Sepsis is a serious syndrome. There are an estimated 31.5 million sepsis and 19.4 million severe sepsis cases worldwide. There may be 5.3 million deaths each year, which has become a heavy burden on 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 sepsis-induced death are mainly due to the strong inflammatory response in the initial stage of severe infection and the imbalance of the anti-inflammatory response in the late stage. Thus it can be seen that in sepsis inflammation cannot be ignored, anti-inflammation is still an important aspect of sepsis treatment. omega-3 fatty acid, as an nutrition agent, the therapeutic effect of has been controversial. In this study, there are 303 patients accepted omega-3 fatty acid supplement at the early stage of sepsis. Although analysis suggests that patients receiving omega-3 fatty acid treatment have a higher mortality rate than the control group, multi-factor analysis showed that these patients had higher disease severity than the control group. After removed these factors that affect the prognosis by multivariate logistic regression analysis, it was found that there was no difference in the mortality of the two groups of patients. This suggests that for relatively critically ill patients, doctors are more inclined to use omega-3 fatty acids. Multivariate logistic regression analysis removed these factors that affect the prognosis and found that, in fact, there was no difference in the mortality of the two groups of patients. On the contrary, from the survival curve, as time goes by, patients treated with omega-3 fatty acids seem to have a better clinical prognosis. Judging from the improvement in the long-term prognosis of patients with sepsis after treatment with omega-3 fatty acids, it seems to consistent with the results of our previous randomized controlled trials.
Patients with sepsis often suffer from obvious hypoproteinemia due to reduced protein synthesis and increased consumption, which affects serum arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaene Metabolism of fatty acids such as DHA, and low AA levels are an important determinant of the prognosis of patients with sepsis. In the study of Oz HS et al, rats were given diets of homocysteine, high omega-3 fatty acid group and non-omega-3 fatty acid group. After injection of endotoxin, these rats experienced different degrees of weight loss and tissue damage, and received omega-3 fatty acids. The liver enzymes and pathological indexes of diet rats are relatively better than other diet groups. Treated mouse bone marrow-derived dendritic cells with n-3 fatty acid-docosahexaenoic acid (DHA), following stimulation with different toll-like receptor (TLR) ligands. Flow cytometry detects cell surface maturation markers and intracellular activity. Real-time RT-PCR and ELISA to detect the expression and secretion of cytokines. 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 a high level of endocytic activity. DHA inhibits the production of pro-inflammatory cytokines by DCs stimulated by TLR2, 3, 4 and 9 ligands, including the interleukin IL-12 cytokine family (IL-12p70, IL-23 and IL-27). The inhibition of IL-12 expression by DHA is mediated by activating PPARγ and inhibiting nuclear translocation of NFKAPABP65. Showed that DHA has anti-inflammatory effects in the body.
In both the cecal ligation and puncture mouse model and patients with sepsis, it was found that dendritic cells were depleted, concluded that the process was related to increased apoptosis。The loss of DCs caused by this 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 their mature state. Both mature and immature DCs are easily lost. CD8 + DCs are preferential loss of local and distant lymph nodes, this suggests the key role of DCs in sepsis. Recent studies have discovered that in the early stages of inflammation, activated dendritic cells are characterized by reduced antigen cross-presentation capacity of newly discovered antigens and decreased production of immunogenic cytokines. The immunosuppression induced by sepsis is mainly due to the depletion of mature immature dendritic cells. On the other hand Immune tolerance in the late stage can cause DCs to release tumor necrosis factor inhibitory cytokines and participate in the maintenance of a local tolerance environment characterized by Treg cell aggregation. By targeting DCs, it is found that the loss of the number and function of DCs caused by sepsis is one of the reasons for the deficiency of CD8 T cell immune function, and the treatment method to improve the status of DC cells after sepsis may contribute to the immune function of CD8 T cells recovery. DHA pretreatment of DC can prevent LPS-induced DC maturation, maintain low