4.6 Article

BK Channels Regulate LPS-induced CCL-2 Release from Human Pulmonary Endothelial Cells

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AMER THORACIC SOC
DOI: 10.1165/rcmb.2020-0228OC

关键词

acute lung injury; large conductance potassium channels; LPS; cytokines; inflammation

资金

  1. U.S. National Institutes of Health [7K08HL118118-03, R01HL134346, R01HL130308]

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Experimental results show that BK channel activation can inhibit LPS-induced CCL-2 secretion in endothelial cells through Em hyperpolarization, independent of intracellular Ca2+ concentrations. However, BK activation does not significantly affect IL-6 or epithelial cells, and BK channel inhibition as well as LPS treatment do not alter Em or intracellular Ca2+ concentrations in either cell type.
We recently established a role for the stretch-activated two-pore-domain K+ (K2P) channel TREK-1 (K2P2.1) in inflammatory cytokine secretion using models of hyperoxia-, mechanical stretch-, and TNF-alpha-induced acute lung injury. We have now discovered the expression of large conductance, Ca2+-activated K + (BK) channels in human pulmonary microvascular endothelial cells and primary human alveolar epithelial cells using semiquantitative real-time PCR, IP and Western blot, and investigated their role in inflammatory cytokine secretion using an LPS-induced acute lung injury model. As expected, LPS induced IL-6 and CCL-2 secretion from pulmonary endothelial and epithelial cells. BK activation with NS1619 decreased LPS-induced CCL-2 but not IL-6 secretion from endothelial cells and had no effect on epithelial cells, although fluorometric assays revealed that BK activation hyperpolarized the plasma membrane potential (Em) of both cell types. Interestingly, BK inhibition (Paxilline) did not alter cytokine secretion or the Em in either cell type. Furthermore, LPS treatment by itself did not affect the Em or intracellular Ca2+ concentrations. Therefore, we propose BK channel activation as a novel targeted approach to counteract LPS-induced CCL-2 secretion from endothelial cells. This protective effect appears to occur via Em hyperpolarization but independent of intracellular Ca2+ concentrations.

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