Maresin 1 Mitigates Inflammatory Response and Protects Mice from Sepsis

Abstract

Sepsis, frequently caused by infection of bacteria, is considered as an uncontrollable systematic inflammation response syndrome (SIRS). Maresin 1 (Mar1) is a new proresolving mediator with potent anti-inflammatory effect in several animal models. However, its effect in sepsis is still not investigated. To address this question, we developed sepsis model in BALB/c mice by cecal ligation and puncture (CLP) with or without Mar1 treatment. Our data showed that Mar1 markedly improved survival rate and decreased the levels of proinflammatory cytokines in CLP mice such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). Furthermore, Mar1 reduced serum level of lipopolysaccharide (LPS) and enhanced the bacteria clearance in mice sepsis model. Moreover, Mar1 attenuated lung injury and decreased level of alanine transaminase (ALT), aspartate transaminase (AST), creatinine (Cre), and blood urea nitrogen (BUN) in serum in mice after CLP surgery. Treatment with Mar1 inhibited activation of nuclear factor kappa B (NF-κb) pathway. In conclusion, Mar1 exhibited protective effect in sepsis by reducing LPS, bacteria burden in serum, inhibiting inflammation response, and improving vital organ function. The possible mechanism is partly involved in inhibition of NF-κb activation.

Figure 1

Improvement of survival rate (n = 20) and weight loss by Mar 1 in CLP mice. (a) Survival rate was significantly improved by Mar 1 administration. (b) Weight loss decreased with treatment of Mar 1. Survival rate was analyzed using the log-rank test. ^# P < 0.05 versus the sham group. ^∗ P < 0.05 versus the CLP group.

Figure 2

Mar1 decreased LPS and bacterial burden in CLP mice. (a) The level of serum LPS in CLP mice. The CFUs (colony-forming units) in blood (b) and in peritoneal lavage (c) in CLP mice. Data are expressed as means ± SEM. n = 6. ^# P < 0.05 versus the sham group. ^∗ P < 0.05 versus the CLP group.

Figure 3

Inhibition of proinflammatory cytokines by Mar1 in CLP animals. Levels of TNF-α (a), IL-6 (b), and IL-1β (c) in serum were determined by enzyme-linked immunosorbent assay. Data are expressed as means ± SEM. n = 6. ^# P < 0.05 versus the sham group. ^∗ P < 0.05 versus the CLP group.

Figure 4

Improvement of lung histopathological changes by Mar1 in CLP mice. Lung tissues were obtained 24 hours after CLP. (a, b, c, and d) Representative micrographs from sham+Mar1, sham, CLP, and CLP+Mar1 group are shown. (e) Lung injury score in each group. Data are expressed as means ± SEM. Black bars represent 100 μm. n = 5. ^# P < 0.05 versus the sham group. ^∗ P < 0.05 versus the CLP group.

Figure 5

Improvement of liver and kidney functions of mice by Mar1 after CLP surgery. The change of serum ALT (a) and AST (b) activities by Mar1 in CLP mice. The change of Cre (c) and BUN (d) in serum by Mar1 in CLP animals. n = 6. Data are expressed as means ± SEM. ^# P < 0.05 versus the sham group. ^∗ P < 0.05 versus the CLP group.

Figure 6

Translocation of PBMC NF-κB p65 subunit was inhibited by Mar1 in CLP mice. (a) NF-κB p65 in cytoplasm decreased after CLP surgery but increased by Mar1. (b) NF-κB p65 increased in CLP mice, but Mar1 decreased level of NF-κB p65 in nucleus. NF-κB p65 band from the experiments was normalized by β-actin or lamin B1. n = 6. Data are expressed as means ± SEM. ^∗ P < 0.05 versus the CLP group.