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
-
The inflammasome is activated in response to pathogen or endogenous danger signals and acts as an initiator and mediator of inflammatory reactions. In this study, we wished to identify whether the inflammasome is activated in vivo by injury. And if so, we wanted to characterize the kinetics, the immune cell distribution, and the functional impact of inflammasome activation on the injury response. ⋯ We also found significant injury-induced caspase-1 activation in NK cells, CD4 T cells, and B cells, but CD8 T cells did not demonstrate caspase-1 activation. Surprisingly, we found that blocking caspase-1 activation with AC-YVAD-CMK in vivo caused significantly higher mortality in burn-injured mice (P < 0.01). Taken together, these findings document that injury induces inflammasome activation in many immune cell subsets, but primarily in macrophages, and that inflammasome activation plays a protective role in the host response to severe injury.
-
Clinical Trial
Modifications in erythrocyte membrane protein content are not responsible for the alterations in rheology seen in sepsis.
Red blood cell (RBC) rheology is altered in sepsis and may contribute to the microcirculatory alterations in these patients, but the mechanisms of these changes are not well defined. An increase in the RBC protein band 3/α-spectrin ratio has been observed in a mouse model of septic shock, suggesting a possible alteration in the RBC membrane integral/peripheral protein ratio. This protein modification could contribute to the alterations in RBC rheology observed in sepsis. ⋯ The majority of RBC membrane protein ratios, including band 3/spectrin, were more elevated in critically ill patients (nonseptic and septic) than in volunteers, but RBC membrane skeletal protein content was similar in septic and nonseptic patients. There were no significant differences in cryohemolysis results among groups. Alterations in RBC rheology in sepsis are therefore mainly due to alterations in membrane compounds other than skeletal proteins, like carbohydrates, such as sialic acid and/or lipids.
-
Sepsis and septic shock are associated with cardiac depression. Cardiovascular instability is a major cause of death in patients with sepsis. Focal adhesion kinase (FAK) is a potential mediator of cardiomyocyte responses to oxidative and mechanical stress. ⋯ Focal adhesion kinase silencing reduced the expression and activation of the kinase in cardiac tissue, as well as protecting against the increased collagen deposition, greater matrix metalloproteinase 2 activity, and reduced cardiac contractility that occur during endotoxemia. In conclusion, FAK is activated in endotoxemia, playing a role in cardiac remodeling and in the impairment of cardiac function. This kinase represents a potential therapeutic target for the protection of cardiac function in patients with sepsis.
-
Mortality in the intensive care unit frequently results from the synergistic effect of two temporally distinct infections. This study examined the pathophysiology of a new model of intra-abdominal sepsis followed by methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Mice underwent cecal ligation and puncture (CLP) or sham laparotomy followed 3 days later by an intratracheal injection of MRSA or saline. ⋯ Systemic cytokines were upregulated in both CLP/saline and sham/MRSA mice, and this was blunted by the combination of CLP/MRSA. In contrast, no synergistic effect on pneumonia severity, white blood cell count, or lymphocyte apoptosis was identified in CLP/MRSA mice compared with animals with either insult in isolation. These results indicate that a clinically relevant model of CLP followed by MRSA pneumonia causes higher mortality than could have been predicted from studying either infection in isolation, and this was associated with a blunted local (pulmonary and peritoneal) and systemic inflammatory response and decreased ability to clear infection.
-
Sepsis is one of the leading causes of death in hospitals worldwide. Even with optimal therapy, severe sepsis results in 50% mortality, indicating variability in the response of individuals towards treatment. We hypothesize that the presence of preexisting antibodies present in the blood before the onset of sepsis induced by cecal ligation and puncture (CLP) in mice accounts for the differences in their survival. ⋯ Compared with naive plasma, depletion of IgM had no effect on the PEK. However, depletion of IgG increased PEK, suggesting that an inhibitory IgG binds to antigenic sites on bacteria preventing optimal opsonization of the bacteria. These data demonstrate that, before CLP, circulating inhibitory IgG antibodies exist that prevent bacterial killing by polymorphonuclear neutrophils in a CLP model of sepsis.