Nuclear Factor Kappa-B Activation by Particles and Fibers

Abstract

In recent years, particle research has focused on activation pathways of transcription factors that are known to regulate genes whose abnormal expression is associated with the pathogenesis of particle-associated lung disorders such as fibrosis, cancer, COPD, and asthma. This article reviews the effects of different particles and fibers on the transcriptional activation of nuclear factor kappa-B (NF-kB), which is involved in the activation of a variety of proinflammatory genes. Particulates that have been found to activate NF-κB, include asbestos, man-made fibers, quartz, and ambient particulates, such as residual oil fly ashes (ROFA) and diesel exhaust particles (DEP). In line with this, a number of NF-κB-regulated genes have been found to be upregulated, such as tumour necrosis factor-alpha (TNFα), macrophage inflammatory protein-2 (MIP-2), the interleukins IL-6 and IL-8, cyclooxygenase- II (COX-II), and inducible nitric oxide synthase (iNOS). Important mechanisms involved in the activation of NF-kB by particles or fibers include a role for reactive oxygen species, arachidonic acid metabolism, and particle- or fiber-specific physiochemical properties (e.g., transition metals, fiber dimensions) in processes such as lipid peroxidation and (frustrated) phagocytosis. Intracellularly, NF-κB may be activated via several pathways, for example, involving protein kinase C, tyrosine kinase, or calpain. Future research on NF-κB activation by particles or fibers should aim to further identify these and other pathways and to determine the in vivo significance of this activation in the pathogenesis of lung disease.