Sepsis is a systemic inflammatory response caused by infection with pathogens, primarily gram-negative bacteria infections as well as other bacterial, fungal and virus infections (1). The pathogenesis of sepsis involves an inflammatory response, oxidative stress, apoptosis, ischemia-reperfusion injury, endothelial dysfunction and effects mediated by endothelin (ET) peptides (2–7). Infection-induced systemic inflammatory response syndrome (SIRS), which if not treated timely, may develop into multiple organ dysfunction syndrome (MODS) (8,9). Despite the widespread use of measures including antibiotics, glucocorticoids and organ function support therapy, these treatments have not significantly improved the prognosis of sepsis, and the mortality rate remains as high as 30–40% (10,11). In fact, the rates of morbidity and mortality were reported to increase yearly within three decades starting in the 1990s (12). It has been reported that at least 750,000 septic shocks occur in the United States each year, and that more than 210,000 sepsis-related mortalities occur, which is associated with annual overall losses of $16 billion in overall economic costs associated with medicine and healthcare (13,14). Thus, sepsis represents a notable burden to health. Finding effective treatments for sepsis, shortening the length of hospital stay, reducing the incidence of severe sepsis, reducing mortality, and reducing hospitalization costs have become a worldwide challenge in the field of critical care medicine.

Resveratrol is a non-flavonoid polyphenolic compound built around a quinone structure with reported anti-inflammatory, anti-oxidant and anticancer functions (15). 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).

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). 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). 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). 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. However, 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.

NRF-2 is an activator of the antioxidant responsive element signaling pathway and is this involved in cellular antioxidant activity. In previous studies, resveratrol enhanced heme oxygenase-1 (HO-1) expression through NRF-2-mediated signal transduction, inhibiting inflammatory responses and activating antioxidant defense systems to protect rats from LPS-induced periodontal tissue damage (26,27). Resveratrol may also upregulate NRF-2 to improve LPS-induced cardiac damage (28). Imamura et al (29) has observed that resveratrol may control NRF-2 expression and attenuate LPS-induced sensory neuronal dysfunction. Furthermore, 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). 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). 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.

However, the role of resveratrol in sepsis-induced injury remains controversial (25,38). Therefore, the present systematic review sought to further clarify the efficacy and safety of resveratrol in the treatment of sepsis, ultimately aiming to provide a more specific theoretical basis for the application of resveratrol in clinical trials in future.

Results from the present systematic review demonstrated the protective effects of resveratrol in sepsis-induced animal model. Resveratrol may exert anti-inflammatory and anti-oxidative effects through two important signaling pathways, NF-κB and NRF-2; however none of the initial 260 reports provided specific values for the systematic evaluation of these factors. Of these literatures, only 11 studies were deemed eligible for inclusion. Meta-analysis of these 11 studies showed that resveratrol significantly reduced the expression of TNF-α and MDA, and increased MAP in the sepsis animal models. However, the effect of resveratrol on downregulation of the inflammatory mediator IL-6 and on upregulation of the anti-inflammatory mediator IL-10 did not show statistical differences. However, previous data has indicated that resveratrol does not significantly improve blood pressure or heart rate in sepsis-induced animal models (36), though was not included in the current systemic review due to the lack of accurate values. Contact with the authors was attempted to obtain more accurate values for NF-κB NRF-2, IL-6 and IL-10; however was unsuccessful. Due to the small sample sizes in each pooled analysis, the analysis of each indicator would have had some bias.

The present article only reported on animal models with regard to the anti-inflammatory and anti-oxidative effects of resveratrol in the treatment of sepsis. However, during the literature search, it was noted that resveratrol also reduced the expression of inflammatory factors and oxidative stress products induced by sepsis at the human cell level. 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. 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). 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.

Due to limited data and the lack of attention to the safety of animal experiments, few studies have reported the safety of resveratrol in animals. The quantity of resveratrol used in the studies included in the current review was within 100 mg/kg, though the number of administrations and the route of administration differed. Two of the studies reported that as the dose of resveratrol increased, the decrease in TNF-α and IL-6, and the increase in IL-10 and MAP were more obvious (40,44). There were also some differences in the timing of administration. Seven of the included studies administered resveratrol following modeling (15,41,42,44–47), and two were administered prior to modeling (43,53). There were two cases of administration both prior to and following modeling (39,40). None of the studies assessed the effect of the time of administration on the efficacy of the drug. However, a study not included herein review reported that post-modeling administration reduced the expression of TNF-α, IL-6, IL-1β and monocyte chemoattractant protein-1 to a greater extent than preoperative administration (50).

There was a degree of heterogeneity in the included studies, and the quality of the methodologies for each study was not high. The studies only illustrated the random grouping of animals and did not indicate how the experimental animals were randomly assigned. The original number of animals, the number of mortalities during the experiment, and the final remaining number were not clearly defined in any study. Furthermore, it was not stated whether the experimental data were blindly evaluated. Obviously these requirements are of key importance for human clinical research. Attempts were also made to contact the authors to obtain more raw data and detailed experimental procedures, including how animals were randomly assigned, experimental data acquisition and analysis methods, but most of the information remained unknown due to unsuccessful attempts at contact with authors. The current article was a systematic review of published studies with complete data, and studies with negative results but incomplete data were not included. Therefore, due to the existence of publication bias, results of the present systematic review are limited.

In conclusion, the present systematic review demonstrated that resveratrol does exert anti-inflammatory, anti-oxidant and pro-microcirculatory effects in sepsis-induced organ damage in animal models. However, in vivo studies of resveratrol in sepsis appear limited to animal models, and considering the quality of the studies included, the study of resveratrol in humans is still required.