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Na-K-2Cl Cotransporter-1 Modulates Functions of Alveolar Macrophage by Cell Volume Regulation
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A2976 - Na-K-2Cl Cotransporter-1 Modulates Functions of Alveolar Macrophage by Cell Volume Regulation
Author Block: K. Huang1, C. Hung2, C. Peng3; 1Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei City, Taiwan, 2Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei City, Taiwan, 3Division of Pulmonary and Critical Care, Tri-Service General Hospital, Taipei, Taiwan.
Rationale. Na+-K+-2Cl- cotransporter-1 (NKCC1) contributes to a variety of well-documented physiological functions including ion transport, alveolar fluid secretion, and cell volume regulations. Far less is known about the role of NKCC1 in modulation of host immunity. Methods and main results. Here we show that LPS stimulates the expression and phosphorylation of NKCC1 on RAW264.7 and primary alveolar macrophage (AM) in vitro. The LPS-induced inflammatory responses and phagocytosis activity of AMs can be inhibited by chemical or biochemical blockage of NKCC1 activation via inhibitors or gene mutations. Enlarging cell volume with low osmotic microenvironment amplifies AM functions, whereas pretreatment with NKCC1 inhibitor attenuates this enhancement. Furthermore, mice treated with NKCC1 inhibitor or with knockout of WNK4 or SPAK showed higher resistance to LPS-induced tissue inflammation and acute lung injury in vivo. Conclusion. Our studies suggest that NKCC1 plays a unique role as an amplifier of LPS-treated AM functions and that NKCC1 might be a novel target for treating sepsis-related ARDS.
Author Block: K. Huang1, C. Hung2, C. Peng3; 1Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei City, Taiwan, 2Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei City, Taiwan, 3Division of Pulmonary and Critical Care, Tri-Service General Hospital, Taipei, Taiwan.
Rationale. Na+-K+-2Cl- cotransporter-1 (NKCC1) contributes to a variety of well-documented physiological functions including ion transport, alveolar fluid secretion, and cell volume regulations. Far less is known about the role of NKCC1 in modulation of host immunity. Methods and main results. Here we show that LPS stimulates the expression and phosphorylation of NKCC1 on RAW264.7 and primary alveolar macrophage (AM) in vitro. The LPS-induced inflammatory responses and phagocytosis activity of AMs can be inhibited by chemical or biochemical blockage of NKCC1 activation via inhibitors or gene mutations. Enlarging cell volume with low osmotic microenvironment amplifies AM functions, whereas pretreatment with NKCC1 inhibitor attenuates this enhancement. Furthermore, mice treated with NKCC1 inhibitor or with knockout of WNK4 or SPAK showed higher resistance to LPS-induced tissue inflammation and acute lung injury in vivo. Conclusion. Our studies suggest that NKCC1 plays a unique role as an amplifier of LPS-treated AM functions and that NKCC1 might be a novel target for treating sepsis-related ARDS.
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