PROCALCITONIN AND ITS COMPONENT PEPTIDES IN SYSTEMIC INFLAMMATION - IMMUNOCHEMICAL CHARACTERIZATION

Background: The systemic inflammatory response syndrome (SIRS) is a ma rked, generalized response to a variety of injuries; if infection is i mplicated, the term ''sepsis'' is used, Systemic inflammatory response syndrome/sepsis, which is initiated by proinflammatory cytokines, has been found to be associated with increased serum levels of the prohor mone of calcitonin, procalcitonin (ProCT) and its aminoterminus peptid e (nProCT), The serum levels of ProCT and nProCT are very useful marke rs for SIRS/sepsis, and may be used to follow the course, the response to therapy, and/or the prognosis, We studied the serum levels and dis tribution of ProCT and its component peptides in normal persons for co mparison with similar immunochemical and separatory studies in patient s with neuroendocrine cancer and with SIRS/sepsis of various etiologie s. Methods: We studied pooled and extracted serum of 13 normal subject s, and sera of patients with neuroendocrine cancer and SIRS/sepsis, us ing region-specific immunoassays, gel filtration, and high performance Liquid chromatography. Results: Normal sera contained small but measu rable levels of the intact ProCT molecule, nProCT, a conjoined calcito nin-calcitonin carboxyterminal peptide (CT:CCP-I), CCP-I, free mature CT, and calcitonin gene-related peptide (CGRP), Sera from neuroendocri ne cancer usually contained high levels of these peptides. In such cas es, free mature CT was always increased, the mean ratio of the intact ProCT to free CT being 168 +/- 68. Gel filtration and HPLC studies of patients with SIRS/sepsis revealed markedly increased levels of ProCT, nProCT, and CT:CCP-I in varying proportions, Mature CT was normal to minimally elevated. The ratio of ProCT to free CT was 2,900 +/- 800, A lthough serum CGRP is commonly increased in neuroendocrine cancer, it was very low or undetectable in SLRS/sepsis. Conclusions: These studie s indicate that ProCT and its component peptides circulate in normal p ersons, The serum of patients with SIRS/sepsis contains greatly increa sed levels of ProCT, nProCT and often, CT:CCP-I, However, in this cond ition, past-translational processing is incomplete, resulting in matur e CT levels that are normal or minimally elevated, In contrast, patien ts with neuroendocrine cancer hale considerably high mature CT levels, Interestingly, although serum CGRP levels often are high in neuroendo crine cancer, they are low in SIRS/sepsis, The marked hyperprocalciton emia of SIRS/sepsis is probably a consequence of the pro-inflammatory cytokine cascade, and appears to be secreted in a constitutive fashion ; the cell(s) of origin of this remarkable hypersecretion is unknown. There is a very marked positive correlation between serum levels of Pr oCT and nProCT, and the lower level of sensitivity for nProCT may make its measurement a more useful marker for early or mild SIRS/sepsis.