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Sepsis and septic shock are frequent and severe clinical pictures in intensive care medicine that result from a dysregulated immune response to an infection and cause a high mortality rate. This article provides an overview of the various extracorporeal procedures used to treat sepsis. Various procedures are used to treat sepsis and septic shock. These include high-volume hemofiltration (HVHF), very high-volume hemofiltration (VHVHF), high cut-off filter (HCO), polymyxin B hemoperfusion and cytokine adsorption filters. The HVHF and VHVHF remove inflammatory mediators but show no significant benefit in terms of stabilization and survival in sepsis patients. The HCO filters effectively eliminate cytokines but so far there is no evidence of a survival benefit. Polymyxin B hemoperfusion shows promising results in initial studies in certain patient groups, while evidence for cytokine adsorption filters is limited. Combined plasma filtration and adsorption (CPFA) and therapeutic plasma exchange (TPE) have so far shown promising results in small studies. Although CPFA shows no survival benefit, TPE may have protective effects on the vascular glycocalyx. Extracorporeal procedures carry risks such as thrombosis and loss of proteins and clotting factors. The therapeutic benefit of these procedures in the treatment of sepsis remains unclear and further prospective randomized multicenter studies are needed to evaluate their efficacy and safety. There are currently no guideline recommendations for the routine use of these procedures in sepsis., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Intracellular sensing of lipopolysaccharide (LPS) is essential for the immune response against gram-negative bacteria and results in activation of caspase-11 and pyroptotic cell death with fatal consequences in sepsis. We found the neuronal guidance receptor plexin C1 (PLXNC1) influences the intracellular response to LPS., Methods: We employed a murine model of sepsis via cecal ligation and binding (CLP), using PLXNC1-/- mice and littermate controls, and additionally transfected murine bone-marrow-derived macrophages (BMDMs) from both genotypes with LPS to achieve activation of the noncanonical inflammasome ex vivo. Additionally, we transfected the PLXNC1 ligand SL4c-d in vivo and ex vivo to examine its effect on intracellular LPS response., Results: We found the neuronal guidance receptor PLXNC1 dampens the intracellular response to LPS by interacting with adenylate cyclase 4 (ADCY4) and protein kinase A activity, which in turn diminishes caspase-11 expression. The absence of PLXNC1 results in excessive inflammation marked by increased cytokine release, increased secondary organ injury and reduced sepsis survival in a murine sepsis model induced by CLP. Notably, administration of SL4c-d-peptide ligand of PLXNC1-reduces the inflammatory response during CLP-induced sepsis and improves survival., Conclusions: These results elucidate a previously unknown mechanism for PLXNC1 suppressing excessive noncanonical inflammasome activity and offer a new potential target for treatment of sepsis with its detrimental effects., (© 2024. The Author(s).)

Abstract: Pulmonary defense mechanisms are critical for host integrity during pneumonia and sepsis. This defense is fundamentally dependent on the activation of neutrophils during the innate immune response. Recent work has shown that semaphorin 7A (Sema7A) holds significant impact on platelet function, yet its role on neutrophil function within the lung is not well understood. This study aimed to identify the role of Sema7A during pulmonary inflammation and sepsis. In patients with acute respiratory distress syndrome (ARDS), we were able to show a correlation between Sema7A and oxygenation levels. During subsequent workup, we found that Sema7A binds to the neutrophil PlexinC1 receptor, increasing integrins, and L-selectin on neutrophils. Sema7A prompted neutrophil chemotaxis in vitro and the formation of platelet-neutrophil complexes in vivo. We also observed altered adhesion and transmigration of neutrophils in Sema7A-/-animals in the lung during pulmonary inflammation. This effect resulted in increased number of neutrophils in the interstitial space of Sema7A-/- animals but reduced numbers of neutrophils in the alveolar space during pulmonary sepsis. This finding was associated with significantly worse outcome of Sema7A-/- animals in a model of pulmonary sepsis. Sema7A has an immunomodulatory effect in the lung, affecting pulmonary sepsis and ARDS. This effect influences the response of neutrophils to external aggression and might influence patient outcome. This trial was registered at www.ClinicalTrials.gov as #NCT02692118., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

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