De-escalation antibiotic therapy alleviates NET-associated organ injury and inflammation in CLP model.
Considering the role of NETs in the progression of sepsis, NET-associated organ injury was assessed. In the early stage of sepsis, both the levels of AST and serum creatinine were significantly lower in the de-escalation group (imipenem for 3 days) than in the escalation group (ceftriaxone for 3 days) and the control group (Fig 3A-B). However, when DNase I was administered to the escalation group for 3 days, there was no significant difference between the levels of AST and serum creatinine in this group, although these levels were lower than those in the control groups. Next, we measured the inflammatory response. Consistent with the levels of AST and serum creatinine, the levels of serum IL-6, IL-10, and IFN-γ were lower in the de-escalation group than in the other groups (Fig 3C-E). Interestingly, the level of MCP-1 was lower in the escalation group. Then, we used DNase I in the de-escalation group. The levels of all the cytokines were elevated, and the level of MCP-1 was decreased (Fig 3F).
Next, we measured these factors in the late stage of sepsis. First, we measured the AST, ALT, LDH, and serum creatinine levels to evaluate organ injury. There were varying degrees of damage in the sepsis group compared with the sham group, and all the serum biochemical values were lower in the de-escalation group than in the escalation group (Fig 4A-D). The levels of the cytokines IL-6, IL-10, IFN-γ, MIP-2 and MCP-1 were consistent with the biochemical values in the two groups (Fig 5A-F).
These findings suggested that NETs exert a protective role in the early stage of sepsis, which can alleviate organ injury and the inflammatory response, and reduced NET production is beneficial to septic mice in the late stage.