During cutaneous wound healing processes, several physiological factors lead to regeneration of functional scar tissues; however, in some pathological conditions (diabetic foot, bedsores) efficient wound healing is hampered by hypoxia, altering the release of molecules associated with matrix turn-over (i.e. matrix metalloproteinases, MMPs; tissue inhibitors of metalloproteinases, TIMPs) from surrounding cells (endothelium, immune cells). Provided that cellular phenotypes in such environments are better understood, impaired chronic wounds could be targeted by new effective oxygenating drugs, such as O2-Loaded Nanobubbles (OLNs). Here we investigated whether dextran-shelled OLNs (500 nm sized and negatively charged) could counteract hypoxia in modulating secretion of gelatinases (MMP-2 and -9) and their inhibitors (TIMP-1 and TIMP-2) from human dermal microvascular endothelial cells (HMEC-1) or primary peripheral monocytes. As emerged from analysis by ELISA and gelatin zymography, under normoxic conditions HMEC-1 released MMP-2, TIMP-1 and TIMP-2, but not MMP-9; monocytes secreted MMP-9, TIMP-1 and TIMP-2, but not MMP-2. Hypoxia enhanced endothelial MMP-2 and monocytic TIMP-1, reduced monocytic MMP-9 and endothelial TIMP-1, and did not affect endothelial/monocytic TIMP-2 levels. As a consequence of hypoxia-unpaired MMP/TIMP balances, invasion abilities of both cells were compromised. Interestingly, OLNs abrogated all hypoxia effects on MMP/TIMP secretion, without displaying any cytotoxic effects. Notably, neither O2–saturated solution (OSS) nor O2–free nanobubbles (OFNs) did mimic OLN effects, which appeared specifically dependent on time-sustained O2 diffusion from OLN core. Collectively, these data support the hypothesis that topical administration of exogenous O2, properly encapsulated in nanobubble formulations, might promote healing of hypoxia-associated chronic wounds.
Oxygen-loaded nanobubbles counteract hypoxia effects on dermal endothelial and monocytic MMP and TIMP secretion: new perspectives for chronic wound healing
PRATO, Mauro;GULINO, GIULIA ROSSANA;KHADJAVI, AMINA;GIRIBALDI, Giuliana;GUIOT, Caterina
2013-01-01
Abstract
During cutaneous wound healing processes, several physiological factors lead to regeneration of functional scar tissues; however, in some pathological conditions (diabetic foot, bedsores) efficient wound healing is hampered by hypoxia, altering the release of molecules associated with matrix turn-over (i.e. matrix metalloproteinases, MMPs; tissue inhibitors of metalloproteinases, TIMPs) from surrounding cells (endothelium, immune cells). Provided that cellular phenotypes in such environments are better understood, impaired chronic wounds could be targeted by new effective oxygenating drugs, such as O2-Loaded Nanobubbles (OLNs). Here we investigated whether dextran-shelled OLNs (500 nm sized and negatively charged) could counteract hypoxia in modulating secretion of gelatinases (MMP-2 and -9) and their inhibitors (TIMP-1 and TIMP-2) from human dermal microvascular endothelial cells (HMEC-1) or primary peripheral monocytes. As emerged from analysis by ELISA and gelatin zymography, under normoxic conditions HMEC-1 released MMP-2, TIMP-1 and TIMP-2, but not MMP-9; monocytes secreted MMP-9, TIMP-1 and TIMP-2, but not MMP-2. Hypoxia enhanced endothelial MMP-2 and monocytic TIMP-1, reduced monocytic MMP-9 and endothelial TIMP-1, and did not affect endothelial/monocytic TIMP-2 levels. As a consequence of hypoxia-unpaired MMP/TIMP balances, invasion abilities of both cells were compromised. Interestingly, OLNs abrogated all hypoxia effects on MMP/TIMP secretion, without displaying any cytotoxic effects. Notably, neither O2–saturated solution (OSS) nor O2–free nanobubbles (OFNs) did mimic OLN effects, which appeared specifically dependent on time-sustained O2 diffusion from OLN core. Collectively, these data support the hypothesis that topical administration of exogenous O2, properly encapsulated in nanobubble formulations, might promote healing of hypoxia-associated chronic wounds.
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