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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Infection is a common and often deadly complication after burn injury. A major underlying factor is burn-induced immune dysfunction, particularly with respect to neutrophils as the primary responders to infection. Temporally after murine scald injury, we demonstrate impaired bone marrow neutrophil chemotaxis toward CXCL1 ex vivo. ⋯ A major signaling event upon CXCR2 activation is Akt phosphorylation and this was reduced when ceramide was elevated. In contrast, PTEN levels were elevated and PTEN-inhibition elevated phospho-Akt levels and mitigated the burn-induced neutrophil chemotaxis defect. Altogether, this study identifies a newly described pathway of ceramide-mediated suppression of neutrophil chemotaxis after burn injury and introduces potential targets to mitigate this defect and reduce infection-related morbidity and mortality after burn.
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Sepsis-induced myocardial dysfunction (MD) is an important pathophysiological feature of multiorgan failure caused by a dysregulated host response to infection. Patients with MD continue to be managed in intensive care units with limited understanding of the molecular mechanisms controlling disease pathogenesis. Emerging evidences support the use of mesenchymal stem/stromal cell (MSC) therapy for treating critically ill septic patients. ⋯ Network analysis and RT-qPCR revealed that septic hearts treated with MSCs resulted in upregulation of five miRNAs, including miR-187, and decrease in three top hit putative hub genes (Itpkc, Lrrc59, and Tbl1xr1). Functionally, MSC administration decreased inflammatory and apoptotic pathways, while increasing cardiac-specific structural and functional, gene expression. Taken together, our data suggest that MSC administration regulates host-derived miRNAs production to protect cardiomyocytes from sepsis-induced MD.
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Hematopoietic stem/progenitor cells (HSPC) have both unique and common responses following hemorrhage, injury, and sepsis. HSPCs from different lineages have a distinctive response to these "stress" signals. ⋯ In this review, we summarize the pathophysiology of emergency myelopoiesis and the role of myeloid-derived suppressor cells, impaired erythropoiesis, as well as the mobilization of HSPCs from the bone marrow. Finally, we discuss potential therapeutic options to optimize HSPC function after severe trauma or infection.
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Review
Calpain Activation and Organ Failure in Sepsis: Molecular Insights and Therapeutic Perspectives.
Sepsis is a severe systemic response to infection; its ensuing organ failure commonly portends an unfavorable prognosis. Despite the fact that sepsis has been studied for decades, the molecular mechanisms underlying sepsis-induced organ dysfunction remain elusive and more complex than previously thought, and effective therapies are extremely limited. Calpain is a type of calcium-dependent cysteine protease that includes dozens of isoforms. ⋯ Further, there is an accumulating body of evidence supporting the beneficial effect of calpain inhibition or regulation on multiple organ failure in sepsis. Better understanding of the underlying molecular mechanisms is helpful in the development of calpain/calpastatin-targeted therapeutic strategies to protect against sepsis-induced organ injury. The aim of this review is to summarize the recent literature and evidence surrounding the role of the calpain/calpastatin system in the process of organ dysfunction caused by sepsis-including regulation of cell death, modulation of inflammatory response, and disruption of critical proteins-to provide guidance for future research and therapy development.
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Physical trauma is one of the leading causes of mortality worldwide. Early post-traumatic upregulation of the pro-inflammatory immune response to traumatic injury is paralleled by an anti-inflammatory reaction. A prevalence of each has been associated with the development of secondary complications, including nosocomial infections, acute lung injury, acute respiratory distress syndrome, sepsis, and death after trauma. ⋯ Altered antigen presentation on neutrophils has been shown to possess biomarker features predicting both outcome and vulnerability to infectious complications in severely injured patients. Dysregulated activation of neutrophils following trauma affects their functions including phagocytizing capacity, production of reactive oxygen species, formation of neutrophil extracellular traps, which all together have been associated with the development of secondary complications. Thus, we highlight neutrophils and their functions as potential future targets for optimizing post-traumatic treatment strategies, which potentially may improve patient outcomes.