In Search of a Cure for Sepsis: Taming the Monster in Critical Care Medicine

Abstract

In spite of over half a century of research, sepsis still constitutes a major problem in health care delivery. Although advances in research have significantly increased our knowledge of the pathogenesis of sepsis and resulted in better prognosis and improved survival outcome, sepsis still remains a major challenge in modern medicine with an increase in occurrence predicted and a huge socioeconomic burden. It is generally accepted that sepsis is due to an initial hyperinflammatory response. However, numerous efforts aimed at targeting the proinflammatory cytokine network have been largely unsuccessful and the search for novel potential therapeutic targets continues. Recent studies provide compelling evidence that dysregulated anti-inflammatory responses may also contribute to sepsis mortality. Our previous studies on the role of regulatory T cells and phosphoinositide 3-kinases in sepsis highlight immunological approaches that could be explored for sepsis therapy. In this article, we review the current and emerging concepts in sepsis, highlight novel potential therapeutic targets and immunological approaches for sepsis treatment and propose a biphasic treatment approach for management of the condition.

Protective Effects of Human and Mouse Soluble Scavenger-Like CD6 Lymphocyte Receptor in a Lethal Model of Polymicrobial Sepsis

“…epsis, severe sepsis, and septic shock still present unmet clinical needs with a predicted increase in occurrence and a huge socioeconomic burden as a result of population aging, increases in invasive medical procedures, the emergence of multidrug-resistant (MDR) bacteria, and the increased prevalence of chronic diseases (1). Sepsis is considered a dysregulated systemic inflammatory response syndrome caused by an infection, leading to an overwhelming and sustained proinflammatory state and, if unresolved, to multiorgan dysfunction (MOD) and death (2).…”

Deficiency of Phosphatidylinositol 3-Kinase δ Signaling Leads to Diminished Numbers of Regulatory T Cells and Increased Neutrophil Activity Resulting in Mortality Due to Endotoxic Shock

“…epsis constitutes a major challenge in critical care medicine and is currently a leading cause of death in intensive care units, particularly among the elderly and immunocompromised patients (1). Studies have shown that the magnitude and quality of the immune response after an infection are better predictors of outcome than the inciting pathogen (2), yet the immune parameters that determine the outcome of sepsis in patients are not completely understood (3). The endotoxin LPS, present on the cell wall of Gram-negative bacteria, is one of the most potent activators of the immune system (4), and Gram-negative infections are the most common in the clinic (5).…”

Going Fishing

“…In patients with severe infectious diseases, systemic inflammatory responses, such as a cytokine storm, are part of the clinical picture [9,10]. These life-threatening conditions are often a consequence of a pathological activation of pattern recognition receptors (PRRs) by microbial pathogens [11].…”