THE EFFECT OF TRAUMA ON NEUTROPHIL L-SELECTIN EXPRESSION AND sL-SELECTIN SERUM LEVELS

Seekamp, Andreas; Griensven, Martijn van; Hildebrandt, Friedhelm; Brauer, Nicole; Jochum, Marianne; Martin, Marion

doi:10.1097/00024382-200115040-00002

Cited by 32 publications

(23 citation statements)

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“…49 This is supported by immunohistochemical findings showing that sL selectin specifically binds to the luminal surface of high endothelial venules at sites of inflammation. 49,50 Thus, increased levels of sICAM-1 and sE selectin, associated with low levels of sL selectin, probably reflect diffuse activation of the endothelium. These results are in keeping with previous data demonstrating the presence of increased numbers of activated circulating endothelial cells 51 and increased plasma levels of sVCAM-1.…”

Section: Discussionmentioning

confidence: 99%

Hydroxyurea corrects the dysregulated L-selectin expression and increased H2O2 production of polymorphonuclear neutrophils from patients with sickle cell anemia

Benkerrou

Delarche

Brahimi

et al. 2002

Blood

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Impaired polymorphonuclear neutrophil (PMN) functions during sickle cell anemia (SCA) may have a pathogenic role in the onset of vasoocclusive events. We used flow cytometry to study, in whole blood, the adhesion molecule expression and respiratory burst of PMNs from children with SCA. Three different clinical groups were studied: (1) patients with no history of vasoocclusive events (n ‫؍‬ 15); (2) patients with a history of vasoocclusive events (n ‫؍‬ 17); and (3) patients receiving hydroxyurea therapy for severe vasoocclusive events (n ‫؍‬ 9). Unstimulated PMNs showed decreased L selectin expression and increased H 2 O 2 production whatever the severity of the disease, reflecting PMN activation. This could contribute to endothelial activation reflected by abnormal plasma levels of soluble adhesion molecules (soluble intercellular adhesion molecule-1, sE selectin, and sL selectin). After stimulation with bacterial N-formyl peptides (N-formyl-methionylleucyl-phenylalanine [fMLP]), PMNs from untreated patients with a history of vasoocclusive events showed dysregulated L selectin shedding and increased H 2 O 2 production. Furthermore, in these patients, tumor necrosis factor priming followed by fMLP stimulation induced an H 2 O 2 production significantly higher than in the other patient groups and controls. These impairments could immobilize PMNs on the endothelium, thereby inducing reduced blood flow and fostering microvascular occlusion and vascular damage. In contrast, children treated with hydroxyurea showed near-normal basal and poststimulation H 2 O 2 production as well as normal L selectin shedding after stimulation but no change in plasma levels of soluble adhesion molecules. To our knowledge, this is the first report showing major qualitative changes of PMN abnormalities upon hydroxyurea treatment in SCA patients. This strongly suggests that PMNs are a primary target of this drug. IntroductionSickle cell anemia (SCA) results from a single point mutation that substitutes valine for glutamic acid at the sixth position in the ␤-globin chain and produces hemoglobin S (Hb S). 1,2 The basic pathophysiologic mechanism, based upon the polymerization of deoxy-Hb S and the ensuing deformation, rigidification, and fragilization of the red cells, explains the 3 hallmarks of the disease: hemolytic anemia, vasoocclusive events, and progressive functional asplenia leading to increased susceptibility to infection. Even though all SCA patients have the same biochemical defect, they show wide variability in the frequency and clinical severity of vasoocclusive crises and remain asymptomatic for long periods, indicating that additional factors must contribute to the pathophysiology of vasoocclusion. 3 Abnormal red blood cell (RBC) adhesion to the endothelium has recently been forwarded as the probable initiating event of vasoocclusion, while variations in the endothelium activation state may modulate the unpredictable occurrence of the major complications. 4 Inflammation plays a major role in this process. 5 To date, hydrox...

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Section: Discussionmentioning

confidence: 99%

Hydroxyurea corrects the dysregulated L-selectin expression and increased H2O2 production of polymorphonuclear neutrophils from patients with sickle cell anemia

Benkerrou

Delarche

Brahimi

et al. 2002

Blood

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“…The adhesion molecule L-selectin, expressed on neutrophils, was identified to mediate the initial phase of transient adhesion [27]. The cell expression of L-selectin as well as the serum concentration of soluble L-selectin change significantly after trauma and may distinguish between patients developing organ failure and those who do not [28]. Therefore, L-selectin was supposed to be a potential target for immunomodulatory therapy [29].…”

