The Role of Nuclear Factor Kappa B in the Pathogenesis of Pulmonary Diseases: Implications for Therapy

The nuclear factor kappa B (NF-kappaB) 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-kappaB in programmed cell death, or apoptosis. NF-kappaB 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-kappaB have been extensively investigated. In COPD, activation of NF-kappaB 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-kappaB activation. Activation of NF-kappaB 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-kappaB pathway offers a variety of potential molecular targets for chemotherapeutic intervention. A variety of agents aimed at modulating NF-kappaB activity are in various stages of investigation.