Repositioning of the antipsychotic drug TFP for sepsis treatment

Sepsis, which is caused by a various bacterial and viral infections, leads to a systemic activation of the innate immune system. As a result of the inflammatory response induced by infected cells, phagocytic cells are activated and release pro-inflammatory cytokine [ 1 ]. During infection, dendritic cells (DCs) play an essential interface between innate and adaptive immunity and exist in most tissues of the reticuloendothelial system, including all lymphoid organs. They are especially prominent in tissues that are exposed to the external environment where frequent exposure to foreign antigen and microorganisms occurs [ 2 ]. Therefore, at the early stage of inflammation, the activated DCs induce immunosuppression reducing pro-inflammatory cytokine production [ 3 ]. In sepsis, since the release of the initial inflammatory cytokine causes cytokine storm and eventually results in death due to loss of organ functions such as lung injection, recent studies emphasized the importance of DC, which improve the aberrant immune response and prolong the life during sepsis progression, in the therapeutic strategy target [ 4 , 5 ]. To date, a large number of therapeutic agents have been developed to treat sepsis, such as antibodies against lipopolysaccharides (LPS), toll-like receptor 4 (TLR4) agonists, antitumor necrosis factor (TNF) agents, drugs targeting platelet-activating factor (PAF), and drugs targeting coagulation cascades [ 6 , 7 , 8 ]. In a clinical trial, Xigris, which is a recombinant human form of protein C, blocks coagulation, inhibits inflammatory effects, and preserves organ function [ 9 , 10 , 11 ]. However, the result was unsuccessful owing to side effects, and the drug was withdrawn from the market in 2012. The specific drug was not yet approved for clinical use to treat sepsis. Once pathogenic organisms invade a host, they spread through the blood stream. In response to systemic infectious agents, innate immune cells are activated and cause cytokine emission. The rapidly increasing level of pro-inflammatory cytokines causes cytokine storm in the host [ 12 ], inducing organ injury or tissue damage, and this phenomenon is defined as a severe sepsis. Finally, septic shock, which is abnormal distribution of blood flow, results in inadequate blood supply to the body tissues, causing ischemia and organ dysfunction and leading to the death of patients [ 13 ]. In general, disrupting cytokine storm is very important in determining the mortality of sepsis patients [ 14 ]. Thus, the regulation of cytokine secretion should be studied and considered a key role in sepsis treatment.