Deterioration of Organ Function As a Hallmark in Sepsis: The Cellular Perspective

Abstract

Development of organ dysfunction discriminates sepsis from uncomplicated infection. The paradigm shift implicated by the new sepsis-3 definition holds that initial impairment of any organ can pave the way for multiple organ dysfunction and death. Moreover, the role of the systemic inflammatory response, central element in previous sepsis definitions, has been questioned. Most strikingly, a so far largely underestimated defense mechanism of the host, i.e., “disease tolerance,” which aims at maintaining host vitality without reducing pathogen load, has gained increasing attention. Here, we summarize evidence that a dysregulation of critical cellular signaling events, also in non-immune cells, might provide a conceptual framework for sepsis-induced dysfunction of parenchymal organs in the absence of significant cell death. We suggest that key signaling mediators, such as phosphoinositide 3-kinase, mechanistic target of rapamycin, and AMP-activated protein kinase, control the balance of damage and repair processes and thus determine the fate of affected organs and ultimately the host. Therapeutic targeting of these multifunctional signaling mediators requires cell-, tissue-, or organ-specific approaches. These novel strategies might allow stopping the domino-like damage to further organ systems and offer alternatives beyond the currently available strictly supportive therapeutic options.

Sepsis therapies: learning from 30 years of failure of translational research to propose new leads

“…Thus a positive fluid balance may be epiphenomenal rather than necessarily causative of a higher mortality. Furthermore, changes in a blood mediator level linked to a poor outcome can be part of the host response to injury, or even a protective element related to disease tolerance (Medzhitov et al , ; Bauer et al , ).…”

Die zelluläre Basis des Organversagens bei Sepsis – Signalwege in Gewebeschädigung und Reparaturprozessen

“…It becomes apparent in all these studies that metabolic processes are closely interlinked to damage and repair processes in cells and tissues [5]. The homeostasis of synthesis and formation of cellular organelles on one site and their degradation is an essential prerequisite for vitality of the cells and, thus, integrity of tissue and organs.…”

A Single Step in vitro Bioassay Mimicking TLR4-LPS Pathway and the Role of MD2 and CD14 Coreceptors

“…It is now well-established that activation of TLR4 is one of the two innate immune pathways triggered during Gram-negative bacterial sepsis in immunocompromised patients (the other one is caspase 11 activation in macrophages) (5,6). Sepsis is defined as a lifethreatening condition that leads to circulatory abnormalities, organ dysfunction, and death due to the overwhelming response of the body's immune system to bloodstream infection (7,8). Recently, a few studies have demonstrated that the repetitive exposure of pathogen associated molecular patterns (PAMPs) such as LPS to innate immune cells can lead to a subsequent increase or decrease in their responsiveness termed as training or tolerance, respectively (9).…”