INTRODUCTION
Sepsis is a life-threatening disease that is characterized by organ
dysfunction and caused by a dysregulated host response to infection;
sepsis remains a distressing public health care problem and ranks among
the top 10 causes of death worldwide [1]. Currently, it is well
known that immunoparalysis is more than the overwhelming pro-inflammatory
response that endangers critically ill patients [2]. The mechanisms
of sepsis-induced immunoparalysis remain unclear, but functional defects
of leukocytes, excessive expression of inhibitory receptors, and
dysregulated production of cytokines may play an important role in the
immune dysfunction in sepsis.
Neutrophil extracellular traps (NETs) are a new antimicrobial function
of neutrophils; NETs are web-like structures accompanied by many
proteins, histones, and DNA [3]. The formation of NETs is a
double-edged sword in sepsis; NETs trap pathogens in the early stage and
cause NET-associated injuries, such as coagulation, thrombotic
disorders, and organ injury, in the later stage [4-6]. The balance
of NET formation and clearance plays a crucial role in sepsis, and
treatments that target the clearance of NETs in the late stage, such as
DNase I and Cl-amidine, have been confirmed to ameliorate the severity
of sepsis [7, 8]. In addition, NETs have been shown to link innate
and adaptive immune responses by regulating the activation of apoptosis
in CD4+ and CD8+ T cells [9]. In lipopolysaccharide-induced
activation of monocytes, NETs can downregulate the maturation of
monocyte-derived dendritic cells, thus reducing the production of
cytokines (TNF-α, IL-6, IL-12, IL-23) [10]. These may be potential
mechanisms of the role of NETs in sepsis.
Empiric broad-spectrum therapy with one or more intravenous
antimicrobials to should be started immediately for patients presenting
with sepsis [11]. Broad-spectrum antimicrobial therapy should be
narrowed when pathogen identification and sensitivities have been
established or discontinued if a decision is made that the patient does
not have infection, which was termed as de-escalation therapy. The link
between early administration of antibiotics for suspected infection and
antibiotic stewardship remains an essential aspect of high-quality
sepsis management [12]. Although both de-escalation and escalation
antibiotic therapy kill bacteria during sepsis [13], it is unclear
why de-escalation, not escalation, therapy reduces mortality, and the
detailed mechanism by which these changes in the sequence of antibiotic
drug administration or the changes in the drugs themselves affect
clinical outcomes are also unknown.
Previous studies have shown that some antibiotics themselves may exert
immunomodulatory effects on phagocytes, cytokines, immunoglobulins, and
cellular immunity [14, 15]. Although specific immunomodulatory
therapy targeting inflammatory cytokines has been confirmed in sepsis
models, clinical trials on the blockade of TNF, IL-1 and other cytokines
failed [16]. Recent studies focused on the optimization of
immunomodulatory effects of NET formation during sepsis, enhancement of
NET formation to trap and eradicate all bacteria in the early stage and
the attenuation of excessive NET formation to prevent NET-associated
injury in the later stage [17]. In this study, we hypothesized that
antibiotics might manifest both antimicrobial and immunomodulatory
functions in the treatment of sepsis and that de-escalation antibiotic
therapy might alleviate organ damage and inflammatory responses through
the modulation of NET formation in the different stages of sepsis.