

*Département d'Anesthésie Réanimation Chirurgicale, CHU de Bicêtre, Université Paris Sud, France; †Division of Pulmonary Sciences and Critical Care Medicine and ‡Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado 80262; §Department of Surgery, Denver General Hospital, University of Colorado, Denver, Colorado 80262

Received 23 Dec 1998; first review completed 22 Feb 1999; accepted in final form 19 Aug 1999

Address reprint requests to Pierre Moine, Département d'Anesthésie Réanimation Chirurgicale, CHU de Bicêtre, Université Paris Sud, 78 Rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.

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Abstract

Activation of the nuclear regulatory factor NF-κB 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-κB activation appears to play in the development of acute lung injury, we examined cytoplasmic and nuclear NF-κB counterregulatory mechanisms, involving lκB proteins, in alveolar macrophages obtained from 7 control patients without lung injury and 11 patients with established ARDS. Cytoplasmic levels of the NF-κB subunits p50, p65, and c-Rel were significantly decreased in alveolar macrophages from patients with ARDS, consistent with enhanced migration of liberated NF-κB dimers from the cytoplasm to the nucleus. Cytoplasmic and nuclear levels of lκBα 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 lκBγ, lκBβ, or p105 proteins were detected in the cytoplasm of alveolar macrophages from control patients or patients with ARDS. The presence of activated NF-κB in alveolar macrophages from patients with established ARDS implies the presence of an ongoing stimulus for NF-κB activation. In this setting, appropriate counterregulatory mechanisms to normalize nuclear levels of NF-κB and to suppress NF-κB-mediated transcription, such as increased cytoplasmic and nuclear lκBα levels or decreased Bcl-3 levels, appeared to be induced. Nevertheless, even though counterregulatory mechanisms to NF-κB activation are activated in lung macrophages of patients with ARDS, NF-κB remains activated. These results suggest that fundamental abnormalities in transcriptional mechanisms involving NF-κB and important in the inflammatory response occur in the lungs of patients with ARDS.