Haemodialysis as a model for studying endogenous plasma DNA: oligonucleosome-like structure and clearance

Abstract

SUMMARYThe rale of clearance of exiracellular plasma DNA in man ha.s importani inipiitalions for palhogenelie mechanisms in systemic lupus erythemalosus (SLE), as well as for eeriain oihcr clinical states. Present knowledge of this parameter is derived exelusively from studies of injected, naked DNA in animals. Recent informalion indicates that the physiologic form of plasma DNA in SLE is that of oligonucleosome-like molecules rather than of naked DNA and eonsists of multimcric complexes of DNA bound to histone, probably arising from an apoplotic process. In order to study the rale at which ihese oligonucleosome-like complexes are removed from plasma and to do so in man rather than experimental animals, we exploited the observation that during haemodialysis large amounts of DNA are released, apparently within the dialysis coil, inlo the paiieni's plasma. Since this release appears lo cease promptly with termination of the procedure, it offered the potential for estimating the rate of removal of such DNA from human plasma. Moreover, if that DNA. as postulated, were shown to possess an oligonucleosome-like structure resembling that fotind endogenously in human SLE, the relevance of such information to the human disease state would be further enhanced. The present results support the conclusion that DNA released into plasma during haemodialysis possesses such an oligonucleosome-like structure. The plasma half-life of ihat DNA in man was found nol lo exceed 4 min. The highly dynamic state thus implied for extracellular endogenous plasma DNA in man has important implications for pathogenetic mechanisms dependent on dsDNA in SLE. Moreover, individuals undergoing chronic hacmodialysi,s, who are thereby exposed to a very large cumulative amount of such DNA., might serve as models for studying its long-term sequelae.

Nucleosomes and CYFRA 21-1 indicate tumor response after one cycle of chemotherapy in recurrent non-small cell lung cancer

“…As cell-free DNA is mainly associated with proteins and organized as nucleosomal complexes in serum to be better conserved from degradation by DNAses [55][56][57], these results are quite comparable with our findings on nucleosomes. Fournie et al [49] as well as Gautschi et al [52] have observed a correlation of DNA kinetics with efficacy of systemic therapy.…”

Pullulan-histone antibody nanoconjugates for the removal of chromatin fragments from systemic circulation

“…Fuchs et al reported recently that chromatin fragments and histones are strong mediators of platelet activation and aggregation. Thus the chromatin fragments can trigger inflammation and also thrombus formation [39]. It is reported that following LPS injection in mice, the inflammatory response that is observed are the elevated serum values of TNF-a, IL-1b and IL-6 [14].…”

Generation of blood circulating DNA: the sources, peculiarities of circulation and structure

“…По данным некоторых авторов, основная часть внДНК циркулирует в крови в составе нуклеосом. Действительно, время жизни нуклеосом, введённых внутривенно мышам, сопоставимо со временем жизни циркулирующей плодной ДНК в крови матери [60,61]. Однако прямые доказательства того, что основная часть ДНК опухолевых или [54,62].…”