Reperfusion Injury After Hemorrhage: A Collective Review

G D. Rushing, MD; L D. Britt, MD, MPH


Annals of Surgery. 2008;247(6):929-937. 

In This Article

NF-κB and Reperfusion Injury

NF-κB, a DNA binding protein, belongs to a family of transcription factors that allow for the production of many proinflammatory molecules. NF-κB exerts its action by binding to a specific decameric DNA sequence motif in the promoter regions of several genes. After hemorrhagic shock NF-κB is involved in apoptosis and the inflammatory cascade. NF-κB is a heterodimer consisting of 2 proteins, either p50 or p52 and p65 (corresponding to their molecular weights). The subunit p50 is also known as nfkB1, p52 is nfkB2, and p65 is Rel-A. They are sequestered in the cytoplasm of nonstimulated cells, through noncovalent interactions, with inhibitor proteins commonly referred to as IκB. Degradation of IκB via phosphorylation, ubiquitination, and proteolysis results in the release of NF-κB dimers and unmasking of a nuclear localization sequence. This results in the nuclear translocation of NF-κB and the transcription of specific target genes (Figure 2). Phosphorylation occurs via several kinases including the alpha and beta inhibitors of kappa light polypeptide gene enhancer in B-cells (IKKα and IKKß).[85,86] A decrease in NF-κB activity is demonstrated by the inhibition of these kinases.[87,88] Biochemical and genetic data suggest that the IKK complex contains 2 catalytic subunits (IKKα and IKKß) and a regulatory subunit (NEMO/IKKγ). IKK is the master regulator of NF-κB-mediated inflammation. NF-κB can be activated by 2 pathways. Interestingly, only the IKKß subunit is essential for NF-κB activation in response to proinflammatory stimuli.[85] This signal-induced phosphorylation targets IKKß for polyubiquitination and subsequent degradation by the proteosome releasing NF-κB that consists of 2 subunits from a family of proteins, such as p65 (also called Rel-A) and p50. However, the NF-κB pathway is complex and can be influenced at many steps. Activation of NF-κB can occur in what appears to be multiple signaling pathways. Serial activation of phosphatidylinositol 3 kinase and protein kinase B (AKT) lead to activation of NF-κB.[89] Another pathway of NF-κB activation, called the alternative pathway, has been elucidated using tumor necrosis factor-associated factors (TRAFs) and NF-κB kinase (NIK).[90] This occurs principally in B cells in response to stimulation of receptors for lymphotoxin ß and CD40 ligand among others. Stimulation of these receptors activates the protein kinase, NIK, which activates IKKα. NIK is a member of the MEKK (mitogen-activated protein kinase/extracellular signal-regulated kinase family). IKKα then phosphorylates another NF-κB family member, p100. Phosphorylation of p100 converts p100 to p52. The p52 subunit and its binding partner RelB, like p65-p50, translocate into the nucleus to regulate gene expression. The 2 NF-κB pathways, the classic and alternative, can be activated by overlapping sets of stimuli.

NF-κB activation. Multiple cytokines can activate their respective receptors such as IL-1, TNF-α, and growth factor. Secondary messengers TRAF-2, TRAF-6, and ALT-K activate the kinase NIK. NIK activates the IKK complex consisting of IKKa, IKKß, and IKKγ the regulatory subunit. IKK phosphorylates the NF-κB complex. This allows ubiquitination via E-3 ubiquitinase. This phosphorylation and ubiqutination tags the NF-κB complex to be taken up by a proteosome, where the inhibitor I-κB is degraded. NF-κB moves into the nucleus where it acts as a transcription factor for cytokines.

Blockade of NF-κB was undertaken by our laboratory in previous studies related to septic shock.[91,92] These studies revealed that blockade of NF-κB abrogated the vasodilation of arterioles exposed to endotoxin. NF-κB is a popular target for blockade and multiple studies have been undertaken to prove its role in reperfusion injury. Several clinical trials have evaluated the blockade of NF-κB end-products, such as TNF-α and IL-6, with limited results.[93,94] Although these may be promising targets, it is our belief that due to the complex nature of NF-κB feedback and regulation, blocking these products may be difficult. NF-κB has been the subject of intense investigation for many years; however, its complex role in the inflammatory cascade is far from elucidated and, therefore, ensures continued research efforts on this topic.


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