E- and P-Selectin Expression Depends on the Resuscitation Fluid Used in Hemorrhaged Rats (original) (raw)
Related papers
Journal of Experimental Medicine, 1999
Resuscitation from hemorrhage induces profound pathophysiologic alterations and activates inflammatory cascades able to initiate neutrophil accumulation in a variety of tissues. This process is accompanied by acute organ damage (e.g., lungs and liver). We have previously demonstrated that significant leukocyte–endothelium interactions occur very early in other forms of ischemia/reperfusion (i.e., splanchnic ischemia/reperfusion and traumatic shock) which are largely mediated by increased expression of the adhesion molecule, P-selectin, on the vascular endothelium. Here we postulated that increased endothelial expression of P-selectin in the microvasculature would play an essential role in initiating the inflammatory signaling of hemorrhagic shock. Using intravital microscopy, we found that hemorrhagic shock significantly increased the number of rolling and adherent leukocytes in the mouse splanchnic microcirculation. In contrast, mice genetically deficient in P-selectin, or wild-typ...
The Journal of Trauma: Injury, Infection, and Critical Care, 2001
Background: Previous studies have shown that mesenteric lymph duct interruption prevents lung injury and decreases lung neutrophil sequestration after hemorrhagic shock (HS). Since endothelial cells rapidly express P-selectin after ischemia/reperfusion injury and HSinduced lung injury appears to involve neutrophil-endothelial cell interactions, we tested the following two hypotheses. First, that HS increases endothelial cell P-selectin expression and that interruption of mesenteric lymph flow in vivo would diminish this expression. Second, that incubation of human umbilical vein endothelial cells with post-HS mesenteric lymph but not sham shock (SS) lymph or postshock portal vein plasma would upregulate P-selectin expression. Methods: Pulmonary microvascular P-selectin expression was measured in male rats subjected to 90 minutes of HS (30 mm Hg), SS, or HS with lymphatic ligation, with a dual radiolabeled monoclonal antibody technique. The lungs from these animals were subsequently harvested and P-selectin expression was expressed as mean ؎ SEM nanograms of monoclonal antibody per gram of tissue. Results: Pulmonary P-selectin expression was 2.0 ؎ 0.4 after SS, 9.7 ؎ 3.0 after HS, but decreased to 2.3 ؎ 0.3 after HS with lymph interruption (p < 0.05 HS vs. SS or HS plus lymph ligation). Incubation of human umbilical vein endothelial cells with shock lymph collected 3 to 4 hours after shock resulted in a nearly fivefold increase in P-selectin expression (p < 0.001) as compared with SS lymph, lymph collected 6 hours after shock, or postshock portal vein plasma. Conclusion: These results support the concept that gut-derived lymph promotes HS-induced lung injury through up-regulation of microvascular adhesion molecules and that intestinal lymph duct interruption may prevent distant organ injury by blunting the expression of these molecules.
Neutrophil-dependent acute lung injury. Requirement for P-selectin (GMP-140)
Journal of Clinical Investigation, 1992
Rapid translocation of P-selectin (GMP-140) from cytoplasmic granules to the cell membrane ofendothelial cells promotes adhesive interactions with neutrophils which, when activated, damage the endothelium. The role ofP-selectin in lung vascular endothelial injury in rats after systemic activation of complement by intravenous infusion of cobra venom factor has been assessed. Within 5-10 min after cobra venom factor infusion, the pulmonary vasculature demonstrated immunohistochemical expression of an epitope that reacts with anti-human P-selectin. Monoclonal antibody to human P-selectin blocked in vitro adherence of rat or human platelets (activated with thrombin) to neutrophils and was demonstrated to react with thrombin-activated rat platelets. The antibody did not react with rat neutrophils. In vivo, the antibody had strongly protective effects against cobra venom factor-induced pulmonary vascular injury as determined by permeability changes and hemorrhage. In parallel, lung myeloperoxidase content was greatly reduced and, by transmission electron microscopy, there was markedly diminished adherence of neutrophils to the pulmonary vascular endothelium and much diminished injury ofendothelial cells, as defined by hemorrhage. These data indicate that anti-human P-selectin reacts with a pulmonary vascular antigen in rats and that this antigen is essential for the full expression of lung injury. (J.
Experimental and Toxicologic Pathology, 2005
The leucocyte expressed surface-bound L-selectin belongs to the selectin family of adhesion molecules. It exhibits adhesive as well as signalling functions. Mainly, it is of importance in lymphocyte homing and in the extravasation of leucocytes into the surrounding tissue during inflammation. Acting in the initial step of the cell adhesion cascade, Lselectin is responsible for the rolling of leucocytes on endothelial layers. Therefore, L-selectin is thought to be an adequate target for pharmacological interventions. Beneath the discussion of the molecules' general features like molecule structure and its regulation, the review focuses firstly on L-selectin in the context of posttraumatic inflammatory disorders, and secondly on the importance of L-selectin specific signalling events.
L-Selectin Blockade and Liver Function in Rats After Uncontrolled Hemorrhagic Shock
Journal of Investigative Surgery, 2001
Hemorrhagic shock (HS) and resuscitation can be seen as a global body ischemia-reperfusion (I/ R) injury characterized by neutrophil in ltration and organ damage. Liver dysfunction occurs early after HS. Adhesion molecules are needed for the rst steps of neutrophil migration. Thus, the purpose of this study was to investigate the role of L-selectin in the liver after uncontrolled HS and resuscitation. Forty-eight Sprague Dawley rats were subjected to uncontrolled HS and resuscitation. Animals were divided into three groups: sham, uncontrolled HS and resuscitation, and uncontrolled HS and resuscitation with anti-L-selectin treatment. At 6 we evaluated liver injury tests, liver tissue myeloperoxidase (MPO), and liver histology. Survival was followed for 3 days and compared between groups. Statistical analysis included Fisher's exact test and one-way analysis of variance. Survival signi cantly increased from 30% in the control group to 60% in the treated group ( p < :05). Hepatocellular and structural injury as well as neutrophil in ltration was signi cantly decreased in treated animals ( p < :05). Thus, blockade of L-selectin resulted in decreased hepatocellular injury and increased survival in our model of uncontrolled HS. Selectins may be important therapeutic targets for blockade in the treatment of HS.
Differing Patterns of P-Selectin Expression in Lung Injury
The American Journal of Pathology, 1998
In the immune complex model , upregulation of P-selectin was defined by Northern and Western blot analysis of lung homogenates , by immunostaining of lung tissue , and by vascular fixation of 125 I-labeled anti-Pselectin. P-selectin protein was detected by 1 hour (long before detection of mRNA) and expression was sustained for the next 7 hours , in striking contrast to the pattern of P-selectin expression in the cobra venom factor model , in which upregulation was very transient (within the 1st hour). In the immune complex model , injury and neutrophil accumulation were P-selectin dependent. Upregulation of P-selectin was dependent on an intact complement system , and the presence of blood neutrophils was susceptible to the antioxidant dimethyl sulfoxide and required C5a but not tumor necrosis factor ␣. In contrast , in the cobra venom factor model , upregulation of P-selectin, which is C5a dependent , was also dimethyl sulfoxide sensitive but neutrophil independent. Different mechanisms that may explain why upregulation of lung vascular P-selectin is either transient or sustained are discussed.
The Journal of Immunology
Cobra venom factor (CVF) induces lung injury through oxidant- and neutrophil-dependent mechanisms. Adhesion molecules, particularly L-selectin, P-selectin, CD11/CD18, and ICAM-1, are required for full expression of injury in rats. This study compared the roles of P-selectin and ICAM-1 using either mutant mice or blocking Abs. Mice deficient in either P-selectin, ICAM-1, or both adhesion molecules were compared with wild-type mice. Wild-type and single mutant mice were given Abs against murine P-selectin or ICAM-1. CVF was injected i.v., and neutrophil sequestration and extravascular albumin were measured 30 min later. Neither P-selectin, ICAM-1, nor P-selectin/ICAM-1 double mutants showed a reduction in neutrophil sequestration or lung injury when compared with wild-type mice. Anti-P-selectin Abs inhibited both sequestration and injury in wild-type mice by 57% and 60%, respectively, but had no effect in P-selectin mutants. Similar results were found using anti-ICAM-1 Ab in wild-type...