The Role of Nuclear Factor Kappa B in the Pathogenesis of Pulmonary Diseases: Implications for Therapy
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The Role of Nuclear Factor Kappa B in the Pathogenesis of Pulmonary Diseases: Implications for Therapy Jeffrey G. Wright and John W. Christman Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, and the Department of Veterans Affairs, Nashville, Tennessee, USA
Abstract
The nuclear factor kappa B (NF-κB) transcription factor plays a key role in the induction of pro-inflammatory gene expression, leading to the synthesis of cytokines, adhesion molecules, chemokines, growth factors and enzymes. Results of studies in in vitro and in vivo models of inflammation and malignancy have also suggested central roles for NF-κB in programmed cell death, or apoptosis. NF-κB plays a central role in a variety of acute and chronic inflammatory diseases. In the common lung diseases associated with a significant inflammatory component such as severe sepsis, acute lung injury, acute respiratory distress syndrome, cystic fibrosis and asthma, the pathogenic roles of NF-κB have been extensively investigated. In COPD, activation of NF-κB has been implicated in disease pathogenesis but its exact role is less clearly demonstrable in this heterogeneous patient population. However, the principal risk factor for COPD, cigarette smoking, is strongly associated with NF-κB activation. Activation of NF-κB has been demonstrated in mineral dust diseases and probably plays a role in the pathogenesis of these chronic illnesses. NF-kB also plays a variety of roles in lung cancer including resistance to chemotherapy, inhibition of tumorigenesis and inducing expression of antiapoptotic genes. The complex NF-κB pathway offers a variety of potential molecular targets for chemotherapeutic intervention. A variety of agents aimed at modulating NF-κB activity are in various stages of investigation.
Nuclear factor kappa B (NF-κB) is a protein transcription factor necessary for maximal transcription of a number of pro-inflammatory molecules associated with an inflammatory response. Since its first description by Sen and Baltimore in 1986,[1] NF-κB has become a central target of investigation and the subject of literally thousands of reports. Proinflammatory genes affected by NF-κB activity include those coding for enzymes such as cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), chemokines such as interleukin (IL)-8, cellular adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1),
cytokines such as IL-1β, IL-6, and tumor necrosis factor-α (TNFα). Since the demonstration of elevated NF-κB activity in macrophages isolated from patients with acute respiratory distress syndrome (ARDS) and in a rat model of ARDS, there have been a growing number of investigations of their role in a variety of lung diseases.[2,3] This brief review describes the NF-κB pathway and the role of NF-κB in the pathogenesis of lung disease, including acute lung injury, ARDS, the systemic inflammatory response syn
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