Essential role of P-selectin in the initiation of the inflammatory response induced by hemorrhage and reinfusion.
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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-type mice given either an anti-P-selectin monoclonal antibody or a recombinant soluble P-selectin glycoprotein ligand (PSGL)-1 immunoglobulin, exhibited markedly attenuated leukocyte-endothelium interaction after hemorrhagic shock. Thus, activation of P-selectin protein on the microvascular endothelium is essential for the initial upregulation of the inflammatory response occurring in hemorrhagic shock. Moreover, endogenous levels of PSGL-1 mRNA were significantly increased in the lung, liver, and small intestine of wild-type mice subjected to hemorrhagic shock. Since PSGL-1 promotes adhesive interactions largely through P-selectin expressed on the vascular endothelium, this result further supports the crucial role played by P-selectin in the recruitment of leukocytes during hemorrhagic shock. (+info)
Hemorrhage decreases macrophage inflammatory protein 2 and interleukin-6 release: a possible mechanism for increased wound infection.
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OBJECTIVE: To determine whether alteration in wound exudate cell immune function occurs after trauma-hemorrhage. BACKGROUND: Although clinical and experimental studies indicate that the rate of wound infection is increased after trauma and hemorrhagic shock, the underlying mechanism for this increased susceptibility remains unknown. METHODS: Male C3H/HeN mice were subjected to a midline laparotomy and polyvinyl alcohol sponges were implanted subcutaneously in the abdominal wound before hemorrhage (35+/-5 mm Hg for 90 minutes and resuscitation) or sham operation. The wound exudate cells from the sponges were harvested on the first, third, and fifth postoperative day and cultured for 24 hours in the presence of lipopolysaccharide (10 microg/ml) or heat-killed Staphylococcus aureus. Interleukin (IL)-1beta, IL-6, monocyte chemotactic protein 1, macrophage inflammatory protein 2, and nitrite levels were determined in the supernatants. The distribution of macrophages and polymorphonuclear leukocytes was assessed in the sponge with and without in vivo injection of S. aureus. The phagocytic activity of isolated wound exudate cells was determined using fluorescent S. aureus. RESULTS: The composition of exudate cells was unaltered by hemorrhagic shock; however, in vivo injection of S. aureus significantly decreased the percentage of macrophages under such conditions. Wound exudate cell phagocytic activity and the release of IL-1beta, IL-6, monocyte chemotactic protein 1, and macrophage inflammatory protein 2 was decreased on the first postoperative day. The release of IL-1beta and IL-6 was also decreased on the third postoperative day in hemorrhaged mice. On the fifth postoperative day, wound exudate cell cytokine production was comparable to that in shams. CONCLUSIONS: Because most wound infections occur early after severe trauma, these results suggest that the dysfunction of wound exudate cells after hemorrhage might contribute to the increased incidence of wound infections. Therefore, attempts to enhance or restore wound cell immune function might be helpful for decreasing the incidence of wound infections in trauma victims. (+info)
Effects of recombinant human endothelial-derived interleukin-8 on hemorrhagic shock in rats.
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AIM: To study the effects of recombinant human endothelial-derived interleukin-8 (IL-8) on hemorrhagic shock. METHODS: A profound hemorrhagic shock in rats was produced by exsanguination from femoral artery with mean arterial blood pressure (MABP) maintained at 5.32 kPa for 90 min. After transfusion, IL-8 250 micrograms.kg-1 was i.v. injected. Plasma endothelin-1 (ET-1) and 6 ketoprostaglandin F1 alpha (6-KPGF1 alpha) contents were determined with radioimmunoassay. RESULTS: After i.v. IL-8, the MABP in IL-8 group was elevated obviously (P < 0.01), the rat survival 2 h after infusion was increased (P < 0.05). During profound shock the plasma ET-1 levels were higher (21 +/- 4 vs 8.2 +/- 1.8 ng.L-1, P < 0.01) and the plasma 6-KPGF1 alpha contents lower than those in normal rats (107 +/- 12 vs 157 +/- 11 ng.L-1, P < 0.01). IL-8 remarkably reduced the plasma ET-1 levels (10 +/- 4 ng.L-1, P < 0.01) and enhanced plasma 6-KPGF1 alpha contents (368 +/- 16 ng.L-1, P < 0.01). CONCLUSION: IL-8 has beneficial antishock effects. (+info)
Inhibition of beta-adrenergic-dependent alveolar epithelial clearance by oxidant mechanisms after hemorrhagic shock.
