Magnesium sulfate ameliorates sepsis-induced diaphragm dysfunction in rats via inhibiting HMGB1/TLR4/NF-κB pathway

Diaphragm dysfunction could be induced by sepsis with subsequent ventilatory pump failure that is associated with local infiltration of inflammatory factors in the diaphragm. It has been shown that the administration of anticonvulsant agent, magnesium sulfate (MgSO4) could decrease systematic inflammatory response. We recently reported that MgSO4 could inhibit macrophages high mobility group box 1 (HMGB1) secretion that confirms its anti-inflammatory properties. Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signal pathway appears to be involved in the pathology of septic experimental animal's inflammatory response and involve in the pathogenic mechanisms of sepsis-induced diaphragm dysfunction. Thus, in this study, we are aiming to explore whether MgSO4 could ameliorate sepsis-induced diaphragm dysfunction via TLR4/NF-κB pathway in a rodent model with controlled mechanical ventilation (CMV) and subsequent septic challenge.

Rats were randomly assigned into (1) control group: having an identical laparotomy but without ligation or puncture in the cecum; (2) CLP group: cecal ligation and puncture (CLP) with continuous saline infusion; (3) CLP + MgSO4 group: CLP with continuous MgSO4 administration; and (4) MgSO4 group: a sham surgery with MgSO4 administration. After surgery, all rats were submitted to CMV for 18 h. After completion of the study protocol, blood inflammatory cytokine/chemokine was detected by ELISA, as well as diaphragm contractility, TLR4, NF-κB (p65), phospho-NF-κB (p65) and HMGB1 protein expression.

The level of inflammatory cytokine/chemokine includes interleukin-6, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2) and HMGB1 in blood were significantly increased at 18-h post-CLP compared with the control group. We found that rats in the CLP group had substantial diaphragm dysfunction with a distinct downshift of the force-frequency curve. Furthermore, expression of HMGB1, TLR4, NF-κB (p65) and phospho-NF-κB (p65) in diaphragm were significantly increased in the CLP group. In contrast, MgSO4 attenuated the septic inflammation reaction in diaphragm and serum and preserved diaphragm function.

MgSO4 protects against sepsis-induced diaphragm dysfunction. This may be associated with its anti-inflammatory effect on HMGB1/TLR4/NF-κB signal pathway.