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Plasma levels of syndecan-1 (Sdc-1), a biomarker of endothelial glycocalyx (EG) damage, correlate with worse outcomes in trauma patients. However, EG injury is not well characterized in injured older adults (OA). The aims of this study were to characterize Sdc-1 shedding in OA trauma patients relative to younger adults (YA) and determine associations with putative regulators of EG sheddases. We performed a secondary analysis of data from the Pragmatic, Randomized Optimal Platelet, and Plasma Ratios (PROPPR) trial, stratifying bluntly injured subjects into OA and YA groups based on upper age quartile (57 y). Plasma Sdc-1 levels were compared in OA and YA at hospital arrival through postinjury day 3, and the independent association between age and Sdc-1 level at arrival was determined after adjusting for differences in gender, shock index (SI), and pre-existing comorbidities. In a follow-up analysis, case-control matching was used to create populations of OA and YA with equivalent SI and injury severity score. Levels of Sdc-1 were compared between these matched groups, and the relationships with candidate regulators of EG shedding were assessed. Of 680 subjects in the Pragmatic, Randomized Optimal Platelet, and Plasma Ratios trial, 350 (51%) had blunt injuries, and 92 (26.3%) of these were OA. Plasma Sdc-1 levels at arrival, 2 h, and 6 h were significantly lower in OA compared to YA (all P < 0.05). After adjusting for sex, pre-existing morbidities and SI, age was associated with decreased Sdc-1 levels at arrival. In the matched analyses, Sdc-1, high-mobility group box 1 and tissue inhibitor of metalloproteinase–2 levels were lower in OA compared to YA. Both high-mobility group box-1 and tissue inhibitor of metalloproteinase–2 significantly correlated with arrival Sdc-1 and were inversely associated with age. This study indicates that increased age is independently associated with decreased Sdc-1 levels among patients with blunt injuries. Suppressed plasma levels of sheddases in relation to diminished Sdc-1 shedding suggest that mechanisms regulating EG cleavage may be impaired in injured older adults. These findings provide novel insight into the age-dependent impact of injury on the vascular endothelium, which could have important implications for the clinical management of older adults following trauma. [Display omitted] [ABSTRACT FROM AUTHOR]

Background The regulation of erythropoiesis involves hematopoietic progenitor cells, bone marrow stroma, and the microenvironment. Following severe injury, a hypercatecholamine state develops that is associated with increased mobilization of hematopoietic progenitor cells to peripheral blood and decreased growth of bone marrow erythroid progenitor cells that manifests clinically as a persistent injury-associated anemia. Changes within the bone marrow microenvironment influence the development of erythroid progenitor cells. Therefore, we sought to determine the effects of lung contusion, hemorrhagic shock, and chronic stress on the hematopoietic cytokine response. Materials and methods Bone marrow was obtained from male Sprague–Dawley rats ( n = 6/group) killed 7 d after lung contusion followed by hemorrhagic shock (LCHS) or LCHS followed by daily chronic restraint stress (LCHS/CS). End point polymerase chain reaction was performed for interleukin-1β, interleukin-10, stem cell factor, transforming growth factor-β, high-mobility group box-1 (HMGB-1), and B-cell lymphoma-extra large. Results Seven days following LCHS and LCHS/CS, bone marrow expression of prohematopoietic cytokines (interleukin-1β, interleukin-10, stem cell factor, and transforming growth factor-β) was significantly decreased, and bone marrow expression of HMGB-1 was significantly increased. B-cell lymphoma-extra large bone marrow expression was not affected by LCHS or LCHS/CS (naïve: 44 ± 12, LCHS: 44 ± 12, LCHS/CS: 37 ± 1, all P > 0.05). Conclusions The bone marrow microenvironment was significantly altered following severe trauma in a rodent model. Prohematopoietic cytokines were downregulated, and the proinflammatory cytokine HMGB-1 had increased bone marrow expression. Modulation of the bone marrow microenvironment may represent a therapeutic strategy following severe trauma to alleviate persistent injury-associated anemia. [ABSTRACT FROM AUTHOR]

Background Coagulation and inflammation are closely linked during acute inflammatory conditions, such as sepsis. Antithrombin (AT) is an anticoagulant that also has anti-inflammatory activities. The effects of therapeutically administering AT III after the onset of endotoxemia or sepsis were not clear. Here, we studied the effects of administering AT III after inducing lethal endotoxemia in mice. Methods Mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxemia. AT III was administered 3 h later. We assessed survival and the severity of endotoxemia and quantified plasma cytokine levels and biochemical markers of liver and kidney function. In the lungs, we examined neutrophil accumulation, neutrophil extracellular traps, alveolar wall thickness, and chemokine (C-X-C motif) ligand 1 (cxcl-1), cxcl-2 , and high mobility group box 1 expression. Results Administering AT III reduced the severity and mortality of LPS-induced endotoxemia as indicated by 24-h survival of 84% of the mice that received LPS + AT III and only 53% of mice given LPS alone ( P < 0.05). AT III treatment attenuated several changes induced in the lungs by endotoxemia including cxcl-2 mRNA expression, high mobility group box 1 protein expression, neutrophil accumulation, alveolar septal thickening, and neutrophil extracellular trap formation. AT III did not decrease plasma cytokine levels or plasma urea nitrogen levels that were upregulated as a result of LPS-induced endotoxemia. Conclusions Administration of AT III after the onset of endotoxemia improved outcomes in a mouse model. The attenuation of lung inflammation may have a large impact on mortality and morbidity. Because lung inflammation increases the likelihood of mortality from sepsis, AT III could be a useful agent in septic patients. [ABSTRACT FROM AUTHOR]

