| Summary: | Neutrophil apoptosis represents a major mechanism involved in the resolution of inflammation. When neutrophils die by apoptosis they retain their granule contents but lose chemotactic and secretory responsiveness and are phagocytosed intact by macrophages via a mechanism, which does not incite an inflammatory response. While the processes involved in regulating neutrophil survival are poorly understood, there is now considerable evidence to indicate that this process is not immutable since many pro-inflammatory mediators can modulate neutrophil apoptosis. For example, under <I>in vitro</I> conditions, LPS, GM-CSF and IL-1 and 6 all inhibit neutrophil apoptosis, while TNFα is able to induce apoptosis in these cells. Thus it appears that such agents act not only in a priming/secretory capacity but also affect neutrophil functional longevity by regulating apoptosis. We were interested to examine whether other physiochemical insults, in particular hypoxia which is highly relevant to the inflamed site, could also effect this cells life span. These data suggest that hypoxia, which characterises many inflammatory sites <I>in vivo</I>, may extend the neutrophils life span by inhibiting both spontaneous apoptosis and TNFα-induced apoptosis, and this may be a contributory factor in neutrophil-mediated tissue damage. The mechanism underlying the inhibition of constitutive neutrophil apoptosis may involve the transcription factor HIF-1 although further work will be required to confirm this. The mechanism underlying TNFα induced apoptosis appears to be largely unrelated to that controlling basal apoptosis and our data suggest the involvement of mitochondria and the caspase family of death-inducing proteases.
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