Abstract
Innate immunity is the first line of defense in human beings against pathogen infection; monocytes/macrophages are the primary cells of the innate immune system. Recently, macrophages/monocytes have been discovered to participate in LPS clearance, and the clearance efficiency determines the magnitude of the inflammatory response and subsequent organ injury. Previously, we reported that artesunate (AS) protected sepsis mice against heat-killed E. coli challenge. Herein, we further confirmed that AS protected cecal ligation/puncture (CLP) sepsis mice. Its protection on sepsis mice was related to not only reduction of pro-inflammatory cytokines and serum LPS levels but also improvement of liver function. Based on the fact that AS did not directly bind and neutralize LPS, we hypothesized that the reduction of serum LPS level might be related to enhancement of LPS internalization and subsequent detoxification. Our results showed that AS increased FITC-LPS internalization by peritoneal macrophage and liver Kupffer cell, but enhancement of LPS internalization by AS was not related to the clathrin-dependent pathway. However, AS induced mRNA expression of important scavenger receptors (SRs); SR-A and MARCO mRNA expression was upregulated, suggesting that AS enhancement of LPS internalization and inhibition of pro-inflammatory cytokines was related to changes in mRNA expression of SRs.
Highlights
Sepsis is a progressive and life-threatening clinical syndrome that is characterized by an exaggerated inflammatory and innate immune response to infections
The mice treated with 100 mg/kg of ampicillin sodium-sulbactam sodium (AMPS) received only eight percent protection within seven days
AS (7.5, 15 and 30 mg/kg) in combination with AMPS (100 mg/kg) provided protection of 32.0%, 36.0%, and 20.0%, respectively (Figure 1). These results demonstrated both AS alone and AS in combination with AMPS provided significant protection against cecal ligation/puncture (CLP) sepsis mice
Summary
Sepsis is a progressive and life-threatening clinical syndrome that is characterized by an exaggerated inflammatory and innate immune response to infections. Within the innate immune system, monocytes/macrophages play a very important role during the immune response through the recognition of pathogens and the release of pro-inflammatory cytokines. LPS can be recognized by monocytes/macrophages and induce the release of large amounts of pro-inflammatory cytokines. The protection was closely related to the reduction of serum LPS and pro-inflammatory cytokines levels in sepsis model mice [5]. LPS, suggesting the protection through AS on sepsis model mice was not related to its direct neutralization of LPS [5]. In the present experiments the effect of AS on cecal ligation/puncture (CLP) mice model was firstly observed, and the influence of AS on LPS internalization from peritoneal macrophage and liver Kupffer cells was investigated in vitro.
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