Oxygen-loaded nanobubbles abrogate hemozoin-enhanced release of human monocyte MMP-9.

Hemozoin (Hz, malarial pigment) compromises functions/phenotype of human monocytes. In vitro, Hz enhances release of monocyte Matrix Metalloproteinase-9 (MMP-9), a proteolytic enzyme promoting inflammation and blood brain barrier (BBB) damage possibly favoring cerebral malaria (CM). CM is a life-threatening complication associated with infected erythrocyte sequester in microvessels, reduced blood flow, and tissue hypoxia. To date, an effective adjuvant therapy aimed at reducing CM symptoms/mortality is missing. Oxygen-loaded nanobubbles (OLNs), recently developed to supply hypoxic tissues with O2, might be good therapeutic tools. Here, the effects of hypoxia and OLNs on MMP-9 regulation in unfed/Hz-fed human monocytes were investigated. Unfed cells cultured in hypoxia secreted lower MMP-9 levels than cells in normoxia; Hz and its lipoperoxidation derivative 15-HETE significantly enhanced MMP-9 release both in normoxic and hypoxic conditions. OLNs - constituted by dextran shell and O2-storing decafluoropentane core, with sizes of about 500 nm and a negative surface charge, showing good capacity of O2 delivery, not accompanied by O3 generation after UV sterilization, and not displaying toxic effects on cells - abrogated either hypoxia-reduced or Hz/15-HETE-enhanced MMP-9 secretion. All effects were specifically dependent on O2 gradual delivery from OLNs, since were not reproduced by using oxygen-free nanobubbles or oxygen saturated solution. According to these data, and provided the underlying mechanisms are better understood, OLNs appear to be promising candidates for CM adjuvant therapy, as they could counteract hypoxia and MMP-dependent inflammation or BBB damage.