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Endogenous release of catecholamines is an important mechanism that can prevent alveolar flooding after brief but severe hemorrhagic shock. The objective of this study was to determine whether this catecholamine-dependent mechanism upregulates alveolar liquid clearance after prolonged hemorrhagic shock. Rats were hemorrhaged to a mean arterial pressure of 30-35 mmHg for 60 min and then resuscitated with a 4% albumin solution. Alveolar liquid clearance was measured 5 h later as the concentration of protein in the distal air spaces over 1 h after instillation of a 5% albumin solution into one lung. There was no upregulation of alveolar liquid clearance after prolonged hemorrhagic shock and fluid resuscitation despite a significant increase in plasma epinephrine levels. The intravenous or intra-alveolar administration of exogenous catecholamines did not upregulate alveolar liquid clearance. In contrast, catecholamine-mediated upregulation of alveolar liquid clearance was restored either by depletion of neutrophils with vinblastine, by the normalization of the concentration of reduced glutathione in the alveolar epithelial lining fluid by N-acetylcysteine, or by the inhibition of the conversion from xanthine dehydrogenase to xanthine oxidase. These experiments provide the first in vivo evidence that a neutrophil-dependent oxidant injury to the alveolar epithelium prevents the upregulation of alveolar fluid clearance by catecholamines in the absence of a major alteration in paracellular permeability to protein after prolonged hemorrhagic shock. (+info)
Systemic and microcirculatory effects of autologous whole blood resuscitation in severe hemorrhagic shock.
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Systemic and microcirculatory effects of autologous whole blood resuscitation after 4-h hemorrhagic shock with a mean arterial pressure (MAP) level of 40 mmHg were investigated in 63 conscious Syrian golden hamsters. Microcirculation of skeletal skin muscle and subcutaneous connective tissue was visualized in a dorsal skinfold. Shed blood was retransfused within 30 min after 4 h. Animals were grouped into survivors in good (SG) and poor condition (SP) and nonsurvivors (NS) according to 24-h outcome after resuscitation and studied before shock, during shock (60, 120, and 240 min), and 30 min and 24 h after resuscitation. Microvascular and interstitial PO2 values were determined by phosphorescence decay. Shock caused a significant increase of arterial PO2 and decrease of PCO2, pH, and base excess. In the microcirculation, there was a significant decrease in blood flow (QB), functional capillary density (FCD; capillaries with red blood cell flow), and interstitial PO2 [1.8 +/- 0.8 mmHg (SG), 1.3 +/- 1.3 mmHg (SP), and 0.9 +/- 1.1 mmHg (NS) vs. 23.0 +/- 6.1 mmHg at control]. Blood resuscitation caused immediate MAP recompensation in all animals, whereas metabolic acidosis, hyperventilation, and a significant interstitial PO2 decrease (40-60% of control) persisted. In NS (44.4% of the animals), systemic and microcirculatory alterations were significantly more severe both in shock and after resuscitation than in survivors. Whereas in SG (31.8% of the animals) there was only a slight (15-30%) but still significant impairment of microscopic tissue perfusion (QB, FCD) and oxygenation at 24 h, SP (23.8% of the animals) showed severe metabolic acidosis and substantial decreases (>/=50%) of FCD and interstitial PO2. FCD, interstitial PO2, and metabolic state were the main determinants of shock outcome. (+info)
Distribution of endotoxins in tissues and circulation and its effects following hemorrhagic shock.
