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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We have recently found that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a lethal model of hemorrhagic shock in rats. The purpose of the present study was to determine whether SAHA treatment would prevent LPS-induced septic shock and improve the survival in a murine model. C57BL/6J mice were randomly divided into two groups. ⋯ Moreover, LPS insult decreased the acetylation of histone proteins (H2A, H2B, and H3), elevated the levels of TNF-alpha in vivo (circulation) and in vitro (culture medium), increased the neutrophilic cell population in the spleen, enhanced the expression of TNF-alpha and IL-1beta genes in lung tissue, and augmented the pulmonary neutrophil infiltration. In contrast, SAHA treatment markedly attenuated all of these LPS-induced alterations. We report for the first time that administration of SAHA (50 mg/kg) significantly attenuates a variety of inflammatory markers and improves long-term survival after a lethal LPS insult.
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Morbidity and mortality after traumatic injury and hemorrhagic shock (HS) are exacerbated in the alcohol-intoxicated individual. The level of hypotension at the time of admittance into the emergency department is a critical indicator of outcome from injury. Previously, we have demonstrated that acute alcohol intoxication (AAI) decreases basal mean arterial blood pressure (MABP), exaggerates hypotension throughout HS, and attenuates the pressor response to fluid resuscitation in male rodents. ⋯ Acute alcohol intoxication blunted choline-induced neuroendocrine activation and prevented the HS-induced increase in norepinephrine, without affecting post-HS epinephrine and AVP levels. Intracerebroventricular choline administration to AAI animals enhanced the HS-induced increase in epinephrine without affecting post-HS norepinephrine or AVP. These results indicate that ICV choline produced immediate neuroendocrine activation and elevation in MABP that was not sustained sufficiently to improve hemodynamic counter-regulation in alcohol-treated animals.
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Sialic-acid-binding immunoglobulin-like lectin (Siglec) 9 mediates death signals in neutrophils. The objective of this study was to determine the heterogeneity of neutrophil death responses in septic shock patients and to analyze whether these ex vivo data are related to the severity and outcome of septic shock. In this prospective cohort study, blood samples of patients with septic shock (n = 26) in a medical-surgical intensive care unit (ICU) were taken within 24 h of starting the treatment of septic shock (phase A), after circulatory stabilization (phase B), and 10 days after admission or at ICU discharge if earlier (phase C). ⋯ Taken together, septic shock patients exhibit different ex vivo death responses of blood neutrophils after Siglec-9 ligation early in shock. Both the resistance and the increased susceptibility to Siglec-9-mediated neutrophil death tend to normalize within 72 h after shock. Further studies are required to understand the role of Siglec-9-mediated neutrophil death in septic shock.
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Delayed granulocyte apoptosis is implicated in persistent inflammation. Although it is known that males develop sepsis more easily than females, the mechanism for this is not fully understood. Serum IL-18 levels correspond to severity of systemic inflammation. ⋯ Nevertheless, levels of IL-18 in the blood of WT mice were significantly higher in males than in females after intraperitoneal LPS, and the survival rate was significantly higher in KO mice compared with WT mice only in males. This indicates that endogenous IL-18 production decreases survival only in males. Thus, excessive myeloid/granulocyte immunity independent of IL-18 and other IL-18-dependent life-threatening factors in males should be taken into account as therapeutic targets during systemic inflammatory states.