Sepsis is a serious syndrome. It is estimated that there are 31.5 million cases of sepsis and 19.4 million cases of sepsis in the world, and 5.3 million people may die every year, which has become a heavy burden in the world . Sepsis is newly defined as fatal multiple organ failure (MODS) caused by severe infection, which weakens the role of systemic inflammatory response syndrome (SIRS) . However, inflammation still plays an important role in the occurrence and development of sepsis. The MODS and death induced by sepsis are mainly attributed to the strong inflammatory response at the initial stage of severe infection and the anti-inflammatory response at the later stage Reaction imbalance, and the complex interaction between inflammation and anti-inflammatory response . It can be seen that the position of inflammation cannot be ignored, and the search for appropriate anti-inflammatory drugs has been the direction of clinical scientists. Among them, omega-3 fatty acid is one of the controversial drugs, but also a nutritional preparation. In this study, 303 patients were treated with omega-3 fatty acids, most of whom were applicated in the early stage of the disease. Although factor analysis suggested that the mortality rate of omega-3 fatty acid patients was higher than that of the control group, multiple factors suggested that the disease severity of these patients was higher than that of the control group. This suggests that doctors may be more inclined to use omega-3 fatty acids in patients with relative crisis. In fact, there was no difference in mortality between the two groups when these factors imbalanced the baseline interacting with application of omega-3 fatty acid. On the contrary, patients treated with omega-3 fatty acids seem to have a better clinical prognosis as time goes on，and none of these randomized trials reported safety concerns. From the long-term prognosis improvement of sepsis patients after omega-3 fatty acid treatment, it seems to echo the results of our earlier randomized controlled trials .
Eicosapentaenoic Acid (EPA) and docosahexaenoic acid (DHA). Low level of AA is an important determinant of prognosis in sepsis patients . The rats were given diets of homocysteine, homoomega-3 fatty acid group and non-omega-3 fatty acid group respectively before the injection of endotoxin, the rats showed different degrees of weight loss and tissue damage among groups. The liver enzyme and pathological outcomes of the rats receiving omega-3 fatty acid diet were better than those of the other diet groups . N-3 fatty acid docosahexaenoic acid (DHA) was used to treat mouse bone marrow-derived dendritic cells, and different toll like receptor (TLR) ligands were used to stimulate them. Flow cytometry was used to detect cell surface maturation markers and intracellular activity. The expression and secretion of cytokines were detected by real-time RT-PCR and ELISA. DHA maintains the immature phenotype of bone marrow-derived DC by preventing the up regulation of MHCII and costimulatory molecules (CD40, CD80 and CD86) and maintaining high level of endocytosis activity. It also inhibited TLR2, 3, 4, and 9 ligand stimulated dendritic cells (DCs) to produce pro-inflammatory cytokines, including IL-12 cytokine family (IL-12p70, IL-23, and IL-27). The inhibit effect of IL-12 expression is through activating PPAR γ and inhibiting NFKAPABP65 translocation. These evidences show that DHA has anti-inflammatory effect in vivo .
It was found that the DCs were depleted in both the cecal ligation and puncture mice model and the sepsis patients. This process is related to the increase of apoptosis. The loss of DCs caused by sepsis occurs after the activation of CD3+, CD4+ T cells and the loss of lymph nodes. Before the loss of DCs, there is no continuous increase in its mature state. Mature and immature DCs are easy to be lost. CD8+ DCs has priority loss in local and remote lymph nodes . This suggests that DCs plays a key role in sepsis. Recently, it has been found that in the early stage of inflammation, the activated DCs are characterized by the decrease of antigen cross presenting ability of newly discovered antigens and the production of immunogenic cytokines. The immunosuppression induced by sepsis is mainly due to the depletion of mature immature dendritic cells. However, the late development of immune tolerance can lead to the release of tumor necrosis factor inhibitory cytokines by DCs, which is involved in maintaining the local tolerance environment characterized by Treg cell aggregation . By targeting DCs, it is found that the loss of DC quantity and function caused by sepsis is one of the reasons for the deficiency of CD8 T cell immune function, and the treatment of improving the state of DCs after sepsis may be helpful to the recovery of immune function of CD8+ T cell . Pretreatment of DCs with DHA can prevent the maturation of DCs induced by LPS, maintain the low expression of costimulatory molecules and the lack of proinflammatory cytokines (IL-12p70, IL-6 and IL-23). T cells co cultured with DC-DHA expressed high levels of TGF β and Foxp3, but showed no functional Treg phenotype. Similar to the results of in vitro experiments, the beneficial effect of DHA is related to the decrease of CD4+ T cells, which was caused by the decrease of IFN γ and IL-17 production in spleen and central nervous system .
In addition, omega-3 fatty acids also have effects on other inflammatory cells. It has been found that it can improve the pathogens clearance ability of neutrophils , which is mainly related to DHA. EPA can inhibit the migration of neutrophils to the focus. Endothelial cells can participate in the migration of neutrophils by producing prostaglandin (PG) D2. When PG D2 is combined with receptor DP-1 on neutrophils, it will lead to the adhesion and migration of neutrophils. However, the endothelial cells pretreated by EPA may reduce the production of PG D2 and increase the production of PG D3, thus inhibiting the migration of neutrophils . At the same time, omega-3 fatty acids have multiple double bonds in their carbon chain. Because each double bond causes the carbon chain to bend, the accumulation of polyunsaturated fatty acids in the cell membrane cannot be as tight as that of saturated fatty acids. This increases the fluidity of immune inflammatory cells, reduces brittleness, and plays an important role in prolonging cell life . This effect can also appear in other different kinds of immune cells, and it can adjust the immune mechanism of patients. Because leukocyte chemotaxis, migration and pathogen clearance are mainly in the early stage of inflammatory response, omge-3 fatty acids may affect this cell behavior in the early stage.
In the long run, omega-3 fatty acids may inhibit DNA methylation of inflammatory cells. Fatty acids can be modified by DNA methylation in vitro, while in vivo studies showed that total DNA methylation and PDK4 specific DNA methylation were positively correlated with eicosapentaenoic acid and arachidonic acid. There was a negative correlation between HDAC4 methylation and arachidonic acid . One study found that 174 patients with Alzheimer's disease (AD) received 1.7g DHA and 0.6g EPA or placebo every day for 6 months. Two of the four CpG sites of peripheral blood leukocytes (PBLs) were significantly reduced in methylation. Hypomethylation at CPG2 and CPG4 sites was negatively correlated with the change of plasma EPA concentration, but not with the change of plasma DHA concentration . However, it is not clear whether omega-3 fatty acids can also play a role in DNA demethylation of blood cells in inflammatory stage of sepsis. However, from bioinformatics research, it was found that the methylation of cg01770232 in IL-6 promoter was related to the increase of IL-6 concentration, while the higher concentration of omega-3 fatty acids inhibited the methylation of cg01770232 in IL-6 promoter, thus also inhibited the expression of IL-6. The relationship between n-3 polyunsaturated fatty acids and cg01770232 methylation depended on rs2961298 genotype . IL-6 is an early indicator of inflammatory reaction, which is caused by severe infection. Patients can soar within 24 hours, then rapidly decline. It is a sensitive and specific indicator for early diagnosis of sepsis . Therefore, the increase of serum concentration of omga-3 fatty acids can possibly inhibit DNA methylation process and early inflammation.
Although omga-3 fatty acids may improve the prognosis of sepsis patients, the dosage and regime are not clear. In our department, the formula of n3: n6 = 1:5 is generally used. The total dose of omega-3 fatty acids used by each patient is different. This study is the first attempt to use the hospital information system to obtain data, collate and analyze, so there is also a serious imbalance of amounts of patients between the control group. In this retrospective study, the treatment plan could not be intervened, and the existing data could not be used to evaluate the patients and the side effects. Nevertheless, we still try our best to sort out and evaluate the patients' condition from the aspects of organ function and auxiliary treatment. Due to the different severity of the patients' condition, only statistical methods can be used to adjust the data of the patients. Pairing study may be helpful to obtain more accurate results and conclusions.