Cytokine-Regulation of Na+-K+-Cl- Cotransporter 1 and Cystic Fibrosis Transmembrane Conductance Regulator-Potential Role in Pulmonary Inflammation and Edema Formation.

Sarah Weidenfeld,Wolfgang M Kuebler

doi:10.3389/fimmu.2017.00393

Abstract

Pulmonary edema, a major complication of lung injury and inflammation, is defined as accumulation of extravascular fluid in the lungs leading to impaired diffusion of respiratory gases. Lung fluid balance across the alveolar epithelial barrier protects the distal airspace from excess fluid accumulation and is mainly regulated by active sodium transport and Cl− absorption. Increased hydrostatic pressure as seen in cardiogenic edema or increased vascular permeability as present in inflammatory lung diseases such as the acute respiratory distress syndrome (ARDS) causes a reversal of transepithelial fluid transport resulting in the formation of pulmonary edema. The basolateral expressed Na+-K+-2Cl− cotransporter 1 (NKCC1) and the apical Cl− channel cystic fibrosis transmembrane conductance regulator (CFTR) are considered to be critically involved in the pathogenesis of pulmonary edema and have also been implicated in the inflammatory response in ARDS. Expression and function of both NKCC1 and CFTR can be modulated by released cytokines; however, the relevance of this modulation in the context of ARDS and pulmonary edema is so far unclear. Here, we review the existing literature on the regulation of NKCC1 and CFTR by cytokines, and—based on the known involvement of NKCC1 and CFTR in lung edema and inflammation—speculate on the role of cytokine-dependent NKCC1/CFTR regulation for the pathogenesis and potential treatment of pulmonary inflammation and edema formation.

Highlights

Pulmonary edema, defined as excessive fluid accumulation in the interstitial and air spaces of the lungs, is a life-threatening condition leading to impaired gas exchange and respiratory failure
We propose that cytokine-dependent regulation of Na+-K+-2Cl− cotransporter 1 (NKCC1) and Cl− channel cystic fibrosis transmembrane conductance regulator (CFTR) may play a critical role in lung edema formation and pulmonary inflammation
Formation of pulmonary edema in inflammatory lung diseases is caused by the loss of endothelial and epithelial barrier and impaired fluid and ion transport across the alveolar epithelium

Summary

INTRODUCTION

Pulmonary edema, defined as excessive fluid accumulation in the interstitial and air spaces of the lungs, is a life-threatening condition leading to impaired gas exchange and respiratory failure. Inflammatory responses involving upregulation of pro-inflammatory cytokines including interleukin-1β (IL-1β), IL-8, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) and their accumulation in BALF and edema fluid are a critical hallmark of ARDS [4,5,6,7]. In addition to their role in immune responses, these proinflammatory mediators are considered to inhibit alveolar fluid transport by regulation of sodium and chloride transporter [7]. We first outline the general principles of alveolar fluid transport and the role of inflammatory cytokines in lung edema formation, focus on the role of NKCC1 and CFTR in pulmonary edema and inflammation, and their regulation by cytokines, and conclude by proposing a critical role for cytokine-dependent regulation of NKCC1 and CFTR as a novel concept in the pathogenesis of pulmonary edema

Fluid Transport of Alveolar Epithelium

Edema Formation

CONCLUSION

Findings

AUTHOR CONTRIBUTIONS