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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Hepatic gene expression patterns following trauma-hemorrhage: effect of posttreatment with estrogen.
The aim of this study was to examine the role of estrogen on hepatic gene expression profiles at an early time point following trauma-hemorrhage in rats. Groups of injured and sham controls receiving estrogen or vehicle were killed 2 h after injury and resuscitation, and liver tissue was harvested. Complementary RNA was synthesized from each RNA sample and hybridized to microarrays. ⋯ Pathway analysis demonstrated predominant changes in the expression of genes involved in metabolism, immunity, and apoptosis. Upregulation of low-density lipoprotein receptor, protein phosphatase 1, regulatory subunit 3C, ring-finger protein 11, pyroglutamyl-peptidase I, bactericidal/permeability-increasing protein, integrin, αD, BCL2-like 11, leukemia inhibitory factor receptor, ATPase, Cu transporting, α polypeptide, and Mk1 protein was found in estrogen-treated trauma-hemorrhaged animals. Thus, estrogen produces hepatoprotection following trauma-hemorrhage likely via antiapoptosis and improving/restoring metabolism and immunity pathways.
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Thromboelastography (TEG) is emerging as the standard in the management of acute coagulopathies in injured patients. Although TEG is sensitive in detecting abnormalities in clot strength, one shortcoming is differentiating between fibrinogen and platelet contributions to clot integrity. Current American algorithms suggest platelet transfusion, whereas European guidelines suggest fibrinogen concentrates for correcting low clot strength. ⋯ Moreover, FF had a stronger correlation to clot strength, and increased levels were directly associated with increased percent contribution to clot strength. In vitro studies also demonstrated an increase in FF, clot strength, and percent fibrinogen contribution to clot strength with the addition of fibrinogen concentrate. These data suggest that fibrinogen should be addressed early in trauma patients manifesting acute coagulopathy of trauma.
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Activation of Fas signaling is a potentially important pathophysiological mechanism in the development of septic acute lung injury (ALI). However, so far the optimal targets within this signaling cascade remain elusive. Thus, we tested the hypothesis that in vivo gene silencing of Fas, Fas-associated via death domain (FADD), or caspase 3 by intratracheal administration of small interfering RNA would ameliorate ALI in a clinically relevant double-hit mouse model of trauma induced septic lung injury. ⋯ Interestingly, only in response to caspase 3 silencing, ALI-induced lung epithelial barrier dysfunction was substantially improved, and histological appearance was beneficially affected. Taken together, downstream inhibition of lung apoptosis via caspase 3 silencing proved to be superior in mitigating ALI when compared with upstream inhibition of apoptosis via Fas or FADD silencing, even in the presence of additional anti-inflammatory effects. This indicates a major pathophysiological role of lung apoptosis and suggests the importance of other than Fas-driven apoptotic pathways in trauma-induced septic ALI.
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Although cardiac troponin I (cTnI) elevations during acute pulmonary embolism (PE) are predictive of in-hospital death, it is not clear whether cTnI measurements at emergency department (ED) admission are predictive of the occurrence of hypotension. The study subjects included all consecutive patients with acute PE (diagnosed by chest computed tomography angiography) in the ED between January 2006 and December 2011. All underwent cTnI tests at ED admission and were divided into two groups based on the occurrence of hypotension within 24 h. ⋯ The sensitivity, specificity, positive predictive value, and negative predictive value of elevated cTnI were 85%, 66%, 20%, and 98%, respectively. This study suggests that a normal cTnI nearly rules out subsequent development of hypotension within 24 h. This may help to select those patients who would benefit most from intensive clinical surveillance and escalated treatment.
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Adenosine 3',5'-cyclic adenosine monophosphate (cAMP) activates intracellular signaling by regulating protein kinase A, calcium influx, and cAMP-binging guanine nucleotide exchange factors (Epac [exchange protein directly activated by cAMP] or cAMP-GEF). Cyclic adenosine monophosphate inhibits cytokine-induced expression of inducible nitric oxide synthase (iNOS) in hepatocytes by a protein kinase A-independent mechanism. We hypothesized that Epac mediates this effect. ⋯ OPTmecAMP also induced c-Jun N-terminal kinase (JNK) phosphorylation in hepatocytes. Overexpression of dominant-negative JNK enhanced cytokine-induced iNOS expression and nitrite production and reversed the inhibitory effects of LEpac2 on nitrite production and iNOS expression. We conclude that Epac regulates hepatocyte iNOS expression through an Akt- and JNK-mediated signaling mechanism.