Sepsis: evolving concepts and challenges

Abstract

Sepsis remains a major cause of morbidity and mortality worldwide, with increased burden in low- and middle-resource settings. The role of the inflammatory response in the pathogenesis of the syndrome has supported the modern concept of sepsis. Nevertheless, a definition of sepsis and the criteria for its recognition is a continuous process, which reflects the growing knowledge of its mechanisms and the success and failure of diagnostic and therapeutic interventions. Here we review the evolving concepts of sepsis, from the “systemic inflammatory response syndrome triggered by infection” (Sepsis-1) to “a severe, potentially fatal, organic dysfunction caused by an inadequate or dysregulated host response to infection” (Sepsis-3). We focused in the pathophysiology behind the concept and the criteria for recognition and diagnosis of sepsis. A major challenge in evaluating the host response in sepsis is to characterize what is protective and what is harmful, and we discuss that, at least in part, the apparent dysregulated host response may be an effort to adapt to a hostile environment. The new criteria for recognition and diagnosis of sepsis were derived from robust databases, restricted, however, to developed countries. Since then, the criteria have been supported in different clinical settings and in different economic and epidemiological contexts, but still raise discussion regarding their use for the identification versus the prognostication of the septic patient. Clinicians should not be restricted to definition criteria when evaluating patients with infection and should wisely use the broad array of information obtained by rigorous clinical observation.

Acute Increase in O-GlcNAc Improves Survival in Mice With LPS-Induced Systemic Inflammatory Response Syndrome

“…During infection, activated macrophages increase the production of inflammatory mediators to fight the infectious agent and to recruit other immune cells. However, a massive synthesis of proinflammatory mediators contributes to all sepsisrelated deleterious effects, as discussed above (Cohen, 2002;van der Poll et al, 2017;Salomão et al, 2019). In our study, BMDM isolated from animals produced the highest levels of cytokines when they were challenged with LPS (Figures 7, 8).…”

“…In conditions of systemic inflammatory responses, such as sepsis, exacerbated inflammation contributes to multiple organ dysfunction, that is strictly related to loss of vasomotor tone, decreased peripheral vascular resistance, decreased blood pressure and cardiac output, hypoperfusion, and hypoxygenation of tissues and organs leading to a significant mortality in intensive care units (De Backer et al, 2014;Hotchkiss et al, 2016;Machado et al, 2017;Salomão et al, 2019). This study shows that acute protein glycosylation, either by increasing flux in the hexosamine pathway, with glucosamine, or by OGA inhibition, with thiamet-G, improves survival of mice with severe endotoxemia in 40 and 60% (Figure 1), respectively, suggesting that acute increase in O-GlcNAc reduces mortality associated to septic condition.…”

“…During an infection, the host immune system recognizes invading pathogens by identifying pathogen-associated molecular patterns (PAMPs) through a variety of cell-surface and intracellular pattern recognition receptors (PRRs) on the innate immune cells, such as Toll-like receptors (TLRs), nucleotidebinding oligomerization domain-like receptors (NLRs; which activation leads to inflammasome formation), retinoic acidinducible gene-like receptors (RLRs) and C-type lectin receptors (CLRs) (Takeuchi and Akira, 2010;van der Poll et al, 2017;Salomão et al, 2019). In most cases, the immune system is able to remove the invading pathogen.…”

“…Both in the early and late phases of sepsis, the activation of immune cells initiates a complex signal transduction pathway that culminates in the activation of nuclear transcription factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPK), with consequent release of large amounts of cytokines, chemokines and activation of the complement system (Munoz et al, 1991;Silasi-Mansat et al, 2010;Takeuchi and Akira, 2010;Wiersinga et al, 2014;Salomão et al, 2019). Indeed, macrophages activated by lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, primarily release inflammatory mediators such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), as well as secondary mediators involved in pathogens elimination, such as nitric oxide (NO) and reactive oxygen species (ROS) (Ayala et al, 1996;Lu et al, 2015;Seo et al, 2016).…”

Chlorogenic acid alleviates sepsis-induced endothelial barrier dysfunction and the underlying mechanism

“…Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infections that can affect multiple organs in the body. Sepsis is a major cause of worldwide mortality, 1 which is most often attributed to multi-organ dysfunction syndrome (MODS). Severe vascular endothelial barrier failure is associated with sepsis.…”