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.

Keywords: disease tolerance; metabolic adaptation; organ dysfunction; sepsis; signaling.

Figure 1

Mutual effects of cellular energy metabolism and organ dysfunction cause continuous deterioration during sepsis. While cardiovascular impairment leads to reduced O₂ delivery, metabolic dysfunction, most markedly mitochondrial dysfunction, contributes to impaired cellular energy supply. This energy crisis contributes to failure of detoxification, which in turn affects primarily kidney and liver. Accumulating toxins, gut microbiome with (antibiotic-induced) dysbiosis, and microbial metabolites (along the gut–liver axis, via organ–organ cross-talk) aggravate and perpetuate deteriorating organ function. The resulting metabolic catastrophe ultimately results in neurologic manifestations and autonomic dysfunction, which again contributes to continuing the downward spiral of metabolic derangement and organ dysfunction.

Figure 2

Key signal mediators connect stress responses to metabolism and can serve to explain a balance between damage and repair processes in immune cells and the majority of parenchymal cells. We hypothesize that dysregulated signaling and metabolic functions, which govern resistance responses and disease tolerance, are the common underlying cause of septic organ failure. Whereas AMPK is considered a key mediator of disease tolerance, mTOR and connected pathways regulate resistance responses and the metabolic reprogramming connected to immune activation. Abbreviations: AMPK, AMP-activated protein kinase; ER, endoplasmic reticulum, FOXO, forkhead box O; HIF-1α, hypoxia-inducible factor-1α; mt, mitochondrion; mTOR, mechanistic target of rapamycin; NRF2, nuclear factor erythroid 2-related factor 2; PI3K, phosphoinositide 3-kinase; PRR, pattern recognition receptor; ROS, reactive oxygen species.