Toll‐like receptor 4 antagonist FP7 alleviates lipopolysaccharide‐induced septic shock via NF‐kB signaling pathway

Abstract

Septic shock is the most severe complication of sepsis occurs when body has an overwhelming response to infection, making it the most prevalent cause of deaths in surgical intensive‐care units. Therefore, it is urgent to understand its pathogenesis and develop new therapeutic candidate drugs for septic shock. Here, we explored the effect of FP7, an antagonist of Toll‐like receptor 4 (TLR4), in the septic shock. First, we injected mice with FP7 and found that FP7 had no effect on immune cells. Then, bone marrow‐derived macrophages (BMDMs) isolated from mice were pretreated with FP7 followed by lipopolysaccharide (LPS) stimulation, and FP7 specifically suppressed LPS‐induced inflammatory responses in BMDMs via Nuclear factor kappa‐light‐chain enhancer of activated B cells (NF‐κB) signaling pathway, with no effect on other TLRs‐mediated inflammations. Finally, we injected mice with LPS and D‐galactosamine to induce septic shock, followed by the treatment of FP7, and FP7 significantly increased survival rate, improved lung necrosis, and inhibited the secretions of proinflammatory cytokines in the mice with septic shock. Therefore, our study suggested that FP7 had a protective role in septic shock and it might serve as a promising therapeutic candidate drug to treat septic shock.

Bacterial lipopolysaccharide-induced endothelial activation and dysfunction: a new predictive and therapeutic paradigm for sepsis

“…Studies have shown that both vitexin and donepezil are able to bind in close proximity to the LPS binding site located on the TLR4-MD-2 complex, which has the potential to be a candidate antagonist for LPS [ 130 ]. TLR4 antagonist treatment significantly increases survival, ameliorates lung necrosis, and inhibits inflammatory cytokine secretion in septic shock mice [ 131 ]. These studies point to the promise of the therapeutic effects of LPS antagonists in the treatment of sepsis.…”

Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions

“…NF-κB represents a therapeutic target since it induces pro-inflammatory gene transcription implicated in the septic shock[ 71 ]. In fact, in LPS-induced septic shock murine models, NF-κB inhibitors such as parthenolide and pyrrolidine dithiocarbamate[ 71 ], or an antagonist of toll-like receptor 4, the FP7[ 72 ] reverse sepsis effects on organ failure and hypotension. G protein-coupled receptors (GPCRs) may be potential targets for pharmacotherapy in sepsis.…”