INHIBITION OF APOPTOSIS AND PROLONGATION OF NEUTROPHIL FUNCTIONAL LONGEVITY BY INFLAMMATORY MEDIATORS

Neutrophil apoptosis leads to macrophage ingestion of intact senescent neutrophils. This may represent a neutrophil removal mechanism that i s important both in the control of inflammatory tissue injury and for the normal resolution processes of inflammation. Because apoptosis is likely to be a key control process in cell and tissue homeostasis, a n umber of inflammatory mediators were tested for their ability to modul ate the rate of apoptosis in populations of neutrophils aging in cultu re. Endotoxic lipopolysaccharide, human recombinant complement factor 5a, and human recombinant granulocyte-macrophage colony-stimulating fa ctor all markedly inhibited the rate of neutrophil apoptosis in a conc entration-dependent fashion, without inducing necrosis (as assessed by trypan blue exclusion). This inhibitory effect on the rate of neutrop hil apoptosis was shown by morphological criteria and confirmed by gel electrophoresis of extracted DNA. Inhibition of apoptosis of aging ne utrophil populations was associated with prolongation of the functiona l life span of the population as assessed by the ability of neutrophil s to spread on glass surfaces, to polarize in response to deliberate s timulation with N-formyl-Met-leu-Phe (fMLP), and to release the granul e enzyme marker myeloperoxidase on fMLP stimulation. These observation s show that inflammatory mediators prolong the functional life span of neutrophils through modulation of apoptosis. Further elucidation of t hese mechanisms will lead to a better understanding of the processes c ontrolling neutrophil residence and function in inflamed tissues and m ay provide further insights into the molecular mechanisms of apoptosis , which is of widespread importance in tissue biology.