Administration of an antibody to E-selectin in patients with septic shock

Friedman, Gilberto; Jankowski, S.; Shahla, M.; Goldman, Michel; Rose, Richard M.; Kahn, Robert J.; Vincent, Jean‐Louis

doi:10.1097/00003246-199602000-00008

Cited by 39 publications

(9 citation statements)

References 21 publications

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“…Pretreatment of Pseudomonas-infused swine with a dual anti-Eand anti-L-selectin monoclonal antibody significantly attenuated lung injury (34). In a preliminary study, administration of a murine monoclonal antibody to E-selectin to patients with septic shock was well tolerated and associated with dose-related improvement in oxygenation and trends for faster resolution of organ failure (35).…”

Section: Discussionmentioning

confidence: 96%

Soluble E-Selectin Levels in Sepsis and Critical Illness

Cummings

Sessler

Beall

et al. 1997

Am J Respir Crit Care Med

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E-selectin, an early mediator of leukocyte-endothelial adhesion, is expressed on activated endothelium. Soluble E-selectin is present in the supernatant of cytokine-activated endothelial cells and elevated serum levels are found in a variety of inflammatory conditions. We documented elevated E-selectin serum levels in 119 critically ill medical ICU patients (log transformed mean E-selectin level, measured by ELISA, was 5.28 ng/ml) compared to normal volunteers (1 ng/ml). Forty-three patients with culture-positive sepsis had higher (p < 0.05) E-selectin levels (15.39 ng/ml) than 24 patients with culture-negative sepsis (4.87 ng/ml), 44 with noninfectious SIRS (2.33 ng/ml), and eight without SIRS (1.97 ng/ml). E-selectin levels related strongly to the degree of hemodynamic compromise (p < 0.0001). Further analysis demonstrated microbiological status and hemodynamic status to be independent variables related to E-selectin level. Day 1 E-selectin levels correlated positively with peak organ failure score over the course of ICU hospitalization (r = 0.30, p = 0.001) and were higher (p < 0.05) for nonsurvivor (10.61 ng/ml, n = 26) than survivors (4.35 ng/ml, n = 93). We conclude that soluble E-selectin levels are higher in serum of patients with microbiologically documented sepsis than in other critically ill medical ICU patients. Day 1 E-selectin levels correlate highly with hemodynamic compromise and modestly with subsequent organ dysfunction and survival.

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Section: Discussionmentioning

confidence: 96%

Soluble E-Selectin Levels in Sepsis and Critical Illness

Cummings

Sessler

Beall

et al. 1997

Am J Respir Crit Care Med

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“…Similarly, blocking the interaction between the endothelium and leukocytes with E-selectin antibodies as well as selectin antagonists also ameliorates various inflammatory diseases. [11][12][13][14][15][16] For instance, anti-Eselectin blocking antibody or E-selectin gene disruption protected mice from ischemia-reperfusion induced acute renal failure. 12 Similarly, antibody blockade of E-selectin decreased adventitial inflammation and attenuated intimal hyperplasia in rat carotid arteries after balloon injury.…”

Section: Discussionmentioning

confidence: 99%

“…10 The importance of E-selectin in initiating inflammation is demonstrated by the potent anti-inflammatory effect of E-selectin blockade. [11][12][13][14][15][16] Hepatocyte growth factor (HGF) is a mesenchymalderived, pleiotropic multifunctional growth factor. 17 Upon binding to its receptor, c-Met, HGF triggers several signal transduction pathways, including phosphatidylinositol 3-kinase (PI3K)-Akt, Ras-Mek-Erk, and Stat3 pathway, and modulates diverse cell processes including mitogenesis, motogenesis, morphogenesis, and antiapoptosis/survival in epithelial and endothelial cells.…”

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confidence: 99%

Hepatocyte growth factor suppresses acute renal inflammation by inhibition of endothelial E-selectin

