Immunoneutralization of the aminoprocalcitonin peptide of procalcitonin protects rats from lethal endotoxaemia: neuroendocrine and systemic studies.
Severe sepsis and septic shock are an important cause of mortality and morbidity. These illnesses can be triggered by the bacterial endotoxin LPS (lipopolysaccharide) and pro-inflammatory cytokines, particularly TNF-α (tumour necrosis factor-α) and IL (interleukin)-1β. Severity and mortality of sepsis have also been associated with high concentrations of N-PCT (aminoprocalcitonin), a 57-amino-acid neuroendocrine peptide derived from ProCT (procalcitonin). Previous 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 explore further 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-PCT-(44-57)]. 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-PCT-(1-57). Next we explored further the therapeutic potential of anti-N-PCT-(44-57) in a rat model of lethal endotoxaemia and determined how this immunoneutralization affected LPS-induced lethality and cytokine production. We show that this specific antibody inhibited the LPS-induced early release of TNF-α and IL-1β and increased survival, even if treatment began after the cytokine response had occurred. In addition, anti-N-PCT-(44-57) may increase long-term survival in LPS-treated rats by up-regulating the late production of counter-regulatory anti-inflammatory mediators such as ACTH (adrenocorticotropic hormone) and IL-10. In conclusion, these results support N-PCT as a pro-inflammatory factor in both the early and the late stages of lethal endotoxaemia, and suggest anti-N-PCT as a candidate for septic shock therapy.
Tavares
Eva
E
Clinical and Experimental Pharmacology Research Unit, Valme University Hospital, Seville, Spain.
Miñano
Francisco J
FJ
D000818:Animals; D002116:Calcitonin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D019446:Endotoxemia / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D015870:Gene Expression; D007031:Hypothalamus / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D018836:Inflammation Mediators / Q000097:blood; D008070:Lipopolysaccharides; D008297:Male; D010446:Peptide Fragments / Q000276:immunology; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis
C000606589:CALCA protein, human; C000606591:Calca protein, rat; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011498:Protein Precursors; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide