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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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.
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Systemic inflammatory response syndrome (SIRS) is a fundamental host response common to bacterial infection and sterile tissue injury. Systemic inflammatory response syndrome can cause organ dysfunction and death, but its mechanisms are incompletely understood. Moreover, SIRS can progress to organ failure or death despite being sterile or after control of the inciting infection. ⋯ Critically, activated protein C pretreatment (n = 4) allowed mtDNA levels to decay after bacterial clearance with sparing of organ function and survival. In summary, host tissue injury correlates with mtDNA whether infective or sterile. Mitochondrial DNA and bDNA polymerase chain reactions can quantify tissue injury incurred by septic or sterile mechanisms and suggest the source of SIRS of unknown origin.
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Gastrointestinal bacteria and epithelia contribute to systemic inflammation and infections in critically ill patients, but the gut microbiota in these diseases has not been analyzed dynamically by molecular fingerprinting methods. This study aimed to identify ileal flora dysbiosis pattern and bacterial species that changed significantly in a rat model of intestinal ischemia and reperfusion and illustrate time courses of both epithelial alterations and gut flora variations in the same injury. Forty-eight rats were randomized into eight groups (n = 6/group). ⋯ The specific dysbiosis were characterized by Escherichia coli proliferation and Lachnospiraceae and Lactobacilli reduction. These bacteria that contributed most were identified by principal component analysis and sequencing and confirmed by real-time polymerase chain reaction. In addition, alterations of ileal microbiota followed epithelial changes in the time course of reperfusion.
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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.