Section: Discussionmentioning

confidence: 99%

“…Shedding of surface L-selectin may result in diminished neutrophil binding sites for the antibody and, in addition, some amount of the antibody may bind to the soluble L-selectin, as shown in vitro [28]. Thus, even higher concentrations of aselizumab may not necessarily result in a 100% saturation of neutrophil L-selectin.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Anti-L-Selectin (Aselizumab) on the Posttraumatic Inflammatory Response in Multiply Traumatized Patients

et al. 2005

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European Journal of Trauma Ab stractPurpose: This prospective phase II parallel-group, double-blind, randomized, placebo-controlled clinical trial was meant to evaluate the effect of a humanized monoclonal anti-L-selectin antibody (aselizumab) on the posttraumatic inflammatory response in severely injured patients. Patients and Methods: To be eligible for the study, patients had to have sustained a trauma due to a blunt or penetrating injury, which involved at least two organ systems according to the Abbreviated Injury Scale (AIS) resulting in a total Injury Severity Score (ISS) of ¹ 25. Included patients (n = 84) received either placebo or 0.5 mg/kg, 1.0 mg/kg, or 2.0 mg/kg of aselizumab within 6 h of the traumatic event. Parameters representing the posttraumatic inflammatory response were monitored for 10 days, patients' general records were monitored for 14 days and discontinuously until day 42. Results: The incidence of multiple organ failure (MOF) defined as a median value of the total Goris MOF score of ¹ 5 on ¹ 2 consecutive days within the first 14 days was not significantly different for the placebo and the 0.5-mg/kg, 1.0-mg/kg, and 2.0-mg/kg groups. The cytokine interleukin-(IL-)6 and IL-10 serum levels as well as neutrophil elastase serum concentrations revealed the well-described posttraumatic acute response which resolved from day 3 after trauma in all four study groups.Also complement factor C3a and procalcitonin followed the same pattern. There were no statistically significant differences between placebo and patients having received anti-L-selectin at different dosages. Conclusion: For all of the measured variables, IL-6, IL-10, elastase, C3a and procalcitonin, there were only a few trends but no significant differences between all study groups indicating that the effect of the administered anti-L-selectin antibody on the posttraumatic inflammatory response was similar to that of placebo.

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“…Kerner et al [65] described a correlation between L-selectin on monocytes and the incidence of MODS during the first 6 days after trauma. On PMN, the maximum expression of L-selectin is detected from 3 to 12 h after trauma, when observing for 24 h [66][67][68][69]. By contrast, some authors found decreased membrane L-selectin expression correlating with SIRS [70,71].…”

Section: L-selectin On Pmnmentioning

confidence: 99%

“…Upon interaction with the endothelium, L-selectin is shedded from the PMN surface. The shedded molecules can be found on their endothelial ligands and as soluble factors (sLselectin) in serum [69,[72][73][74]. Therefore, this shedding is associated with the activity level of PMN.…”

Section: L-selectin On Pmnmentioning

confidence: 99%

Immune Reactions after Trauma

2003

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Activation of the immune system for wound healing following accidental trauma is a well-studied phenomenon. The reaction comprises both the cellular and humoral systems. The various steps in the reaction are all temporally defined and influence each other. The main cells involved are polymorphonuclear granulocytes (PMN), monocytes, and lymphocytes. They interact and adhere to the endothelium via adhesion molecules such as L-selectin and ICAM-1. The humoral mediators discussed in this review are tumor necrosis factor-␣ (TNF-␣) and its receptors, interleukin-1␤ (IL-1␤), IL-6, IL-10 and interferon-␥ (IFN-␥). The kinetics of the cells appearing and of the cytokines are discussed. The actions of these players are reviewed along with the most recent literature. Furthermore, we attempt to elucidate causal relationships. The immune system can be hyper-or hypoactive. Both exaggerated pro-and antiinflammatory reactions may have the same endpoint: multiple organ dysfunction syndrome (MODS). This knowledge should be used to meticulously monitor the patient's immunologic status. Depending on the state, hyper-or hypoinflammatory, the treatment should comprise anti-inflammatory and immune-restoring properties, respectively. What is decisive to survival is timely, adequate management based on the individual patient's status.

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THE EFFECT OF TRAUMA ON NEUTROPHIL L-SELECTIN EXPRESSION AND sL-SELECTIN SERUM LEVELS

Cited by 32 publications

References 0 publications

Hydroxyurea corrects the dysregulated L-selectin expression and increased H2O2 production of polymorphonuclear neutrophils from patients with sickle cell anemia

Hydroxyurea corrects the dysregulated L-selectin expression and increased H2O2 production of polymorphonuclear neutrophils from patients with sickle cell anemia

The Effect of Anti-L-Selectin (Aselizumab) on the Posttraumatic Inflammatory Response in Multiply Traumatized Patients

Immune Reactions after Trauma

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