Neutrophil migration during endotoxemia

Abstract

Endotoxemia is marked by a global activation of inflammatory responses, which can lead to shock, multiple organ failure, and the suppression of immune and wound healing processes. Neutrophils (PMNs) play a central role in some of these responses by accumulating in tissues and releasing reactive oxygen species and proteases that injure host structures. This review focuses on altered PMN migratory responses that occur during endotoxemia and their consequences in the development of pulmonary infection. The inflammatory mediators that might be responsible for these altered responses are discussed. The oxidant potential of PMNs is increased after exposure to endotoxin both in vitro and during clinical and experimental endotoxemia. However, other functions such as chemotaxis and phagocytosis are often depressed in these same cells. Endotoxin exposure renders PMNs hyperadhesive to endothelium. The sum of these effects produces activated inflammatory cells that are incapable of leaving the vasculature. As such, the endotoxic PMN is more likely to promote tissue injury from within microvascular beds than to clear pathogens from extravascular sites. Moreover, the functional characteristics of endotoxic PMNs are similar to those observed during trauma, burn injury, sepsis, surgery, and other inflammatory conditions. Accordingly, several clinical conditions might have a common effector in the activated, yet migratorially dysfunctional, PMN. Direct effects of endotoxin on PMNs as well as effects of endogenous mediators released during endotoxemia are discussed. Understanding PMN behavior during endotoxemia may provide basic and critical insights that can be applied to a number of inflammatory scenarios. J. Leukoc. Biol. 66: 10-24; 1999.

Lipopolysaccharide-Induced Leukocyte-Endothelial Cell Interactions: A Role for CD14 Versus Toll-Like Receptor 4 Within Microvessels

“…6A), which may reflect our work (Fig. 2) and previous reports of leukocytopenia (3,13). By contrast, LPS did not alter the flux of rolling cells in either CD14 Ϫ/Ϫ or TLR4 d mice treated with LPS (Fig.…”

“…By contrast, systemic, Gram-negative septicemia continues to elude effective therapy with 50% mortality, i.e., the death of ϳ200,000 people a year in North America (1,2). In these cases, it is the inappropriate activation of inflammatory processes including inappropriate leukocyte infiltration into tissues that causes the progression to uncontrolled whole body inflammation (3). It is thought that a major contributor to 1) localized infections as well as 2) the morbidity associated with systemic infections is the shedding of LPS from Gram-negative bacteria into the circulation (4).…”

“…Because CD14 is a GPI-anchored protein devoid of a transmembrane domain, by itself, it presumably cannot transmit the activating signal into the cell. Indeed, in vitro work has demonstrated that Toll-like receptor 4 (TLR4) 3 activates the immune system by functioning as a transmembrane coreceptor to CD14 (16,17). Both TLR4-deficient (TLR4 d ) mice and mice with a single point mutation at aa 712 (proline to histidine) in the TLR4 gene (C3H/HeJ) are resistant to the immunostimulatory and pathophysiological effects of LPS (18,19).…”

Granulocyte-Macrophage Colony Stimulating Factor Up-Regulates CCR1 in Human Neutrophils

“…Alternatively, systemic activation of endothelial cells has been shown to cause GM-CSF-dependent intravascular activation of PMN (40). It has long been known that in systemic inflammatory states, peripheral PMN lose their responsiveness to CXC chemokines (54,55). Our work poses the question of whether these cells might gain responsiveness to CC chemokines, providing a possible mechanism for the PMN-mediated tissue damage associated with a variety of inflammatory conditions (55,56).…”

“…It has long been known that in systemic inflammatory states, peripheral PMN lose their responsiveness to CXC chemokines (54,55). Our work poses the question of whether these cells might gain responsiveness to CC chemokines, providing a possible mechanism for the PMN-mediated tissue damage associated with a variety of inflammatory conditions (55,56). Such scenarios of local and systemic PMN activation and responsiveness to CC chemokines lead to new and interesting questions on PMN participation in cytokine networks and in the pathogenesis of inflammatory lesions.…”