Endotoxin Inhibits Apoptosis but Induces Primary Necrosis in Neutrophils
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Endotoxin Inhibits Apoptosis but Induces Primary Necrosis in Neutrophils Matthias Turina,1,2,4 Frederick N. Miller,2 Patrick P. McHugh,1 William G. Cheadle,3 and Hiram C. Polk, Jr.1
Abstract—Lipopolysaccharide (LPS) is known to prolong the functional lifespan of neutrophils at a site of infection by preventing apoptosis through inhibitor of apoptosis proteins (IAPs). We hypothesized that the increased neutrophil lifespan ultimately leads to a larger fraction of cells undergoing uncontrolled, primary necrosis. Diluted venous whole blood was incubated with increasing concentrations of LPS for up to 36 hr. The percentages of apoptotic, necrotic and viable neutrophils were assessed using the Annexin V/propidium iodide flow cytometric assay. LPS led to a reduction of neutrophil apoptosis and increased the number of viable cells at 12, 24, and 36 hr of incubation. At the same time intervals, there was a significant increase in the percentage of cells undergoing primary necrosis for all concentrations of LPS (e.g., 10 ng/ml LPS at 24 h produced a mean increase from 9.6% in controls to 30.6%, p < 0.001). This increase in direct neutrophil necrosis following LPS activation may amplify local proinflammatory effects through less well controlled release of neutrophil contents into surrounding tissue. KEY WORDS: endotoxin; LPS; neutrophil granulocyte; apoptosis; necrosis.
INTRODUCTION
endotoxin (lipopolysaccharide, LPS), or other bacterial cell wall products such as muramyl dipeptide (MDP) (3). Following activation, they exert their defensive role by intracellular killing of invading microbes and by the release of lytic enzymes such as lysozyme or elastase (4, 5). Having fulfilled their purpose at a site of infection, neutrophils undergo apoptosis, which is a genetically controlled process characterized by the activation of specific endonucleases, culminating in the death and efficient disposal of cells through macrophage ingestion (6, 7). Morphologic features of apoptosis include the condensation of chromatin and its migration to the nuclear periphery, fragmentation of nuclear DNA, and the blebbing of cell membranes, forming apoptotic bodies ready for ingestion by phagocytes or neighboring cells (6, 8). The recognition of apoptotic neutrophils by antigenpresenting cells (APC’s) occurs through a reduction in the expression of different surface receptors, most importantly Fcγ RII (CD32), complement receptor type 1 (CD35), the receptor for TNF-α (CD120b), CD 43, and
Neutrophil granulocytes comprise the first line of cellular defense during bacterial infections.They are released from bone marrow at a rate of approximately 1011 mature neutrophils/day (1). Under stable, non-infectious conditions, the half-life of these cells in the systemic circulation is approximately 6–9 hr, before transmigration into the extravascular space occurs (2). During infection, neutrophils are activated by bacterial contents and inflammatory mediators such as interferon gamma (IFN-γ ), 1 Department
of Surgery, The Price Institute of Surgical Researc
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