With-No-Lysine Kinase 4 Mediates Alveolar Fluid Regulation in Hyperoxia-Induced Lung Injury*. Issue 10 (October 2015)

• Record Type: Journal Article
• Authors: Lin, Hsueh-Ju; Wu, Chin-Pyng; Peng, Chung-Kan; Lin, Shih-Hua; Uchida, Shinich; Yang, Sung-Sen; Huang, Kun-Lun
• Is Part Of: Critical care medicine. Volume 43:Issue 10(2015)
• Publication Date: 2015-10
• Subjects: Critical care medicine -- Periodicals; Soins intensifs -- Périodiques; 616.028
• DOI: 10.1097/CCM.0000000000001144
• Languages: English
• ISSNs: 0090-3493

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Objectives:</title> <p>To investigate mechanisms involved in the regulation of epithelial ion channels and alveolar fluid clearance in hyperoxia-induced lung injury.</p> </sec> <sec> <title>Design:</title> <p>Laboratory animal experiments.</p> </sec> <sec> <title>Setting:</title> <p>Animal care facility procedure room in a medical center.</p> </sec> <sec> <title>Subjects:</title> <p>Wild-type, STE20/SPS1-related proline/alanine-rich kinase knockout (SPAK<sup>–/–</sup>), and with-no-lysine kinase 4 knockin (<italic>WNK4</italic><sup>D561A/+</sup>) mice.</p> </sec> <sec> <title>Interventions:</title> <p>Mice were exposed to room air or 95% hyperoxia for 60 hours.</p> </sec> <sec> <title>Measurements and Main Results:</title> <p>Exposure to hyperoxia for 60 hours increased the lung expression of with-no-lysine kinase 4 and led to STE20/SPS1-related proline/alanine-rich kinase and sodium-potassium-chloride cotransporter phosphorylation, which resulted in the suppression of alveolar fluid clearance and increase of lung edema. <italic>WNK4</italic><sup>D561A/+</sup> mice at the baseline presented an abundance of epithelium sodium channel and high levels of STE20/SPS1-related proline/alanine-rich kinase and sodium-potassium-chloride cotransporter phosphorylation. Compared with the wild-type group, hyperoxia caused greater epithelium sodium channel expression in <italic>WNK4</italic><sup>D561A/+</sup> mice, but no significant difference in STE20/SPS1-related proline/alanine-rich kinase and sodium-potassium-chloride cotransporter phosphorylation. The functional inactivation of sodium-potassium-chloride cotransporter by gene knockout in SPAK<sup>–/–</sup> mice yielded a lower severity of lung injury and longer animal survival, whereas constitutive expression of with-no-lysine kinase 4 exacerbated the hyperoxia-induced lung injury. Pharmacologic inhibition of sodium-potassium-chloride cotransporter by inhaled furosemide improved animal survival in <italic>WNK4</italic><sup>D561A/+</sup> mice. By contrast, inhibition of epithelium sodium channel exacerbated the hyperoxia-induced lung injury and animal death.</p> </sec> <sec> <title>Conclusions:</title> <p>With-no-lysine kinase 4 plays a crucial role in the regulation of epithelial ion channels and alveolar fluid clearance, mainly via phosphorylation and activation of STE20/SPS1-related proline/alanine-rich kinase and sodium-potassium-chloride cotransporter.</p> </sec> </abstract>