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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Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. ⋯ Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function.
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Interleukin-22 (IL-22) maintains gut epithelial integrity and expression of antimicrobial peptides Reg3β and Reg3γ. Our laboratory has shown that acute alcohol/ethanol (EtOH) exposure before burn injury results in increased gut permeability, intestinal T-cell suppression, and enhanced bacterial translocation. Herein, we determined the effect of combined EtOH intoxication and burn injury on intestinal levels of IL-22 as well as Reg3β and Reg3γ expression. ⋯ Treatment with IL-22 normalized Reg3β and Reg3γ expression and attenuated the increase in intestinal permeability after EtOH and burn injury. Qualitatively, IL-22 treatment reduced the bacterial load in nearly half of mice receiving EtOH combined with burn injury. Our data indicate that IL-22 maintains gut epithelial and immune barrier integrity after EtOH and burn injury; thus, the IL-22/antimicrobial peptide pathway may provide a therapeutic target for the treatment of patients who sustain burn injury under the influence of EtOH.
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The Wnt/β-catenin signaling pathway is well characterized in stem cell biology and plays a critical role in liver development, regeneration, and homeostasis. We hypothesized that pharmacologic activation of Wnt signaling protects against hepatic ischemia/reperfusion (I/R) injury through its known proliferative and antiapoptotic properties. Sprague-Dawley rats underwent 70% hepatic ischemia by microvascular clamping of the hilum of the left and median lobes of the liver for 90 min, followed by reperfusion. ⋯ Wnt agonist also significantly decreased the amount of apoptosis, as evidenced by decreases in both TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining as well as caspase 3 activity levels. Finally, the 10-day survival rate was increased from 27% in the vehicle group to 73% in the pretreated Wnt agonist group and 55% in the Wnt agonist postischemia treatment group. Thus, we propose that direct Wnt/β-catenin stimulation may represent a novel therapeutic approach in the treatment of hepatic I/R.
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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.