Background: High mobility group box 1 (HMGB-1) has recently received attention as a late mediator of lipopolysaccharide-induced shock, and is thought to function as a mediator in such a disorder as multi-organ failure (MOF). In Japan, we have access to an immobilized polymyxin B fiber column using a direct hemoperfusion (PMX-DHP) for patients with septic shock to improve hemodynamics and organ dysfunction. In this study, we looked at HMGB-1 levels in each category based on the sequential organ failure assessment (SOFA) scores to further dissect its importance in specific aspects of organ failure in patients undergoing PMX-DHP. Patients and Methods: Sixty patients with septic shock (40 survivors and 20 non-survivors). We analyzed HMGB-1 and IL-6 levels before and after PMX-DHP and defined organ failure as two or more SOFA points. Results: There was a significant positive correlation between SOFA score and HMGB-1 level (P <0.05). The HMGB-1 level before PMX-DHP significantly increased as the number of organ failures increased (P <0.01: comparing 2 versus 5 organ failures). IL-6 levels decreased after PMX-DHP (P <0.05 compared with before PMX-DHP), but HMGB-1 levels remained unchanged. HMGB-1 levels of survivors with organ failure in liver decreased after PMX-DHP, but those of non-survivors significantly increased 24h after PMX-DHP compared with before PMX-DHP (P <0.01). In non-survivors with organ failure in liver, HMGB-1 levels were significantly higher than among survivors 24h after PMX-DHP (P <0.01). Conclusions: Our results indicate that HMGB-1 is a useful prognostic biomarker in sepsis-induced organ failure in patients undergoing PMX-DHP. [Copyright &y& Elsevier]

Background: High-mobility group 1 (HMGB-1) is a late mediator of endotoxin lethality in mice. The release of HMGB-1 is delayed compared to other proinflammatory cytokines that mediate shock and tissue injury. The purpose of this study was to investigate the role of HMGB-1 levels in response to hepatic ischemia, hepatic I/R injury, and the relationship between changes in HMGB-1 and other cytokines. Materials and methods: Three murine models were employed: our robust model of segmental hepatic warm ischemia (SHWI), a model of partial hepatic ischemia/reperfusion injury (PHIRI), and a model of total hepatic ischemia/reperfusion injury (THIRI). Over a 48-h period following ischemic insult and reperfusion using these models, serum HMGB-1 concentrations, concentrations of HMGB-1 in ischemic and nonischemic lobes, and serum concentrations of TNF-α and IL-6 levels were determined in mice. An anti-HMGB-1 antibody treatment was used in SHWI and THIRI to evaluate what aspects of response to ischemia and reperfusion were potentially mediated by HMGB-1. Results: Hepatic HMGB-1 tissue concentrations exhibited biphasic changes in SHWI mice, which were increased in the ischemic lobes relative to nonischemic lobes at 12 h but decreased relative to nonischemic lobes at 24 h after ischemic insult. These results suggested that HMGB-1 was released into the systemic circulation by necrotic cells over the first 12 h but this process may be complete by 24 h postischemia. By 6 to 12 h after SHWI, serum TNF-α began to increase significantly and continued to increase for 18 h, followed by a sudden decline. Similarly, serum IL-6 increased over 1–3 h after SHWI and then decreased over the next 6 h. Treatment with an anti-HMGB-1 antibody significantly prolonged survival time in SHWI and THIRI. Conclusions: HMGB-1 plays a significant role in the response to hepatic ischemia and hepatic ischemia/reperfusion injury. The present study demonstrated a time-dependent production of HMGB-1 following hepatic warm ischemia in mice. The inherent HMGB-1 in ischemic areas was exhausted and HMGB-1 may be released by necrotic cells. HMGB-1 activation is involved in immediate proinflammatory stress response to I/R and anti-HMGB-1 antibody treatment remarkably improved survival. We demonstrated that systemic HMGB-1 accumulation was measured at an earlier phase of the hepatic ischemia and ischemia/reperfusion injury model than LPS-induced endotoxemia. [Copyright &y& Elsevier]

Objective: To clarify the time course of changes in the serum HMGB-1 concentrations in patients undergoing major gastrointestinal surgery, and to investigate whether the serum HMGB-1 levels correlate with the postoperative clinical course of the patients. Methods: Twenty-eight patients with alimentary tract carcinoma who underwent elective gastrointestinal surgery were enrolled in this study. The correlation between the serum HMGB-1 levels and the postoperative clinical course were evaluated. Results: Serum HMGB-1 concentrations in patients who underwent surgery for gastrointestinal cancer increased gradually during postoperative days, and reached peak concentrations on postoperative day 3 (POD3). There was a statistically significant positive correlation between the serum HMGB-1 levels on POD3 or POD5 and the duration of SIRS (r = 0.68, P < 0.001, r = 0.45, P < 0.05, respectively). A significantly positive correlation was found between the serum HMGB-1 levels on POD3 or POD5 and the heart rates on POD3 or POD5. Furthermore, there was a negative correlation between the serum HMGB-1 levels and PaO2/FiO2 ratio on POD3. Conclusions: Serum HMGB-1 levels increase after major gastrointestinal surgery, and the serum peak HMGB-1 levels correlate with the duration of SIRS and postoperative pulmonary dysfunction. [Copyright &y& Elsevier]