From Molecular Mechanisms to Clinical Therapy: Understanding Sepsis-Induced Multiple Organ Dysfunction

Abstract

Sepsis-induced multiple organ dysfunction arises from the highly complex pathophysiology encompassing the interplay of inflammation, oxidative stress, endothelial dysfunction, mitochondrial damage, cellular energy failure, and dysbiosis. Over the past decades, numerous studies have been dedicated to elucidating the underlying molecular mechanisms of sepsis in order to develop effective treatments. Current research underscores liver and cardiac dysfunction, along with acute lung and kidney injuries, as predominant causes of mortality in sepsis patients. This understanding of sepsis-induced organ failure unveils potential therapeutic targets for sepsis treatment. Various novel therapeutics, including melatonin, metformin, palmitoylethanolamide (PEA), certain herbal extracts, and gut microbiota modulators, have demonstrated efficacy in different sepsis models. In recent years, the research focus has shifted from anti-inflammatory and antioxidative agents to exploring the modulation of energy metabolism and gut microbiota in sepsis. These approaches have shown a significant impact in preventing multiple organ damage and mortality in various animal sepsis models but require further clinical investigation. The accumulation of this knowledge enriches our understanding of sepsis and is anticipated to facilitate the development of effective therapeutic strategies in the future.

Keywords: gut microbiota; herbal extracts; melatonin; metformin; multiple organ failure; palmitoylethanolamide (PEA); sepsis; sepsis treatment.

Figure 1

Cascade activation of the immune system in sepsis. DAMPs: damage-associated molecular patterns; PAMPs: pathogen-associated molecular patterns; STATs: signal transducers and activators of transcription; MAPK: mitogen-activated protein kinase; ERK1/2: extracellular signal-regulated kinase 1/2; JAKs: Janus kinases; NF-kB: nuclear factor-kappa B.

Figure 2

The interplay of inflammation and oxidative stress in sepsis pathogenesis. PAMPs: pathogen-associated molecular patterns; DAMPs: damage-associated molecular patterns; HMGB1: high mobility group box 1; RAGE: receptor for advanced glycation end products; LPS: lipopolysaccharide; TLR4: Toll-like receptor 4; ROS: reactive oxygen species; NLRP: NLR family pyrin domain-containing; NLRC4: NLR family card domain-containing 4; NAIP: NOD-like receptor family apoptosis inhibitory protein; GSDMD: gasdermin D; NOD1/2: nucleotide-binding oligomerization domain-containing protein 1/2; IKK: the inhibitor of NF-kB kinase complex; NF-kB: nuclear factor-kappa B.

Figure 3

Sepsis-related multiple organ dysfunction. In response to infection, developing inflammation, oxidative stress, endothelial dysfunction, and mitochondrial dysfunction can result in sepsis. Pathophysiological changes are a consequence of the cause–effect link between these processes. Together, they lead to organ damage that can progress to multiple organ dysfunction. HMGB1: high-mobility group box-1; NF-kB: nuclear factor-kappa B; TNF: tumor necrosis factor; IL: interleukins; IFN: interferons; RNS: reactive nitrogen species; ROS: reactive oxygen species.

Figure 4

Different strategies are used in the treatment of sepsis.

Figure 5

Chemical structure of melatonin [93].

Figure 6

Chemical structure of metformin [115].

Figure 7

Chemical structure of palmitoylethanolamide (PEA) [128].