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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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.
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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.
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Renal ischemia/reperfusion (I/R) injury is a major clinical problem where main metabolic pathways are compromised and cellular homeostasis crashes after ATP depletion. Fatty acids are major energy source in the kidneys. Carnitine palmitoyltransferase I (CPT1), a mitochondrial membrane enzyme, utilizes carnitine to transport fatty acids to mitochondria for the process of β-oxidation and ATP generation. ⋯ Moreover, the combined treatment significantly improved the survival rate in comparison to the vehicle group. In contrast, administration of either drug alone did not show a significant improvement in most of the measurements. In conclusion, enhancing energy metabolism by combination of carnitine and AICAR provides a novel modality to treat renal I/R injury.
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The relationship between end-tidal carbon dioxide (EtCO(2)) and arterial carbon dioxide (PaCO(2))-if better defined-could facilitate the difficult task of ventilation in prehospital trauma patients. We aimed to study the PaCO(2)-EtCO(2) relationship before, during, and after chest trauma, hemorrhage, and resuscitation in swine. Twenty-four swine were intubated, anesthetized, and monitored in an animal intensive care unit during three phases: phase 1 (day 1, healthy animals); phase 2 (day 2, injury), which consisted of blunt chest trauma, hemorrhage, and resuscitation; and phase 3 (day 2, after injury). "Respiratory maneuvers" (changes in respiratory rate and tidal volume [TV], intended to vary the PaCO(2) over a range of 25 to 85 mmHg, were performed during phases 1 and 3. ⋯ This work demonstrated that EtCO(2) alone can reliably be used to estimate PaCO(2) in uninjured subjects and in those subjects who have been resuscitated from severe injury. Immediately after blunt chest injury, the correlation between EtCO(2) and PaCO(2) is temporarily unstable. Under these circumstances (with abnormal oxygenation and/or hemodynamics), greater caution and other monitoring tools may be required.
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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.