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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Vascular hyporeactivity is an important factor in irreversible shock, whereas calcium desensitization is one of the mechanisms of vascular hyporeactivity, and the intestinal lymphatic pathway plays an important role in multiple organ injury after severe hemorrhagic shock (HS). In this study, our aims were to determine the effects of mesenteric lymph on vascular reactivity during HS and the mechanisms involved. First, the in vivo pressor response was observed by intravenous injection of norepinephrine (3 μg/kg) at different time points after HS. ⋯ These results indicate that mesenteric lymph return plays an important role in biphasic changes in vascular reactivity during HS. Even more importantly, mesenteric lymph 1 h after shock was an important contributor to vascular hyporeactivity, and its mechanism of action was related to calcium desensitization. Targeting lymph may therefore have therapeutic potential in the treatment of severe shock-induced hypotension.
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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.
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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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Clinical deterioration among hemodynamically stable sepsis patients occurs frequently, and patients with intermediate lactate levels (between 2.0 and 4.0 mmol/L) are particularly at risk for mortality. The aim of this study was to identify factors for predicting early deterioration in sepsis patients with intermediate levels of serum lactate. A retrospective cohort study of adult sepsis patients with lactate levels between 2.0 and 4.0 mmol/L was conducted in the emergency department of a tertiary care hospital between August 2008 and July 2010. ⋯ In patients with a Sequential Organ Failure Assessment score of 5 or greater, the predicted rate of progression to tissue hypoperfusion was 38.9%. Our study demonstrates potential risk factors, including organ failure, for progression to sepsis-induced tissue hypoperfusion in patients with intermediate levels of serum lactate. We suggest that an early aggressive treatment strategy is needed in patients with these risk factors.
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Nicotinic stimulation of the α7 acetylcholine receptors (α7AChRs) mitigates the lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNF-α) and other cytokines release in macrophages. This effect is blocked by α7AChR antagonist, α-bungarotoxin (BTX). We tested and confirmed the hypotheses that LPS upregulates α7AChRs, and the prototypical α7AChR antagonists, vecuronium and BTX, do not block the effects of GTS-21, a specific α7AChR agonist, on TNF-α release. ⋯ Moreover, GTS-21 reduced mortality after burn injury in mice. These results indicate that (i) LPS upregulates α7AChRs; (ii) the therapeutic beneficial effects of GTS-21 on cytokine release are specifically mediated via α7AChRs and are preserved even when cotreated with prototypical antagonist, BTX, or clinically used muscle nicotinic antagonist, vecuronium; (iii) activation of α7AChRs by GTS-21 partially reverses the LPS-induced proliferation arrest; and (iv) GTS-21 reduces mortality in mice with burn injury. The in vivo beneficial effects of GTS-21 in burn injury warrant further studies.