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Sepsis still represents an important clinical and economic challenge for intensive care units. Severe complications like multiorgan failure with high mortality and the lack of specific diagnostic tools continue to hamper the development of improved therapies for sepsis. Fundamental questions regarding the cellular pathogenesis of experimental and clinical sepsis remain unresolved. According to experimental data, inhibiting macrophage migration inhibitory factor, high-mobility group box protein 1 (HMGB1), and complement factor C5a and inhibiting the TREM-1 (triggering receptor expressed on myeloid cells 1) signaling pathway and apoptosis represent promising new therapeutic options. In addition, we have demonstrated that blocking the signal transduction pathway of receptor of advanced glycation endproducts (RAGE), a new inflammation-perpetuating receptor and a member of the immunglobulin superfamily, increases survival in experimental sepsis. The activation of RAGE by advanced glycation endproducts, S100, and HMGB1 initiates nuclear factor kappa B and mitogen-activated protein kinase pathways. Importantly, the survival rate of RAGE knockout mice was more than fourfold that of wildtype mice in a septic shock model of cecal ligation and puncture (CLP). Additionally, the application of soluble RAGE, an extracellular decoy for RAGE ligands, improves survival in mice after CLP, suggesting that RAGE is a central player in perpetuating the innate immune response. Understanding the basic signal transduction events triggered by this multi-ligand receptor may offer new diagnostic and therapeutic options in patients with sepsis. IntroductionIn the United States, sepsis is the main cause of death in noncardiac intensive care units and is linked with increasing costs for patient care. Sepsis represents a range of disorders involving bacterial, fungal, or viral infections that can be disseminated by the bloodstream [1]. Epidemiological data from North America show an incidence of 3.0 cases per 1,000 persons. The overall mortality is approximately 50% in patients with severe septic shock [2]. Even high-priority engagement in sepsis research has led to only slight improvements in existing treatment strategies for sepsis. Currently, the detailed mechanisms linking the foreign bacterial agent (for example, in the bloodstream or in the abdomen) with the sophisticated ongoing transcription work of the cell nucleus are not completely understood.The combined use of the pre-existing innate and inducible adaptive immune systems ensures that the host will be able to mount an appropriate immune response against different types of pathogenic agents [1]. The first line of defense is the innate immune system, which is characterized by non-clonally distributed leukocytes that react rapidly to microbial products without antigenic specificity. Host innate responses to bacterial or fungal infections are primarily mediated by neutrophils and monocytes/macrophages. These cells express germline-encoded pattern-recognition receptors (PRRs), w...

Introduction Severe sepsis, septic shock, and resulting organ failure represent the most common cause of death in intensive care medicine, with mortality ranging from 40% to 70%. It is still unclear whether necrosis or apoptosis plays the predominant role in severe sepsis. Determining the prevalent mode of cell death would be valuable, as new therapeutic agents (eg, antiapoptotic drugs such as caspase inhibitors) may improve unsatisfactory outcomes in patients with severe sepsis. Furthermore, the prognostic value of newly developed cell death serum biomarkers is of great interest.

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NCT02288650.