CYTOKINES AND PARTICLE-INDUCED INFLAMMATORY CELL RECRUITMENT

The inflammatory response is a key component of host defense. However, excessive or persistent inflammation can contribute to the pathogenes is of disease. Inflammation is regulated, in part, by cytokines, which are small, typically glycosylated proteins that interact with membran e receptors to regulate cellular processes such as proliferation, diff erentiation, and secretion. During the past 10 years studies in humans and experimental animals have demonstrated that a cytokine called tum or necrosis factor alpha (TNF-alpha) plays a key role in the initiatio n of inflammatory responses in the lung and other tissues, including i nflammation resulting from inhalation of noxious particles. There is n ow compelling evidence that one of the pathways by which inhaled parti cles stimulate the recruitment and subsequent activation of inflammato ry cells is through the activation of lung macrophages to release TNF- alpha. TNF-alpha then acts via paracrine and autocrine pathways to sti mulate cells to release other cytokines known as chemokines, which are directly chemotactic to leukocytes and other cells that participate i n inflammatory and wound healing responses. in addition to a TNF-alpha -mediated pathway, there is growing evidence that some particles such as quartz and crocidolite can directly activate lung epithelial cells to release chemokines such as macrophage inflammatory protein-2, cytok ine-induced neutrophil chemoattractant, and interleukin-8. A direct st imulatory effect of particles on lung epithelium may represent an addi tional or alternate pathway by which inhaled particles may elicit infl ammation in the lung. Recent studies have suggested that oxidative str ess may be a component of the mechanism by which particles activate cy tokine production in cells such as macrophages and epithelial cells. T he contribution of oxidative stress to particle-induced cytokine gene expression appears to be mediated, at least in part, through activatio n of the transcription factor nuclear factor kappa B.