Summary
Empiric broad-spectrum antimicrobials therapy is suggested to be started
immediately for sepsis patients. Empiric antimicrobial therapy should be
narrowed once pathogen identification and sensitivities are established.
However, the detail mechanisms of de-escalation strategy are still
unclear. Here we hypothesized neutrophil extracellular trap (NETs)
played an essential role and de-escalation strategy might alleviate
organs injury through regulation of NETs formation in sepsis.
We evaluated the effect of imipenem and ceftriaxone on NETs formationin vitro and examined the role of reactive oxygen species (ROS).
Next, we designed de-escalation and escalation
strategy
based on their effects on NETs formation in CLP model. Organ injury,
inflammatory cytokines, NETs levels were compared and evaluated.
The in vitro study showed that imipenem and ceftriaxone had
opposite effects on NETs formation in activated neutrophils.
De-escalation therapy resulted in an evaluated MPO-DNA during early
stage and decreased MPO-DNA during late stage, which exerted the reverse
effects in escalation therapy sepsis animal model. Inflammatory response
and organ injury exacerbated when eliminated NETs with DNAseI during
early stage of sepsis (p<0.01). Histopathological analysis
showed decreased injury in lung, liver and intestine in de-escalation
therapy compared with escalation therapy (p<0.01).
De-escalation therapy results in the highest 6-day survival rate
compared with the control group (p<0.01), however, no
significant difference was found between de-escalation and escalation
group (p=0.051).
We demonstrate that de-escalation, not escalation, therapy reduces organ
injury, decreases inflammatory response by promoting NETs formation in
the early stage and inhibiting NETs formation in the late stage of
sepsis.
Key words : Inflammation, Neutrophils, Reactive Oxygen Species,
Cytokines, Lung.