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.