Systemic inflammatory response syndrome (SIRS) is a life threatening condition and the leading cause of death in intensive care units. Although single aspects of pathophysiology have been described in detail, numerous unknown mediators contribute to the progression of this complex disease. The aim of this study was to elucidate the pathophysiological role of CAAP48, a C-terminal alpha-1 antitrypsin fragment, that we found to be elevated in septic patients and to apply this peptide as diagnostic marker for infectious and noninfectious etiologies of SIRS. Incubation of human polymorphonuclear neutrophils with synthetic CAAP48, the SNP-variant CAAP47, and several control peptides revealed intense neutrophil activation, induction of neutrophil chemotaxis, reduction of neutrophil viability, and release of cytokines. We determined the abundance of CAAP48 in patients with severe sepsis, severe SIRS of noninfectious origin, and viral infection. CAAP48 levels were 3-4-fold higher in patients with sepsis compared to SIRS of noninfectious origin and allowed discrimination of those patients with high sensitivity and specificity. Our results suggest that CAAP48 is a promising discriminatory sepsis biomarker with immunomodulatory functions, particularly on human neutrophils, supporting its important role in the host response and pathophysiology of sepsis.
Abstract. Within cytogenetic preparations chromosomal breaks can be observed in patients suffering from Fanconi anemia (FA), a recessively inherited syndrome with an extremely elevated cancer risk, but also in healthy individuals as so-called fragile sites (FS). It is known that FS cytogenetically co-localize with tumor-and evolutionaryconserved chromosomal break-points. The also suggested colocalization of FS and FA associated break-points (FA-bp) was studied here for the first time systematically by molecular cytogenetics. Metaphase chromosomes were obtained from lymphocytes of two FA patients (FANC-A and FANC-C, respectively). Overall 50.58% of the investigated FA-bp correspond to cytogenetic regions with known FS. A detailed molecular cytogenetic study applying FS-spanning probes revealed that 24/29 (82.8%) of analyzed FS are in concordance with FA-bp. Notably, FA-bp show a distribution pattern deviating from that of Aphidicolin induced FS. FA-bp appear more frequently within GTG-light bands and additionally, a yet unreported correlation was observed between break rate and chromosomal banding level. In future, FA-bp might serve as model for the mapping and analysis of otherwise rarely observable FS.
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