Neutrophil serine proteinases and defensins in chronic obstructive pulmonary disease: effects on pulmonary epithelium

Neutrophils have the capacity to accumulate in high numbers in the lung dur ing infection and inflammation, Because they play an important role in host defence against infection, but may also cause tissue injury, these cells a re thought to be involved in the pathogenesis of various inflammatory lung disorders, including chronic bronchitis and chronic obstructive pulmonary d isease. Neutrophil products that may mediate tissue injury at sites of neut rophil-dominated inflammation include the neutrophil serine proteinases ela stase, cathepsin G and proteinase 3, and the nonenzymatic defensins, One of the targets of the neutrophil is the lung epithelium, and in vitro studies have revealed that both the serine proteinases and neutrophil defensins ma rkedly affect the integrity of the epithelial layer, decrease the frequency of ciliary beat, increase the secretion of mucus, and induce the synthesis of epithelium-derived mediators that may influence the amplification and r esolution of neutrophil-dominated inflammation, Both neutrophil elastase an d defensins induce the release of the neutrophil chemoattractant chemokine interleukin-g from respiratory epithelial cells. The alpha(1)-protcinase in hibitor (alpha(1)-PI) is a well-characterized inhibitor of neutrophil elast ase, that also blocks the cytotoxic and stimulatory activity of defensins t owards epithelial cells. The elastase inhibitory activity of alpha(1)-PI is also abrogated by the binding of defensins to this inhibitor. Incubation o f epithelial cells with neutrophil defensins in combination with either ela stase or cathepsin G resulted in decreased effects on the epithelial cells compared with those observed when the cells were incubated with defensins, elastase or cathepsin G separately. These results suggest that neutrophil defensins and serine proteinases caus e injury and stimulate epithelial cells to produce chemokines that attract more neutrophils to the site of inflammation, The effects of neutrophil def ensins and serine proteinases on epithelial cells appear to be restricted b y proteinase inhibitors and by inhibitory interactions between these sets o f neutrophil granule proteins.