title: Altered inhibitory κBα expression in LPS-stimulated alveolar macrophages following resuscitated hemorrhagic shock.
abstract: Patients resuscitated from hemorrhagic shock are at increased risk for the development of organ dysfunction, particularly acute respiratory distress syndrome. The "two-hit hypothesis" wherein shock/resuscitation (S/R) renders the immune system more responsive to subsequent inflammatory stimuli has been suggested as a major mechanism contributing to organ injury. Previous work has shown that S/R primes alveolar macrophages for increased nuclear factor κB (NF-κB) translocation in response to LPS, culminating in increased lung cytokine and chemokine production. Inhibitory κB (IκB) is known to be an important regulator of NF-κB activity. In this article, we investigated the effect of S/R on regulation of IκBα expression in response to LPS both in vitro and in vivo. Two discrete effects on IκB regulation were observed after S/R, which served to augment NF-κB activity. First, antecedent exposure of alveolar macrophages to S/R resulted in increased LPS-induced IκBα degradation through activation of upstream signaling, an effect that resulted in increased NF-κB translocation and cytokine-induced neutrophil chemoattractant gene expression. Second, cells recovered from rodents after S/R had reduced levels of IκB mRNA in response to LPS compared with sham/LPS treatment. This effect was primarily due to the ability of S/R to reverse the prolongation of IκB mRNA stability observed after LPS-alone treatment. Together, these effects on the important regulatory molecule IκB in the macrophage may contribute to the heightened inflammatory response observed after S/R.
authors.affiliation: Li Ka Shing Knowledge Institute and the Keenan Research Centre, St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Guiseppe
authors.initials: G
authors.lastname: Papia
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.forename: Andras
authors.initials: A
authors.lastname: Kapus
authors.forename: Katalin
authors.initials: K
authors.lastname: Szaszi
authors.forename: John C
authors.initials: JC
authors.lastname: Marshall
authors.forename: Patrick
authors.initials: P
authors.lastname: Tawadros
authors.forename: Menachem
authors.initials: M
authors.lastname: Ailenberg
authors.forename: Ori D
authors.initials: OD
authors.lastname: Rotstein
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D020672:I-kappa B Proteins / Q000096:biosynthesis*; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000378:metabolism / Q000628:therapy*
chemical_list: D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha