290640 The Effects of Pressure On the Pharmacological Action of Antioxidants On Macrophages

Monday, October 29, 2012
Hall B (Convention Center )
Casey Kukielski, Department of Bioengineering, Clemson University, Clemson, SC, Hainsworth Y. Shin, Center for Biomedical Engineering, University of Kentucky, Lexington, KY and Dr. Thomas Dziubla, Chemical and Materials Engineering, University of Kentucky, Lexington, KY

The tissue-biocompatibility interface is the single-most critical determinant of implant biocompatibility and successful integration into host tissue.  Reactive oxygen species play a significant role in modulating the foreign body response at the tissue-implant interface, which is characterized by high macrophage densities and elevated interstitial pressure levels. Theoretically, it is conceivable that local delivery of antioxidants can be used to modulate the oxidative status of the implant site, thereby improving material biocompatibility.  Several antioxidant class molecules, including Quercetin and Trolox, have been shown to exhibit a biphasic antioxidant/pro-oxidant dose-response at ambient pressure, offering a possible countermeasure for pressure-sensitive reductions in ROS generation which are known to cause cell detachment. For this purpose, we explored the possibility that delivery of Quercetin or Trolox at doses that induce their pro-oxidant activity opposes the antioxidant effects of pressure stimulation. To test this hypothesis, we used a custom pressure chamber in conjunction with fluorescence-based spectrophotometry to quantify superoxide release in cells exposed elevated hydrostatic pressures in the presence or absence of either 1, 10, 20, or 50 uM  quercetin or 20, 200, 400, or 800 uM trolox. Interestingly, under all antioxidant treatments tested, cells exposed to 20 mmHg exhibited a delayed antioxidant-prooxidant transition relative to controls, which prevented them from counteracting the pressure-sensitive reductions in macrophage superoxide production. However, the observed delay in antioxidant-to-proxidant transition suggests that pressure has a significant effect on the action of antioxidants and suggests that the efficacy of these drugs depends on the pressure mechanoenvironment of macrophages at sites of inflammation.

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