Stattic: Can a New Drug Reduce the Inflammatory Responses after Cardiopulmonary Bypass Surgery?

Background: Deep therapeutic hypothermia is a standard therapy for neuroprotection during complex pediatric cardiac surgery but severe side effects are associated with the treatment. Therefore, the authors investigated the use of STATTIC, a small-molecular inhibitor of STAT3 activation, to attenuate IL-6 expression in place of deep hypothermia.

Methods: Both BV-2 microglia monoculture and HT-22 neurons plus BV-2 microglia direct coculture were either cooled to 17 °C for 2 hours, rewarmed to 37 °C within 2 hours, and maintained under 37 °C for 24 hours or STATTIC was applied for 4 hours instead of cooling and rewarming. Cells were treated with either 1 µg/mL lipopolysaccharid (LPS) or 1 µg/mL LPS plus 100 mM glutamate to simulate inflammatory responses during heart surgery involving extracorporal circulation. Cytokine expression was measured by qRT-PCR and ELISA. Protein expression of Phospho-Stat3 (Tyr705) was analyzed using Western blotting.

Results: Phospho-Stat3 was observed to be significantly down-regulated under deep hypothermic conditions, corresponding with a significant reduction in IL-6 expression in the BV-2 monoculture. However, no significant reduction in phospho-Stat3 was observed in the direct coculture cell model, although deep hypothermia attenuated IL-6 secretion. Similar to the protective antiinflammatory effects of deep hypothermia, the application of STATTIC under normothermic conditions resulted in significantly reduced IL-6 secretion in both the BV-2 monoculture and direct coculture of neurons and microglia.

Conclusion: Hypothermia significantly reduces the inflammatory response in both monoculture and coculture cell models. In the future, attenuating IL-6 expression by blocking the phospho-STAT3 pathway offers an interesting therapeutic option to reduce inflammatory responses after cardiopulmonary bypass surgery.