3 research outputs found
The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover
Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem
Aneurisma mic贸tico de aorta abdominal por Listeria monocytogenes
Sr. Editor: Listeria monocytogenes es un pat贸geno poco frecuente que puede causar enfermedad tanto en forma espor谩dica como en brotes generalmente relacionados con los alimentos. En individuos inmunocompetentes la infecci贸n no es invasiva y ocasiona un cuadro cl铆nico similar a una diarrea febril [1], mientras que en embarazadas, inmunocomprometidos, neonatos y ancianos puede adquirir forma invasiva, generalmente sepsis e infecci贸n del SNC [2,3,4]. Las formas localizadas son menos frecuentes, habi茅ndose descrito casos de endocarditis, aneurismas mic贸ticos, artritis, osteomielitis, absceso intraabdominal (abscesos hep谩ticos o espl茅nicos o peritonitis), infecciones pleuropulmonares, osteomielitis y endoftalmitis [1].
Se presenta un caso de aneurisma mic贸tico sobre aorta abdominal infrarrenal por L. monocytogenes con buena respuesta al tratamiento.
Var贸n de 65 a帽os con antecedentes de hipertensi贸n, dislipemia, obesidad, c贸licos renales, hiperuricemia y aneurisma de aorta abdominal diagnosticado en 2009. Acudi贸 a urgencias por dolor dorsolumbar, irradiado a extremidad inferior izquierda de 3 d铆as de evoluci贸n que aumentaba con la movilizaci贸n y no se asociaba a traumatismo. ..
Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis
Aims: Peritonitis is one of the most common causes of sepsis, a serious syndrome characterized by a dysregulated systemic inflammatory response. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role and the therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis. Methods: The level of extracellular GzmA as well as GzmA activity were analyzed in serum from healthy volunteers and patients with confirmed peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (WT) and GzmA-/- mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics alone or in combination serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days, levels of some proinflammatory cytokines were measured in serum and bacterial load and diversity was analyzed in blood and spleen at different times. Results: Clinically, elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen and GzmA did not affect bacterial replication in macrophages in vitro, indicating that GzmA has no role in bacterial control. Analysis of GzmA in lymphoid cells following CLP showed that it was mainly expressed by NK cells. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFa. Conclusions: Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis and provide solid evidences about its therapeutic potential for the treatment of this severe pathology