Plasmin and plasminogen prevent sepsis severity by reducing neutrophil extracellular traps and systemic inflammation.

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.

Vascular Inflammation in Hypertension: Targeting Lipid Mediators Unbalance and Nitrosative Stress.

Arterial hypertension is a worldwide public health threat. High Blood Pressure (BP) is commonly associated with endothelial dysfunction, nitric oxide synthases (NOS) unbalance and high peripheral vascular resistance. In addition to those, inflammation has also been designated as one of the major components of BP increase and organ damage in hypertension. This minireview discusses vascular inflammatory triggers of high BP and aims to fill the existing gaps of antiinflammatory therapy of hypertension. Among the reasons discussed, enhanced prostaglandins rather than resolvins lipid mediators, immune cell infiltration and oxidative/nitrosative stress are pivotal players of BP increase within the inflammatory hypothesis. To address these inflammatory targets, this review also proposes new concepts in hypertension treatment with non-steroidal antiinflammatory drugs (NSAIDs), nitric oxide-releasing NSAIDs (NO-NSAIDs) and specialized proresolving mediators (SPM). In this context, the failure of NSAIDs in hypertension treatment seems to be associated with the reduction of endogenous NO bioavailability, which is not necessarily an effect of all drug members of this pharmacological class. For this reason, NO-releasing NSAIDs seem to be safer and more specific therapy to treat vascular inflammation in hypertension than regular NSAIDs.