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OBJECTIVE: To systemically investigate 1) distribution of endogenous endotoxin (ET) in tissues and circulation; 2) its relationship with shock duration and organ damage; and 3) its possible mechanism after hemorrhagic shock. METHODS: To further elucidate the intrinsic relationship between endogenous endotoxin translocation and hemorrhagic shock, the present study systematically investigated the distribution of endogenous ET into the liver, lungs, kidneys and circulation, and the relationship between ET levels and the corresponding organ dysfunction with limulus amebocyte lysate (LAL) chromogenic assay following hemorrhagic shock in rats. RESULTS: It was found that ET levels in hepatic homogenate markedly increased (P = 0.09) 1.5 hours following shock compared with that in the sham group. After resuscitation, ET levels in hepatic, pulmonary and renal tissues were all significantly elevated. The levels kept increasing with the prolonged experimental time, and reached as high as 3.88 +/- 0.95 EU (endotoxin unit)/g in the livers, 2.53 +/- 1.46 EU/g in the lungs and 2.51 +/- 0.89 EU/g in the kidneys 12 hours after shock. ET levels in plasma reached a peak of 1.13 +/- 0.42 EU/ml at 1 hour following resuscitation, then rapidly decreased to the sham levels 3 hours following resuscitation. There was a close relationship between endotoxin translocation and shock duration. Correlation analysis further indicated that the changes in glutamic-pyruvic transaminase (GPT), blood urea nitrogen (BUN) in plasma and angiotensin I-converting exzyme (ACE) in pulmonary homogenate were significantly and positively correlated with the ET levels in the liver, kidneys and lungs after hemorrhagic shock. CONCLUSIONS: Hemorrhagic shock can induce obvious endogenous ET translocation, which is closely related to the shock duration. Although only transient endotoxemia occurs after hemorrhagic shock, ET can massively accumulate in tissues (liver, lungs and kidneys), and may play an important role in the development of shock. (+info)
A novel nitric oxide scavenger decreases liver injury and improves survival after hemorrhagic shock.
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We tested the ability of a nitric oxide (NO) scavenger to reduce tissue injury in a rodent model of hemorrhagic shock. Rats were hemorrhaged to a mean arterial blood pressure (MAP) of 40 mmHg and then resuscitated when either 30% of their shed blood had been returned (group 1) or after 100 min of continuous shock (group 2). Selected animals were treated with the NO scavenger NOX (30 mg. kg(-1). h(-1)) infused over 4 h. Hemorrhaged rats had a lower MAP after resuscitation compared with sham-shock control rats. NOX treatment significantly increased MAP after resuscitation from hemorrhage. Hemorrhagic shock also increased liver injury as reflected by elevated ornithine carbamoyltransferase (OCT) plasma levels, and NOX treatment significantly reduced OCT release. In addition, NOX was associated with significantly decreased hepatic neutrophil infiltration and improved 24-h survival (n = 8 of 9) compared with saline-treated shock animals (n = 3 of 9). These data suggest that excess NO mediates shock-induced tissue injury and that suppression of NO availability with NO scavengers may reduce the pathophysiological sequelae of severe hemorrhage. (+info)
Reversal by vasopressin of intractable hypotension in the late phase of hemorrhagic shock.
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BACKGROUND: Hypovolemic shock of marked severity and duration may progress to cardiovascular collapse unresponsive to volume replacement and drug intervention. On the basis of clinical observations, we investigated the action of vasopressin in an animal model of this condition. METHODS AND RESULTS: In 7 dogs, prolonged hemorrhagic shock (mean arterial pressure [MAP] of approximately 40 mm Hg) was induced by exsanguination into a reservoir. After approximately 30 minutes, progressive reinfusion was needed to maintain MAP at approximately 40 mm Hg, and by approximately 1 hour, despite complete restoration of blood volume, the administration of norepinephrine approximately 3 micrograms . kg(-1). min(-1) was required to maintain this pressure. At this moment, administration of vasopressin 1 to 4 mU. kg(-1). min(-1) increased MAP from 39+/-6 to 128+/-9 mm Hg (P<0.001), primarily because of peripheral vasoconstriction. In 3 dogs subjected to similar prolonged hemorrhagic shock, angiotensin II 180 ng. kg(-1). min(-1) had only a marginal effect on MAP (45+/-12 to 49+/-15 mm Hg). Plasma vasopressin was markedly elevated during acute hemorrhage but fell from 319+/-66 to 29+/-9 pg/mL before administration of vasopressin (P<0.01). CONCLUSIONS: Vasopressin is a uniquely effective pressor in the irreversible phase of hemorrhagic shock unresponsive to volume replacement and catecholamine vasopressors. Vasopressin deficiency may contribute to the pathogenesis of this condition. (+info)