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Novel Role for the BK Channel in Macrophage Phagocytosis

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A4496 - Novel Role for the BK Channel in Macrophage Phagocytosis
Author Block: M. P. Goldklang1, T. Jean-Louis1, J. Chen1, A. Gerber1, K. Stearns1, T. Zelonina1, S. Marx2, J. M. D'Armiento1; 1Anesthesiology, Columbia University, New York, NY, United States, 2Medicine, Columbia University, New York, NY, United States.
INTRODUCTION: Ion channels play key roles in the regulation of cells within the lung, and contribute to the pathophysiology of disease. Large conductance, voltage- and calcium-activated potassium (BK) channels control membrane potential and calcium flux, and have well-established roles in excitable cells, including excitation-contraction coupling and neuronal signaling. To date, a role for BK channels in macrophage function has not yet been defined, in particular pertaining to the response to cigarette smoke exposure. METHODS: Wild type mice underwent 4 weeks of smoke exposure, and lung BK beta-1 and BK alpha subunit expression was assessed by RT-PCR. BK beta-1 subunit knockout and wild-type mice were then injected with thioglycollate under room air or smoke exposure conditions. Peritoneal macrophages were retrieved 4 days later. RNA was isolated and macrophage expression of the protease MMP-9 was assessed. Macrophage phagocytosis was quantified by a fluorescent latex bead assay. Finally, the impact of pharmacologic manipulation of the BK channel on macrophage phagocytosis was assessed using paxilline as a BK channel inhibiting agent. RESULTS: In the setting of smoke exposure, there is a significant increase in BK beta-1 and BK alpha subunit expression in the lungs. Immunofluorescence staining identified the BK beta-1 subunit in pulmonary macrophages following smoke exposure. MMP-9 is potently induced in peritoneal macrophages of smoke-exposed wild-type mice with BK beta-1 knockout mice exhibiting reduced MMP-9 induction under similar conditions. While in vivo smoke exposure reduces macrophage phagocytosis in wild-type mice, BK beta-1 knockout mice demonstrate reduced macrophage phagocytosis at baseline, which remains low under smoke exposure conditions when compared to wild-type mice. In vitro, BK channel blockade with Paxilline reduced macrophage phagocytosis in wild-type mice, but had no effect in the BK beta-1 knockout macrophage. CONCLUSION: The BK channel influences macrophage function and phagocytosis, potentially through alterations in intracellular calcium concentration and membrane potential. The influence of the BK channel on macrophage cellular function has not previously been described and opens up a new potential therapeutic target in inflammatory lung disease.
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