expression of costimulatory molecules, and pro-inflammatory cytokines (IL-12p70, IL-6 and IL-23). T cells co-cultured with DC-DHA express higher levels of TGFβ and Foxp3, but do not show a functional Treg phenotype. Similar to the results of in vitro experiments, the beneficial effects of DHA are related to the decrease in the number of IFNγ and IL-17 produced in the spleen and central nervous system, resulting in a decrease in the number of CD4+ T cells.In addition, omega-3 fatty acids also have an effect on other inflammatory cells. Studies have found that it can improve the ability of neutrophils to remove the pathogen, which mainly related to DHA . EPA plays a certain role in inhibiting the migration of neutrophils to the lesion site. Studies have found that endothelial cells can participate in the migration of neutrophils by producing prostaglandin D2. When prostaglandin D2 binds to the receptor DP-1 on neutrophils, it causes neutrophils to adhere and migrate. Endothelial cells pretreated with EPA may reduce the production of prostaglandin D2 by endothelial cells and increase the production of prostate D3, thereby inhibiting the migration of neutrophils. At the same time, for polyunsaturated fatty acids have multiple double bonds in their carbon chains, each double bond will cause the carbon chain to bend, so the accumulation of polyunsaturated fatty acids in the cell membrane cannot be as tight as saturated fatty acids. This increases the fluidity of immune inflammatory cells, reduces fragility, and plays an important role in prolonging cell life. This effect can also appear in other different types of immune cells, and it can adjust the patient's immune mechanism. Since the chemotaxis, migration, and pathogen clearance of leukocytes are mainly in the early stages of inflammatory response, omge-3 fatty acids may affect this cell behavior in the early stage.
In the long term, the effect of Omega-3 fatty acids on inflammatory cells may be to inhibit cell DNA methylation. Fatty acids can modify DNA methylation in vitro, and in vivo studies have found that total DNA methylation and gene specific DNA methylation of PDK4 are positively correlated with eicosapentaenoic acid and arachidonic acid. Postprandial HDAC4 methylation is negatively correlated with arachidonic acid. A study found that 174 Alzheimer’s disease (AD) patients received 1.7g DHA and 0.6g EPA or placebo every day for 6 months. It was found that patients receiving omega-3 fatty acid treatment had peripheral blood white blood cells (PBLs). ) 2 out of 4 CpG sites have significantly reduced methylation. Hypomethylation of CpG2 and CpG4 sites is negatively correlated with changes in plasma EPA concentration, but no related to the changes of plasma DHA concentration. However, it is still unclear whether omega-3 fatty acids supplemented parenterally can also demethylate blood cell DNA. However, bioinformatics studies have found that the methylation of IL-6 promoter cg01770232 is related to the increase of IL-6 concentration, and higher concentrations of omega-3 fatty acids inhibit the methylation of IL6 promoter cg01770232, which can also inhibit IL. -6 expression, the relationship between n-3 polyunsaturated fatty acids and cg01770232 methylation depends on the rs2961298 genotype. IL-6 is an early indicator of inflammatory response. For severe inflammatory response caused by severe infection, patients can soar within 24 hours and then rapidly decrease. It is a sensitive and specific indicator for early diagnosis of sepsis. Therefore, the increased blood concentration of omega-3 fatty acids can inhibit the DNA methylation process and have an inhibitory effect on early inflammation.
Although omga-3 fatty acids may improve the prognosis of patients with sepsis, the dosage and method of use are not yet clear. In our department of intensive care medicine, a formula of n3:n6 = 1:5 is generally used, and the total dose of omega-3 fatty acids used by each patient is different. This study was the first attempt to analysis the information system in the hospital, therefore, there was also a serious imbalance between the control group and the treatment group, which had a certain impact on the data analysis and results. And retrospective research, unable to intervene in the treatment plan, and existing data can not be used to score patients and evaluate side effects. Nonetheless, we tried to analyzed the patient’s organ failure data, and evaluated the patient’s condition from various organ functions and adjuvant treatments. Due to the different severity of the patient’s condition, only statistical methods can be used to adjust the patient’s data. Paired studies may help to obtain more precise results and conclusions.