Chest
Volume 117, Issue 5, May 2000, Pages 1482-1487
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The Role of Nuclear Factor-κ B in Pulmonary Diseases

https://doi.org/10.1378/chest.117.5.1482Get rights and content

Nuclear factor-κ B (NF-κB) is a family of DNA-binding protein factors that are required for transcription of most proinflammatory molecules, including adhesion molecules, enzymes, cytokines, and chemokines. NF-κB activation seems to be a key early event in a variety of cell and animal model systems developed to elucidate the pathobiology of lung diseases. The purpose of this short review is to describe what is known about the molecular biology of NF-κB and to review information that implicates NF-κB in the pathogenesis of lung disease, including ARDS, systemic inflammatory response syndrome, asthma, respiratory viral infections, occupational and environmental lung disease, and cystic fibrosis.

Section snippets

Molecular Biology of NF-κB

As with other transcription factors, NF-κB binds to DNA in the promoter regions of target genes as a dimer usually composed of two Rel family proteins, p50 (also called NF-κB1) and RelA (also called p65). In the NF-κB heterodimer, both subunits contact DNA, but only RelA contains a transactivation domain that activates transcription by direct interaction with the basal transcription apparatus.4 In quiescent cells, NF-κB is sequestered in the cytoplasm by its interaction with a member of the

NF-κB Activation Pathway

Although a wide variety of stimuli can activate NF-κB, among the most potent inducers are Gram-negative endotoxin or lipopolysaccharide (LPS), TNF-α, and IL-1β. A simplified version of the key signaling events that link LPS, TNF-α, and IL-1β through their cell surface receptors to NF-κB activation is shown in Figure 1 . Mercurio and Manning8 have recently written a concise and scholarly review that deciphers much of the most current information about activation of NF-κB. As indicated above,

Role of NF-κB in the Pathogenesis of Acute Lung Injury and SIRS

Although many animal and cell studies have implicated the NF-κB pathway in the pathogenesis of acute lung injury (ALI) and SIRS, only a few clinical studies have been published. The hypothesis is that in ALI and SIRS, the triad of endotoxin (LPS), TNFα, and IL-1β results in activation of NF-κB in the lung and other organs, which leads to cytokine and chemokine gene expression and neutrophil-associated organ dysfunction, clinically recognized as multiple organ dysfunction syndrome. In this

Role of NF-κB in the Pathogenesis of Asthma

Asthma is an inflammatory disease of the airways that is associated with reversible bronchial hyperreactivity. The pathogenesis of asthma seems to involve expression of a broad array of inflammatory proteins, including cytokines, enzymes, and adhesion molecules, that are regulated by NF-κB. Three lines of evidence suggest a central role of NF-κB in the pathogenesis of asthma: (1) activated NF-κB has been identified in key locations in the airways of asthmatic patients; (2) agents such as

Role of NF-κB in the Pathogenesis of Mineral Dust Disease

Two groups have intensely investigated the role of NF-κB in asbestosis using in vitro cell lines and animal models.31, 3233, 3435, 36 The hypothesis is that iron present in asbestos fibers induces cellular redox changes by facilitating production of intracellular reactive oxygen species through Fenton-like chemistry, resulting in activation of NF-κB. Reactive oxygen species are potent stimuli, which activate at least two transcription factors, NF-κB and activator protein-1, through a mechanism

CF

CF is a chronic inflammatory airway disease that is caused by mutations of the CFTR gene. Lung disease in CF presumably results from chronic airway inflammation related to increased viscosity of respiratory secretions and colonization with Pseudomonas and other bacterial species. Pseudomonas aeruginosa apparently leads to activation of NF-κB and could have a role in overproduction of mucin through activation of MUC2 mucin transcription.42 Although little in vivo data exist, increased activation

Summary

NF-κB has been shown to regulate production of acute inflammatory mediators in a variety of cell and animal models developed to elucidate the pathobiology of lung diseases. In addition, there are some emerging clinical data relating NF-κB activation to the pathogenesis of ARDS, SIRS, and asthma. In ARDS and SIRS, NF-κB activation in alveolar macrophages and other lung cell types very likely modulates neutrophilic alveolitis and lung injury. In asthma, NF-κB activation in airway epithelial cells

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    Supported by The Cystic Fibrosis Foundation, the US Department of Veterans Affairs, and grants HL 61419 and HL 07123 from the National Heart, Lung, and Blood Institute, National Institutes of Health.

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