Tzu-Chi Medical Journal (Jan 2022)

The roles of sodium-potassium-chloride cotransporter isoform-1 in acute lung injury

  • Po-Chun Hsieh,
  • Yao-Kuang Wu,
  • Chan-Yen Kuo,
  • Yen-Hsien Lee,
  • Mei-Chen Yang,
  • Chou-Chin Lan

DOI
https://doi.org/10.4103/tcmj.tcmj_50_21
Journal volume & issue
Vol. 34, no. 2
pp. 119 – 124

Abstract

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Acute lung injury (ALI) is often characterized by severe lung inflammation and pulmonary edema with poor gas exchange and hypoxemia. Alveolar inflammation and water flooding are, in fact, notable features of ALI pathogenesis. The sodium-potassium-chloride co-transporter isoform 1 (NKCC1), localized at the basolateral surface of the lung epithelium, drives water transport via back transport of Na+ and Cl− to the alveolar air space. NKCC1, therefore, is crucial in regulating alveolar fluid. Increased expression of NKCC1 results in increased alveolar fluid secretion and impaired alveolar fluid clearance. During ALI, the with no lysine kinase (WNK), oxidative stress responsive kinase 1 (OSR1), and STE20/SPS1-related proline/alanine-rich kinase (SPAK) pathways are activated, which upregulates NKCC1 expression. Proinflammatory cytokines also enhance the expression of NKCC1 via c-Jun N-terminal kinase-and p38-dependent pathways. NKCC1 activation also increases the expression of proinflammatory cytokines via cell rupture and activation of macrophages. Increased proinflammatory cytokines, in turn, recruit inflammatory cells to the site of injury and cause further lung damage. Animals with high expression of NKCC1 show more severe lung injury with presentations of more severe pulmonary edema and microvascular permeability, higher expression of proinflammatory cytokines, and greater neutrophilic infiltration. In contrast, animals with low expression of NKCC1 or those treated with NKCC1 inhibitors show less severe lung injury with milder levels of presentations of ALI. These reports collectively highlight a novel role of NKCC1 in ALI pathogenesis. Manipulation of NKCC1 expression levels could, therefore, represent novel modalities for effective ALI treatment.

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