Introduction. Hemozoin (Hz, malarial pigment) and its lipoperoxidation product 15-eicosatetraenoic acid (15-HETE) were previously shown to enhance matrix metalloproteinase-9 (MMP-9) release from human monocytes in normoxic conditions. MMP-9, a proteolytic enzyme promoting inflammation and blood brain barrier (BBB) damage, might favor cerebral malaria (CM), a life-threatening complication associated with infected erythrocyte sequester in microvessels, reduced blood flow, and tissue hypoxia. Here, Hz/15-HETE effects on MMP-9 regulation in hypoxic monocytes were investigated, and the potential therapeutic role of dextran-shelled/decafluoropentane-containing OLNs, recently developed to supply hypoxic tissues with O2, was evaluated. Methods. Human monocytes, isolated from peripheral blood, were fed/unfed with Hz or treated/untreated with 15-HETE (1 M) for 2 h and further incubated in serum-free medium for 24 h in the presence/absence of OLNs, O2-free nanobubbles (OFNs) or O2-saturated solution (OSS), both in normoxia and hypoxia. Thereafter, MMP-9 protein levels in cell supernatants were studied by gelatin zymography and densitometry. Results. Hypoxic monocytes secreted lower MMP-9 levels than normoxic cells. However, Hz and its lipoperoxidation derivative 15-HETE significantly enhanced MMP-9 release both in normoxia and hypoxia. OLNs abrogated either hypoxia-reduced or Hz/15-HETE-enhanced MMP-9 secretion. All effects were specifically dependent on O2 gradual delivery from OLNs, since they were not reproduced by using OFNs or OSS. Conclusion. According to these data, and provided the underlying mechanisms are better understood, OLNs appear to be promising candidates as CM adjuvant therapeutics, counteracting either brain hypoxia or MMP-dependent inflammation and BBB damage. Acknowledgements. Work supported by funding from Ateneo-Compagnia di San Paolo (ORTO11CE8R 2011).
Nanotechnology and infection: dextran-shelled/decafluoropentane-containing oxygen-loaded nanobubbles counteract malarial pigment effects on human monocyte matrix metalloproteinase-9 release.
PRATO, Mauro;VALENTE, Elena;GUIOT, Caterina;GIRIBALDI, Giuliana
2013-01-01
Abstract
Introduction. Hemozoin (Hz, malarial pigment) and its lipoperoxidation product 15-eicosatetraenoic acid (15-HETE) were previously shown to enhance matrix metalloproteinase-9 (MMP-9) release from human monocytes in normoxic conditions. MMP-9, a proteolytic enzyme promoting inflammation and blood brain barrier (BBB) damage, might favor cerebral malaria (CM), a life-threatening complication associated with infected erythrocyte sequester in microvessels, reduced blood flow, and tissue hypoxia. Here, Hz/15-HETE effects on MMP-9 regulation in hypoxic monocytes were investigated, and the potential therapeutic role of dextran-shelled/decafluoropentane-containing OLNs, recently developed to supply hypoxic tissues with O2, was evaluated. Methods. Human monocytes, isolated from peripheral blood, were fed/unfed with Hz or treated/untreated with 15-HETE (1 M) for 2 h and further incubated in serum-free medium for 24 h in the presence/absence of OLNs, O2-free nanobubbles (OFNs) or O2-saturated solution (OSS), both in normoxia and hypoxia. Thereafter, MMP-9 protein levels in cell supernatants were studied by gelatin zymography and densitometry. Results. Hypoxic monocytes secreted lower MMP-9 levels than normoxic cells. However, Hz and its lipoperoxidation derivative 15-HETE significantly enhanced MMP-9 release both in normoxia and hypoxia. OLNs abrogated either hypoxia-reduced or Hz/15-HETE-enhanced MMP-9 secretion. All effects were specifically dependent on O2 gradual delivery from OLNs, since they were not reproduced by using OFNs or OSS. Conclusion. According to these data, and provided the underlying mechanisms are better understood, OLNs appear to be promising candidates as CM adjuvant therapeutics, counteracting either brain hypoxia or MMP-dependent inflammation and BBB damage. Acknowledgements. Work supported by funding from Ateneo-Compagnia di San Paolo (ORTO11CE8R 2011).
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