Bacterial endotoxin, also known as "pyrogen", is a unique structure on the cell wall of Gram-negative bacteria. It is not released when the bacteria are alive. It is released outside the cell only when the bacteria die and autolyze, showing various toxic effects. Bacterial endotoxins are high molecular weight complexes composed of proteins, lipopolysaccharides (LPS), and phospholipids. Endotoxins are potent mediators of a variety of pathophysiological effects in humans, and these activities are primarily mediated by lipid A residues within the molecule. The toxic effects of endotoxins of various bacteria are weak and roughly the same, which can cause fever, microcirculation disturbance, endotoxin shock, and disseminated intravascular coagulation. Based on this, endotoxin has long been considered not only as a potential marker of Gram-negative bacterial infection but also as a mediator as a potential target for specific anti-endotoxin therapy.
Figure 1. The organization of lipopolysaccharide (LPS) from Gram-negative bacteria. (Monie T P, 2017)
Anti-endotoxin therapy focuses on the structural characteristics of endotoxin, known endotoxin-binding receptors, and action pathways. Current anti-endotoxin therapy mainly focuses on reducing endotoxin release, inhibiting endotoxin synthesis, and binding or neutralizing endotoxin. Prevent endotoxin from interacting with host effector cells, interfere with endotoxin-mediated signal transduction pathways, etc. For example, the acetylglucosamine transacylase inhibitors L-573655 and L-161240 can competitively inhibit the LPS synthesis of bacteria by 80% to 90%, and can quickly kill bacteria within 4 hours. Phage can produce short nucleotide sequences that can also block bacterial LPS biosynthesis. LF-33 is a peptide derived from lactoferrin, which can neutralize the endotoxin in the body and reduce the concentration of LPS. Human recombinant bactericidal/permeability-increasing protein (BPI) has a high affinity with endotoxin and can effectively remove endotoxin in blood circulation. Anti-CD14 monoclonal antibodies can block the combination of LPS and CD14, thereby blocking the activation of monocytes, and has a protective effect on endotoxemia animals. With in-depth research on endotoxin receptors, endotoxin receptors will become potential targets for the development of new anti-endotoxin drugs. Therefore, it is of great significance to develop new anti-endotoxin drugs with high affinity, strong neutralization ability, and low toxicity to reduce the morbidity and mortality of endotoxin. At the same time, the study of endotoxin antibodies provides a new way of immunotherapy for Gram-negative bacterial infection. The research and development of monoclonal antibodies has potential clinical practical value and bright prospects.
Endotoxemia is one of the common clinical complications of infection. Given the prevalence of infections caused by multi-antibiotic-resistant bacteria and the lack of effective antimicrobial agents, anti-endotoxin antibodies deserve more attention in the prevention and treatment of endotoxemia. Due to the complex effects of endotoxin on the body, most anti-endotoxin treatments are still in the stage of experimental research. At the same time, the research on anti-endotoxin drugs has been one of the most active research fields in the international medical community in recent decades. Therefore, the reliability and durability of the clinical efficacy of anti-endotoxin preparations need scientific research, and more research funds are invested to develop endotoxin detection reagents and anti-endotoxin treatments.
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