Revisiting caspases in sepsis.
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ABSTRACT:
SUBMITTER: Aziz M
PROVIDER: S-EPMC4260746 | biostudies-other | 2014 Nov
REPOSITORIES: biostudies-other
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Project description:Sepsis is a dysregulated host response to infection related to devastating outcomes. Recently, interest has been shifted towards apoptotic and antiapoptotic pathobiology. Apoptosis is executed through the activation of caspases regulated by a number of antiapoptotic proteins, such as survivin. The survivin and caspases' responses to sepsis have not yet been elucidated. This is a multicenter prospective observational study concerning patients with sepsis (n?=?107) compared to patients with traumatic systemic inflammatory response syndrome (SIRS) (n?=?75) and to healthy controls (n?=?89). The expression of survivin was quantified through real-time quantitative polymerase chain reaction for the different survivin splice variants (wild type-WT, ?Ex3, 2B, 3B) in peripheral blood leukocytes. The apoptotic or antiapoptotic tendency was specified by measuring survivin-WT, caspase-3, and -9 serum protein concentrations through enzyme-linked immunosorbent assay. The survivin-WT, -2B, -??x3 mRNA, survivin protein, and caspases showed an escalated increase in SIRS and sepsis, whereas survivin-3B was repressed in sepsis (p?<?0.05). Survivin correlated with IL-8 and caspase-9 (p?<?0.01). For discriminating sepsis, caspase-9 achieved the best receiver operating characteristic curve (AUROC) of 0.95. In predicting mortality, caspase-9 and survivin protein achieved an AUROC of 0.70. In conclusion, specific apoptotic and antiapoptotic pathways might represent attractive targets for future research in sepsis.
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Project description:BACKGROUND:Decline in mitochondrial function occurs with aging and may increase mortality. We discuss mitochondrial contribution to Covid-19 sepsis, specifically the complex interaction of innate immune function, viral replication, hyper-inflammatory state, and HIF-?/Sirtuin pathways. METHODS:Articles from PubMed/Medline searches were reviewed using the combination of terms "SARS-CoV-2, Covid-19, sepsis, mitochondria, aging, and immunometabolism". RESULTS:Evidence indicates that mitochondria in senescent cells may be dysfunctional and unable to keep up with hypermetabolic demands associated with Covid-19 sepsis. Mitochondrial proteins may serve as damage-associated molecular pattern (DAMP) activating innate immunity. Disruption in normal oxidative phosphorylation pathways contributes to elevated ROS which activates sepsis cascade through HIF-?/Sirtuin pathway. Viral-mitochondrial interaction may be necessary for replication and increased viral load. Hypoxia and hyper-inflammatory state contribute to increased mortality associated with Covid-19 sepsis. CONCLUSIONS:Aging is associated with worse outcomes in sepsis. Modulating Sirtuin activity is emerging as therapeutic agent in sepsis. HIF-?, levels of mitochondrial DNA, and other mitochondrial DAMP molecules may also serve as useful biomarker and need to be investigated. These mechanisms should be explored specifically for Covid-19-related sepsis. Understanding newly discovered regulatory mechanisms may lead to the development of novel diagnostic and therapeutic targets.
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Project description:BackgroundFluid challenge (FC) is one of the most common practices in Intensive Care Unit (ICU). The present study aimed to evaluate whether echocardiographic assessment of the response to FC at the end of the infusion or 20 min later could affect the results of the FC.MethodsThis is a prospective, observational, multicenter study including all ICU patients in septic shock requiring a FC of 500 mL crystalloids over 10 min. Fluid responsiveness was defined as a > 15% increase in stroke volume (SV) assessed by velocity-time integral (VTI) measurements at baseline (T0), at the end of FC (T10), then 10 (T20) and 20 min (T30) after the end of FC.ResultsFrom May 20, 2014, to January 7, 2016, a total of 143 patients were enrolled in 11 French ICUs (mean age 64 ± 14 years, median IGS II 53 [43-63], median SOFA score 10 [8-12]). Among the 76/143 (53%) patient responders to FC at T10, 37 patients were transient responders (TR), i.e., became non-responders (NR) at T30 (49%, 95%CI = [37-60]), and 39 (51%, 95%CI = [38-62]) patients were persistent responders (PR), i.e., remained responders at T30. Among the 67 NR at T10, 4 became responders at T30, (6%, 95%CI = [1.9-15.3]). In the subgroup analysis, no statistical difference in hemodynamic and echocardiographic parameters was found between groups.ConclusionsThis study shows that 51.3% of initial responders have a persistent response to fluid 30 min after the beginning of fluid infusion and only 41.3% have a transient response highlighting that fluid responsiveness is time dependent.Trial registrationClinicalTrials.gov , NCT02116413 . Registered on April 16, 2014.
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Project description:Caspases exert critical functions in diverse cell death pathways, including apoptosis and pyroptosis, but some caspases also have roles in the processing of cytokines into their functional forms during inflammation. The roles of many caspases have been unravelled by the generation of knockout mice, but still very little is known about the overlapping functions of caspases as only a few studies report on double or triple caspase knockout mice. For example, the functions of caspase-12 in cell death and inflammation, on its own or overlapping with the functions of caspase-1 and caspase-11, are only poorly understood. Therefore, we generated a novel mutant mouse strain lacking all three inflammatory caspases, caspases-1, -11 and -12. Analysis under steady state conditions showed no obvious differences between caspase-1/11/12-/- and wildtype (WT) mice. Since caspases-1 and -11 are involved in endotoxic shock, we analysed the response of caspase-1/11/12-/- mice to high-dose LPS injection. Interestingly, we could not detect any differences in responses between caspase-1/11/12-/- mice vs. caspase-1/11 double knockout mice. Furthermore, cell lines generated from caspase-1/11/12-/- mice showed no differences in their apoptotic or necroptotic responses to a diverse set of cytotoxic drugs in vitro when compared to WT cells. Importantly, these drugs also included ER stress-inducing agents, such as thapsigargin and tunicamycin, a form of cell death for which a critical pro-apoptotic function of caspase-12 has previously been reported. Additionally, we found no differences between caspase-1/11/12-/- and WT mice in their in vivo responses to the ER stress-inducing agent, tunicamycin. Collectively, these findings reveal that caspase-12 does not have readily recognisable overlapping roles with caspases-1 and -11 in the inflammatory response induced by LPS and in necroptosis and apoptosis induced by diverse cytotoxic agents, including the ones that elicit ER stress.
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