Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Sepsis is still a leading cause of death on intensive care units. Despite intensive research, only few new therapies have been developed and used in the clinical setting. The fibrin fragment Bβ15-42 was already shown to preserve endothelial barrier function by binding to VE-cadherin and thus stabilize the interendothelial junctions. ⋯ Analysis alanine aminotransferase and aspartate aminotransferase further indicated reduced liver damage following polymicrobial sepsis. In vitro experiments using endothelial cells and macrophages further revealed that Bβ15-42 had no direct effect on Toll-like receptor-mediated inflammation. Therefore, we assume that attenuated inflammation is rather due to sustained vascular integrity and thus suppresses vascular leakage and subsequently leukocyte infiltration during sepsis.
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17β-Estradiol (E2) treatment activates a set of protective response that has been found to protect cells from injury and more importantly to significantly abate the injuries associated with trauma-hemorrhage in vivo. Rapid NF-κB activation has been found to be an important signaling step in E2-mediated protection in cell culture, in vivo ischemia, and trauma-hemorrhage. In the current study, we investigated the signaling cascades linking E2 signaling with NF-κB activation and the protective response and compared them with the effects of two selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen. ⋯ However, E2, unlike either SERM, led to modest increases in apoptosis through the JNK pathway. Selective estrogen receptor modulator treatment led to increased expression of the protective proteins, Mn superoxide dismutase, and endothelial nitric oxide synthase, which was not seen with E2. These results provide new insight into the pathways activating NF-κB by E2 and SERMs and demonstrate that SERMs may have greater protective benefits than E2 in adult endothelial cells and potentially in vivo, as well.
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Sepsis is the leading cause of mortality in intensive care units. Early detection and intervention are critical to prevent death. The acute radiation syndrome is characterized by damage of the gastrointestinal and hematopoietic systems. ⋯ Moreover, plasma PCT levels were elevated already from day 3.5 onward, whereas LPS was elevated from day 7 and LPS-binding protein only 10 days after TBI. Receiver operating characteristic analysis revealed that PCT levels measured 3.5 days after TBI predicted lethality at 10 days. These data demonstrate the value of PCT as an early biomarker in radiation-induced bacteremia for mouse studies and suggest that clinical results from other septic conditions may apply to postradiation septicemia in humans.
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Programmed death 1 (PD-1) is an inhibitor protein receptor for the immune system and has been shown to be upregulated in animal models of critical illness as well as after trauma and in burn victims in humans. It is believed that PD-1 may play a role in the immune dysfunction seen in surgical critical illness. However, although prior studies have associated changes in PD-1 expression with altered immune cell function, it is not known if a correlation with clinical status exists. ⋯ In addition, among patients with an APACHE II score of greater than 20, there was a larger percentage of CD3 cells (44% vs. 29%; P = 0.015) expressing PD-1. When only patients with an APACHE II score greater than 20 were assessed, PD-1 expression on monocytes correlated positively with interleukin levels in the serum (r = 0.525, P = 0.05). Variability in the expression of PD-1 on leukocytes in critical surgical illness correlates with physiological dysfunction and suggests that PD-1 may be a valuable tool in the assessment of immune dysfunction following trauma or severe surgical insult.
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The adipocyte-specific protein adiponectin reveals anti-inflammatory, antioxidant, antiatherosclerotic and vasoprotective effects. This study aims to investigate adiponectin expression in cultured human adipocytes within an inflammatory model and in patients with severe sepsis and evaluates treatment effects of drotrecogin α (activated) (DAA). In an in vitro inflammatory model of adipocyte cell culture, the effect of DAA on adiponectin mRNA expression was evaluated. ⋯ On day 5 after 96-h infusion of DAA (24 μg/kg per hour), adiponectin levels significantly increased in DAA patients and equalized toward DAA patients (P > 0.1). Adiponectin might be involved in the pathogenesis of the systemic inflammatory response during sepsis. Administration of DAA upregulates adiponectin expression under circumstances of systemic inflammation.