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
-
The host inflammatory response in sepsis may be resolved by endogenous anti-inflammatory immune cell responses, avoiding fatal pathogenesis, organ injury, and death. The intracellular signaling mediator cyclic 3'5'-adenosine monophosphate is a potent modulator of inflammatory responses and initiates the polarization of immune cells in a direction that suppresses inflammatory activation. Cyclic 3'5'-adenosine monophosphate is enzymatically produced by adenylyl cyclases (ACs). ⋯ A correlation between increased miR142-3p and decreased AC9 expression was found in the liver, kidney, and spleen, and when hepatocytes, Kupffer cells (KCs), and liver sinusoidal endothelial cells were isolated after CLP, reduced AC expression and increased miR142-3p expression were found in KCs and liver sinusoidal endothelial cells. Transfecting a miR142-3p inhibitor probe in rat KCs abolished LPS-mediated AC9 inhibition in vitro. These results indicate that CLP leads to miR142-3p-mediated AC9 reduction in liver macrophages, which may further limit cyclic 3'5'-adenosine monophosphate signaling and the ability of macrophages to resolve the proinflammatory response.
-
Randomized Controlled Trial
Influence of severity of illness on the effects of eritoran tetrasodium (E5564) and on other therapies for severe sepsis.
Disease severity varies widely in patients with severe sepsis. Eritoran tetrasodium (E5564), a TLR4 antagonist, blocks the binding of endotoxin and is being evaluated as a novel therapy for severe sepsis. This analysis aimed to assess the efficacy of eritoran based on severity of illness and similar effects in other recent sepsis trials. ⋯ Potential survival benefits of eritoran in severe sepsis patients were associated with high severity of illness. These findings were used to design a phase 3 trial. Similar treatment by severity-of-illness interaction was found in most recent sepsis trials.
-
Controlled Clinical Trial
The influence of experimental alcohol load and alcohol intoxication on S100B concentrations.
Because nearly 50% of patients with mild head trauma are alcohol intoxicated, it often remains unclear if the neurological deficits are due to alcohol intoxication or to intracerebral damage. To avoid unnecessary head computed tomography investigations in patients with mild head trauma, S100B is currently used as an exclusion marker for cellular brain damage. However, whether S100B levels are influenced by alcohol itself remains to be unclear. ⋯ In contrast, compared with the control group (n = 60 sober and healthy), the ethyl alcohol-intoxicated patients (n = 61; mean ethyl alcohol, 251 [SD, 87] mg/dL) had higher S100B concentrations (0.193 [SD, 0.45] vs. 0.063 [SD, 0.059] μg/L; P < 0.001), and 39% of them had levels greater than the pathologic cutoff at greater than 0.104 μg/L. However, no significant correlation was found between ethyl alcohol concentrations and S100B within the respective group. Our clinical data suggest that blood alcohol concentrations far in excess of 100 mg/dL are associated with increased S100B levels in alcohol-intoxicated patients.
-
The purpose of this study was to evaluate the prognostic significance of classification of patients with septic shock into different critical illness-related corticosteroid insufficiency subgroups. A retrospective observational study was conducted in patients with septic shock who underwent a short corticotropin stimulation test within 72 h of the onset of shock. Patients were classified into normal adrenal function (NOM), low basal cortisol (LBC) (basal cortisol, <10 μg/dL), or low Δ cortisol (LDC) (basal cortisol, ≥10 μg/dL; cortisol, <9 μg/dL) groups. ⋯ The 28-day mortalities of the NOM, LBC, and LDC groups were 40.5%, 38.5%, and 63.2%, respectively (P = 0.007). Classification into the LDC group significantly increased the odds of 28-day mortality (odds ratio, 2.717; 95% confidence interval, 1.452-5.082; P = 0.002) and remained an independent risk factor for mortality even after controlling for all the other potential risk factors identified (odds ratio, 3.638; 95% confidence interval, 1.418-9.028; P = 0.006). Classification into the LDC group is an independent risk factor for mortality in hydrocortisone-treated septic shock patients.
-
We investigated the effect of the angiotensin-converting enzyme (ACE) inhibitor captopril in a clinically relevant ovine model of smoke and burn injury, with special reference to oxidative stress and activation of poly(ADP-ribose) polymerase, in the lung and in circulating leukocytes. Female, adult sheep (28-40 kg) were divided into three groups. After tracheostomy and under deep anesthesia, both vehicle-control-treated (n = 5) and captopril-treated (20 mg/kg per day, i.v., starting 0.5 h before the injury) (n = 5) groups were subjected to 2 × 20%, third-degree burn injury and were insufflated with 48 breaths of cotton smoke. ⋯ Our results suggest that the ACE inhibitor captopril exerts beneficial effects on the pulmonary function in burn/smoke injury. The effects of the ACE inhibitor may be related to the prevention of reactive oxygen species-induced poly(ADP-ribose)polymerase overactivation. Angiotensin-converting enzyme inhibition may also exert additional beneficial effects by inhibiting the expression of the profibrotic mediator transforming growth factor β.