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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Exocytosis of granules containing the cytolytic effector (CE) molecules granzyme A (GzmA), granzyme B (GzmB), and perforin is one major pathway of lymphocyte-mediated cytotoxicity. Studies in murine models and the finding of elevated granzyme levels in the plasma of septic patients have implicated cytotoxic lymphocytes in the pathogenesis of sepsis. We sought to evaluate the role of cytotoxic cells and CE in sepsis and determine if intracellular levels of CE in cytotoxic cells correlate with disease severity. ⋯ The GMFI of each GzmA and GzmB in CTLs were associated with the Acute Physiology and Chronic Health Evaluation II score (P = 0.01). A significant increase in the number of granulocytes in the peripheral blood mononuclear cells of SS patients consisted primarily of low-density neutrophils, which expressed increased levels of GzmA (P < 0.01). The results suggest that CTLs are activated in SS and express significantly higher intracellular levels of GzmB and that GzmA and B levels correlate with disease severity.
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β-Catenin, a key regulator of barrier integrity, is an important component of the adherens junctional complex. Although the roles of β-catenin in maintaining the adherens junctions and Wnt signaling are known, the dynamics of β-catenin following insult and its potential role in vascular recovery/repair remain unclear. Our objective was to define β-catenin's dynamics following disruption of the adherens junctional complex and subsequent recovery. ⋯ Inhibition of GSK-3β and the transfection of β-catenin vector increased Tcf-mediated transcription significantly (P < 0.05). The dissociated adherens junctional protein β-catenin translocates into the cytoplasm, resulting in microvascular hyperpermeability followed by a time-dependent recovery and relocation to the cell membrane. Our data suggest a recycling pathway for β-catenin to the cell junction.
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Ischemia-reperfusion (I/R) renal injury is considered the most common cause of acute kidney injury (AKI). The pathophysiology of I/R AKI involves a complex interplay among tubular epithelial cell injury, microcirculation dysfunction, and inflammation. Interleukin 18-binding protein (IL-18BP) is a natural inhibitor of IL-18 a cytokine that plays an important role in the pathogenesis of AKI. ⋯ Macrophage infiltration was inhibited, and inflammatory cytokines were downregulated. Increased expression of vascular endothelial growth factor and decreased expression of thrombospondin 1 were also observed. Exogenous IL-18BP attenuated renal injury caused by I/R via inhibiting inflammation in the renal tissue and protecting tubular epithelium and PTC endothelium.
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We hypothesized that severely injured obese patients would display increased concentrations of proinflammatory cytokines when compared with patients of normal body mass index (BMI) and that this would be associated with multiple organ failure (MOF). This was a retrospective review of prospectively collected data in the "Inflammation and the Host Response to Injury" trauma-related database. Data were collected prospectively from US level I trauma centers. ⋯ Despite prior reports suggesting a proinflammatory cytokine profile in obese individuals, obese patients sustaining severe injury show a depressed early cytokine response when compared with patients of normal BMI. This may confer increased susceptibility to nosocomial infection and later MOF. Further study of immune dysfunction in the postinjury obese patient should assess the possibility of early immune suppression.