Evidence suggests that the neutrophil has both beneficial and harmful effects in sepsis and septic shock. The neutrophil is a key component of the host defense. Data from neutropenic animals and humans suggest that augmented neutrophil count and function reduce the risk of infection. Conversely, studies have also shown that the neutrophil and its toxic byproducts produce tissue injury and organ dysfunction in sepsis and septic shock.
One area of intense interest is the leukocyte endothelium interaction. This interaction appears to be a crucial step in the inflammatory cascade during sepsis. A membrane glycoprotein complex termed CD11/18 has been suggested as the primary adhesion receptor site on endothelial cells and leukocytes for this interaction, and has been the target of many investigators. This complex is a cell-surface receptor that regulates neutrophil-endothelial cell adhesion, the first step in the neutrophil migration to sites of infection or inflammation.
Researchers have developed monoclonal antibodies against the CD11/18 complex. These antibodies, both in vitro and in vivo, prevent endotoxin, TNF, and complement-induced neutrophil adhesion; injury to endothelial cells; and neutrophil extravascular migration. In some animal models of sepsis and meningitis, monoclonal anti-CD 11/18 antibodies improved mortality rates, decreased adverse hemodynamic parameters, and decreased meningeal inflammation. In a study of dogs pretreated with CD11/18 monoclonal antibody and challenged with TNF, animals treated with CD11/18 had a reduced mortality rate and better arterial oxygenation in the first 24 hours; but this effect was not sustained and the overall survival between the two groups was not significantly different. In a subsequent study in dogs using a similar design but challenged with E. coli, investigators found that the CD11/18 monoclonal antibody worsened cardiovascular instability and decreased tissue perfusion during sepsis. In conclusion, studies to date suggest that efforts to inhibit neutrophil function may lead to more tissue injury and more adverse outcomes.
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