Gong

Rifai

Dworkin

2006

Kidney International

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Vascular endothelial activation, marked by de novo expression of E-selectin, is an early and essential event in the process of leukocyte extravasation and inflammation. Evidence suggests that hepatocyte growth factor (HGF) ameliorates inflammation in animal models of renal disease, implying that HGF might inhibit specific components of the inflammatory response. This study examined the effect of HGF on endothelial E-selectin expression in acute inflammation induced by tumor necrosis factor (TNF)-alpha. In vitro, HGF suppressed TNF-alpha-induced cell surface expression of E-selectin in human umbilical vein endothelial cells (HUVEC) and inhibited E-selectin mediated monocytic adhesion to endothelial monolayers. HGF activated phosphatidylinositol 3-kinase (PI3K)-Akt that in turn inhibited its downstream transducer glycogen synthase kinase (GSK)3. Blockade of the PI3K-Akt pathway with specific inhibitors abrogated HGF induced inhibitory phosphorylation of GSK3 and suppression of E-selectin. In addition, selective inhibition of GSK3 activity by lithium suppressed TNF-alpha-induced E-selectin expression and monocytic adhesion, reminiscent of the action of HGF. Moreover, ectopic expression of an uninhibitable mutant GSK3beta, in which the regulatory serine-9 is replaced by alanine, abolished HGF's suppressive effect on endothelial E-selectin. In vivo, administration of exogenous HGF reduced endothelial expression of E-selectin induced by bolus injection of TNF-alpha. This was associated with less sequestration of circulating fluorescence-labeled macrophages in the kidney. These findings suggest that HGF ameliorates acute renal inflammation in part by downregulating E-selectin mediated macrophage adhesion to the inflamed endothelium.

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“…However, blocking cell adhesion molecules may be beneficial in blunting detrimental inflammatory responses during sepsis, particularly if bacteremia can be controlled with antibiotics. Thus, clinical attempts to use mAbs to E-selectin to reverse gram-negative shock (33) have the potential risk of impairing the host response to bacteremia, but the potential benefit of blunting a detrimental inflammatory response, and the net effect can only be judged by carefully designed clinical trials. Furthermore, the increased mortality observed in all of the selectin-deficient mice studied emphasizes that these molecules are evolutionarily important for host defense against infection.…”

Section: Discussionmentioning

confidence: 99%

Host defense against systemic infection with Streptococcus pneumoniae is impaired in E-, P-, and E-/P-selectin-deficient mice.

et al. 1997

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Endothelial selectins mediate rolling of leukocytes on endothelium, a crucial step for leukocyte firm adhesion and emigration into sites of tissue injury and infection. To characterize the role of the endothelial selectins during bacterial sepsis in vivo, Streptococcus pneumoniae (1-10 ϫ 10 6 colony-forming units) was inoculated intraperitoneally into wild-type mice and mice with E-, P-, or E-/P-selectin deficiencies. Mice were followed 10 d for morbidity, survival, clearance of bacteremia, and leukocyte migration to the peritoneal cavity and organs 48 h after infection. All selectin-deficient mice showed a more pronounced morbidity, a significantly higher mortality associated with persistent bacteremia, and a higher bacterial load when compared with wild-type mice. These differences were most remarkable in the E-selectin-deficient mice, which showed the highest rate of mortality and bacteremia ( P Յ 0.0001). No significant differences were observed among the groups in the inflammatory response present in the peritoneal cavity, brain, liver, spleen, or kidney at 48 h after inoculation. Extensive hepatic and splenic necrosis and thrombosis were noted in E-and P-selectin-deficient mice. Although the absence of endothelial selectins did not substantially impair leukocyte emigration to sites of infection 48 h after pneumococcal sepsis, it resulted in increased mortality and a higher bacterial load in the bloodstream of selectin-deficient mice. These results demonstrate a definitive phenotypic abnormality in E-selectin-deficient mice, and suggest that E-and P-selectin are important in the host defense against S. pneumoniae infection. (

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Administration of an antibody to E-selectin in patients with septic shock

Abstract: This pilot study indicates that this antibody to E-selectin appears to be safe and may represent a promising form of therapy in septic shock.

Cited by 39 publications

References 21 publications

Soluble E-Selectin Levels in Sepsis and Critical Illness

Soluble E-Selectin Levels in Sepsis and Critical Illness

Hepatocyte growth factor suppresses acute renal inflammation by inhibition of endothelial E-selectin

Host defense against systemic infection with Streptococcus pneumoniae is impaired in E-, P-, and E-/P-selectin-deficient mice.

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