Immunoneutralization of the Aminoprocalcitonin Peptide of Procalcitonin Protects Rats from Lethal Endotoxemia: Neuroendocrine and Systemic Studies
Résumé
Severe sepsis and septic shock are an important cause of mortality and morbidity. These illnesses can be triggered by the bacterial endotoxin lipopolysaccharide (LPS) and proinflammatory cytokines, particularly tumor necrosis factor (TNF)-a and interleukin (IL)-1b. Severity and mortality of sepsis have also been associated with high concentrations of aminoprocalcitonin (N-PCT), a 57-amino acid neuroendocrine peptide derived from procalcitonin. Prior studies in a lethal model of porcine polymicrobial sepsis have revealed that immunoneutralization with IgG that is reactive to porcine N-PCT significantly improves short-term survival. To further explore the pathophysiological role of N-PCT in sepsis, we developed an antibody raised against a highly conserved amino acid sequence of human N-PCT (N-PCT44-57). This sequence differs by only one amino acid from rat N-PCT. First, we demonstrated the specificity of this antibody in a well proven model of anorexia induced in rats by central administration of human N-PCT1-57. We next further explored the therapeutic potential of anti-N-PCT44-57 in a rat model of lethal endotoxemia and determined how this immunoneutralization affected LPS-induced lethality and cytokine production. We showed that this specific antibody inhibits LPS-induced early release of TNF-a and IL-1b and increased survival; even if treatment began after cytokine response has occurred. Also, anti-N-PCT44-57 may increase long-term survival in LPS-treated rats by up-regulating the late production of counterregulatory anti-inflammatory mediators such as ACTH and IL-10. These data support N-PCT as a proinflammatory factor in both the early and the late stages of lethal endotoxemia and suggest N-PCT as a candidate for septic shock therapy.
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