Sepsis may directly lead to multiple organ failure, which is among the leading causes of mortality in critically ill patients. According to data released by the Global Sepsis Alliance, the number of mortalities due to sepsis exceeded the number for cancer and AIDS.
Resveratrol exerted significant protective effect in sepsis, through anti‑inflammatory, anti‑oxidant and pro‑microcirculatory functions.
While nuclear factor κB (NF‑κB) and nuclear factor E2‑related factor 2 (NRF‑2) are the two major signalling pathways to have been associated with the anti‑inflammatory and anti‑oxidative effects of resveratrol.
Resveratrol is a non-flavonoid polyphenolic compound built around a quinone structure with reported anti-inflammatory, anti-oxidant and anticancer functions (15).
Studies demonstrating the protective effect of resveratrol in Sepsis:
- Studies by Kolgazi et al (15) and Sebai et al (16) demonstrated that resveratrol reduced the expression of tumor necrosis factor-α (TNF-α), malondialdehyde (MDA) and glutathione by reducing the accumulation of neutrophils in the lungs and kidneys, reducing the activity of myeloperoxidase and lactate dehydrogenase and further alleviating multiple organ damage induced by sepsis and improving the survival rate of rats and mice.
- Murakami et al (17) reported that resveratrol could reduce the activity of phospholipase A2 and reduce the expression of potent inflammatory factors including prostaglandin and lymphotoxin. Study has also indicated that resveratrol may alleviate sepsis-induced lung injury in rats by downregulating lung tissue high mobility group protein B1 and Toll-like receptor 4 (18).
- Kim et al (20) reported that resveratrol inhibited the expression of inducible nitric oxide synthase and prostaglandin E2 by regulating NF-κB activity, and effectively inhibited LPS-induced neurodegenerative diseases caused by microglial activation.
- Lei et al (21) reported that resveratrol activated the silent information regulator 1 (SIRT1) pathway, inhibiting nuclear translocation of NF-κB and acetylation of p65, and alleviating interleukin (IL)-β-induced inflammation of chondrocytes. In LPS-induced human monocyte cell line THP-1, resveratrol inhibited IL-8 secretion by blocking mitogen-activated protein kinase and NF-κB phosphorylation (22).
- Ma et al (24) reported that resveratrol exerted anti-inflammatory effects by inhibiting NF-κB and Janus kinase/signal transducers and activators of transcription pathways.
- Gualdoni et al (25) reported that resveratrol activated the NF-κB pathway, upregulated TNF-α expression and decreased IL-10 expression, and had a pro-inflammatory effect in human peripheral blood.
- Wang et al (30) showed that resveratrol relieved sepsis-induced acute lung injury via the phosphatidylinositol-3-kinase/NRF-2/HO-1 pathway in rats.
- Hao et al (31) observed that resveratrol could enhance the activity of NRF-2 in vitro and in vivo, increase the expression of HO-1 and glutamate cysteine ligase, reduce the release of TNF-α, IL-1β, macrophage inflammatory protein-1α and 1-methylcyclopropene, and reduce the production of reactive oxygen species (ROS) induced by LPS, thereby reducing inflammation and oxidative stress damage. In recent years, studies have confirmed that the activity of NF-κB may be regulated by inositol-requiring enzyme-1 (IRE-1) located on the endoplasmic reticulum membrane (32).
- Pendurthi et al (37) identified that resveratrol significantly reduced the expression of tissue factor and improved the body’s coagulation function in human endothelial cells and monocytes induced by sepsis.
- Imamura et al (29) has observed that resveratrol may control NRF-2 expression and attenuate LPS-induced sensory neuronal dysfunction.
- Cerqueira et al (54) reported that resveratrol significantly reduced the production of ROS, intercellular adhesion molecule 1 (ICAM-1), human β-defensin-2 and cell surface Fas receptor, inhibited caspase-3 and −7 activation, and upregulated glutathione peroxidase expression in a Pseudomonas aeruginosa-induced A549 cell injury model.
- Silswal et al (55) reported that resveratrol inhibited expression of inflammatory factors in LPS-induced human cluster of differentiation (CD)14+ monocytes, including of vascular cell adhesion molecule 1, ICAM1, C-reactive protein and resistin, and activity of proteasome subunit low-molecular-weight protein 7.
- Sebai et al (58) suggested that resveratrol may participate in anti-inflammatory responses by downregulating the expression of CD14 on the cell surface, and anti-oxidation effects through the TLR4-myeloid differentiation primary response 88 or TIR-domain-containing adapter-inducing interferon-β pathway.
- Other studies have shown that resveratrol inhibited the phosphorylation of NF-κB-p65 and the expression of inflammatory factors in human THP-1 cells following LPS induction (37,56). Furthermore, it has been reported that in vitro, resveratrol served as an activator of SIRT-1, which significantly downregulated the expression of inflammatory factors, such as TNF-α (57).
Discussion:
Nuclear factor-κB (NF-κB) and nuclear factor E2-related factor-2 (NRF-2) signaling pathways exert important functions in cells. Resveratrol has been implicated to be widely involved in the protection of various diseases of the body via effects on NF-κB and NRF-2. For instance, it was reported that resveratrol could reduce lipopolysaccharide (LPS)-induced brain damage by downregulating NF-κB (19).
In an adult mouse model of LPS-induced depression, resveratrol increased phosphorylated cyclic AMP response element binding protein/brain-derived neurotrophic factor expression in the frontal cortex and hippocampus by inhibiting NF-κB, to alleviate the depressive behavior of mice (23).
Resveratrol may also upregulate NRF-2 to improve LPS-induced cardiac damage (28).
Taking resveratrol as soon as possible following sepsis may reduce acute kidney injury by inhibiting the inflammatory response induced by the IRE1-NF-κB pathway (32).
More notably, data suggests that NF-κB-P65 may negatively regulate the expression and activity of NRF-2 (33), contributing to our present research focus on NF-κB and NRF-2 in the treatment of sepsis.
Other studies have observed that microcirculatory dysfunction served an important role in the process of organ damage caused by endotoxin shock (34,35). In this context, it has been reported that resveratrol increased the perfusion pressure and blood flow of organs by improving microcirculation to relieve sepsis-induced organ damage (36).
Conclusion:
It was concluded that resveratrol exerted significant anti‑inflammatory and anti‑oxidative effects through NF‑κB and NRF‑2 signalling pathways in sepsis‑induced multiple organ injury, manifesting as significant downregulation of TNF‑α and MDA expression and improved microcirculation, therefore ameliorating septic damage to the body, which may ultimately improve survival ratios.