Sepsis is a lethal syndrome characterized by systemic inflammation and abnormal coagulation. Despite therapeutic advances, sepsis mortality remains substantially high. Herein, we investigated the role of the plasminogen/plasmin (Plg/Pla) system during sepsis. Plasma levels of Plg were significantly lower in mice subjected to severe compared with nonsevere sepsis, whereas systemic levels of IL-6, a marker of sepsis severity, were higher in severe sepsis. Plg levels correlated negatively with IL-6 in both septic mice and patients, whereas plasminogen activator inhibitor-1 levels correlated positively with IL-6. Plg deficiency render mice susceptible to nonsevere sepsis induced by cecal ligation and puncture (CLP), resulting in greater numbers of neutrophils and M1 macrophages, liver fibrin(ogen) deposition, lower efferocytosis, and increased IL-6 and neutrophil extracellular trap (NET) release associated with organ damage. Conversely, inflammatory features, fibrin(ogen), and organ damage were substantially reduced, and efferocytosis was increased by exogenous Pla given during CLP- and LPS-induced endotoxemia. Plg or Pla protected mice from sepsis-induced lethality and enhanced the protective effect of antibiotics. Mechanistically, Plg/Pla-afforded protection was associated with regulation of NET release, requiring Pla-protease activity and lysine binding sites. Plg/Pla are important host-protective players during sepsis, controlling local and systemic inflammation and collateral organ damage.
Extracellular Traps , Sepsis , Mice , Animals , Fibrinolysin , Plasminogen , Extracellular Traps/metabolism , Interleukin-6/metabolism , Inflammation/metabolism , Sepsis/metabolism , Fibrin/metabolism
Nonphlogistic migration of macrophages contributes to the clearance of pathogens and apoptotic cells, a critical step for the resolution of inflammation and return to homeostasis. Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide of the renin-angiotensin system that acts through Mas receptor (MasR). Ang-(1-7) has recently emerged as a novel proresolving mediator, yet Ang-(1-7) resolution mechanisms are not fully determined. Herein, Ang-(1-7) stimulated migration of human and murine monocytes/macrophages in a MasR-, CCR2-, and MEK/ERK1/2-dependent manner. Pleural injection of Ang-(1-7) promoted nonphlogistic mononuclear cell influx alongside increased levels of CCL2, IL-10, and macrophage polarization toward a regulatory phenotype. Ang-(1-7) induction of CCL2 and mononuclear cell migration was also dependent on MasR and MEK/ERK. Of note, MasR was upregulated during the resolution phase of inflammation, and its pharmacological inhibition or genetic deficiency impaired mononuclear cell recruitment during self-resolving models of LPS pleurisy and E. coli peritonitis. Inhibition/absence of MasR was associated with reduced CCL2 levels, impaired phagocytosis of bacteria, efferocytosis, and delayed resolution of inflammation. In summary, we have uncovered a potentially novel proresolving feature of Ang-(1-7), namely the recruitment of mononuclear cells favoring efferocytosis, phagocytosis, and resolution of inflammation. Mechanistically, cell migration was dependent on MasR, CCR2, and the MEK/ERK pathway.
Angiotensin I , Macrophages , Monocytes , Peptide Fragments , Phagocytosis , Proto-Oncogene Mas/metabolism , Angiotensin I/metabolism , Angiotensin I/pharmacology , Animals , Cells, Cultured , Disease Models, Animal , Humans , Inflammation/metabolism , MAP Kinase Signaling System/physiology , Macrophages/drug effects , Macrophages/physiology , Male , Mice , Mice, Inbred BALB C , Monocytes/drug effects , Monocytes/physiology , Peptide Fragments/metabolism , Peptide Fragments/pharmacology , Peritonitis , Phagocytosis/drug effects , Phagocytosis/physiology , Phenotype , Receptors, CCR2/metabolism
BACKGROUND: Atorvastatin (ATV) inhibits the conversion of 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) to mevalonate formation and promotes lowering of the LDL cholesterol fraction. However, ATV exhibits pleiotropic metabolic actions beyond cholesterol-lowering properties. OBJECTIVE: We aimed to evaluate the effect of ATV on oxidizing species generation and cytokine secretion in Peripheral Blood Mononuclear Cells (PBMNC) of Type 2 Diabetes Mellitus (T2DM) patients in comparison to healthy control. METHODS: Both NADPH-oxidase-dependent and mitochondrial ROS generation were assessed by chemoluminescence luminol-dependent assay and fluorometric experiment, using Dichlorofluorescein Assay (DCFH-DA), respectively. IL-1ß and IL-6 were quantified by classical ELISA. RESULTS: ATV inhibited NADPH-oxidase dependent ROS generation, but showed no effect on mitochondrial ROS generation and activated IL-1ß and IL-6 secretions in PBMNC from control and T2DM patients. ROS generation and cytokine secretion in the presence of an inhibitor of Protein Kinase Cß (iPKCß) and ATV led to similar results. The secretion of IL-1ß, PDB-induced in the presence of iPKCß, but not ATV, was increased. ATV and iPKCß exacerbated PDB-induced IL-6 secretion. LPS activated the secretion of IL-1ß and IL-6 which was potentiated by ATV. CONCLUSION: ATV inhibited ROS generation and activated IL-1 ß/IL-6 secretion in PBMNC of diabetes patients. Its effect was not affected by the hyperglycemia.
Antioxidants/pharmacology , Atorvastatin/pharmacology , Diabetes Mellitus, Type 2/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Leukocytes, Mononuclear/drug effects , Reactive Oxygen Species/metabolism , Adult , Aged , Aged, 80 and over , Case-Control Studies , Diabetes Mellitus, Type 2/diagnosis , Female , Humans , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , NADPH Oxidases/metabolism , Protein Kinase C beta/metabolism , Secretory Pathway
O sarcoma sinovial primário da cabeça e pescoço é um tumor raro. Em torno de 90 casos foram descritos na literatura. Relatamos um caso adicional ocorrido em um paciente jovem do sexo masculino comprometendo a orofaringe. O tumor apresentou típico crescimento bifásico, fibrossarcomatoso e epitelial, com estruturas pseudo-glandulares. O diagnóstico final foi obtido pelo exame da peça cirúrgica com preparaçöes histológicas de rotina e análise imunohistoquímica
