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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


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(A) Schematic model of the normal alveolus (left) and the injured alveolus (right) with edema formation in inflammatory lung disease. In pulmonary inflammation, the epithelial and endothelial barrier become disrupted leading to influx of protein-rich edema fluid and migration of neutrophils from the vasculature into the alveolar space. In the air space, alveolar macrophages secrete proinflammatory cytokines that stimulate chemotaxis and activate neutrophils which in turn produce and release further cytokines. (B) Distribution of epithelial ion transporter and proposed mechanism of alveolar fluid clearance (AFC) (left) and secretion (right). In alveolar type II and presumably also type I cells, AFC is mediated through apical Na+ entry by sodium channels like epithelial Na+ channel (ENac), sodium-coupled amino acid transporter (SNATs), and sodium glucose transporter (SGLT). Basolateral extrusion is driven by Na+-K+-ATPase and sodium hydrogen exchanger (NHE). Water and Cl− follow for electroneutrality. In pulmonary edema, ENaC and probably other sodium transporter are inhibited generating a gradient for Na+ influx via basolateral NKCC1. Cl− enters in cotransport with Na+, and exits along an electrochemical gradient on the apical side through CFTR, resulting in Cl−-driven fluid secretion and formation of lung edema.
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Figure 1: (A) Schematic model of the normal alveolus (left) and the injured alveolus (right) with edema formation in inflammatory lung disease. In pulmonary inflammation, the epithelial and endothelial barrier become disrupted leading to influx of protein-rich edema fluid and migration of neutrophils from the vasculature into the alveolar space. In the air space, alveolar macrophages secrete proinflammatory cytokines that stimulate chemotaxis and activate neutrophils which in turn produce and release further cytokines. (B) Distribution of epithelial ion transporter and proposed mechanism of alveolar fluid clearance (AFC) (left) and secretion (right). In alveolar type II and presumably also type I cells, AFC is mediated through apical Na+ entry by sodium channels like epithelial Na+ channel (ENac), sodium-coupled amino acid transporter (SNATs), and sodium glucose transporter (SGLT). Basolateral extrusion is driven by Na+-K+-ATPase and sodium hydrogen exchanger (NHE). Water and Cl− follow for electroneutrality. In pulmonary edema, ENaC and probably other sodium transporter are inhibited generating a gradient for Na+ influx via basolateral NKCC1. Cl− enters in cotransport with Na+, and exits along an electrochemical gradient on the apical side through CFTR, resulting in Cl−-driven fluid secretion and formation of lung edema.

Mentions: In the intact lung, AFC constantly moves fluid from the alveolar space across the epithelial barrier into the interstitial space. Na+ is actively absorbed on the apical side of alveolar epithelial cells, which is mediated by several sodium channels (Figure 1), most notably the amiloride-sensitive ENaC (9), the sodium glucose transporter (SGLT) (10, 11) and the sodium-coupled neutral amino acid transporter (SNAT) (12–14). On the basolateral surface, Na+ extrusion to the interstitial space is driven through the Na+-K+-ATPase (8) and the Na+/H+ antiporter (15). For electroneutrality and osmotic balance, Cl− and water follow the electrochemical gradient partly paracellularly and partly through aquaporins (specifically aquaporin 5) (16) and chloride channels, predominantly CFTR (17). Although it was thought that channels and transporter are primarily expressed in ATII cells, recent data demonstrated that ATI cells contain ENaC, CFTR, and the Na+-K+-ATPase suggesting a role for ATI cells in alveolar fluid transport (9, 18).


Cytokine-Regulation of Na + -K + -Cl − Cotransporter 1 and Cystic Fibrosis Transmembrane Conductance Regulator — Potential Role in Pulmonary Inflammation and Edema Formation
(A) Schematic model of the normal alveolus (left) and the injured alveolus (right) with edema formation in inflammatory lung disease. In pulmonary inflammation, the epithelial and endothelial barrier become disrupted leading to influx of protein-rich edema fluid and migration of neutrophils from the vasculature into the alveolar space. In the air space, alveolar macrophages secrete proinflammatory cytokines that stimulate chemotaxis and activate neutrophils which in turn produce and release further cytokines. (B) Distribution of epithelial ion transporter and proposed mechanism of alveolar fluid clearance (AFC) (left) and secretion (right). In alveolar type II and presumably also type I cells, AFC is mediated through apical Na+ entry by sodium channels like epithelial Na+ channel (ENac), sodium-coupled amino acid transporter (SNATs), and sodium glucose transporter (SGLT). Basolateral extrusion is driven by Na+-K+-ATPase and sodium hydrogen exchanger (NHE). Water and Cl− follow for electroneutrality. In pulmonary edema, ENaC and probably other sodium transporter are inhibited generating a gradient for Na+ influx via basolateral NKCC1. Cl− enters in cotransport with Na+, and exits along an electrochemical gradient on the apical side through CFTR, resulting in Cl−-driven fluid secretion and formation of lung edema.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383711&req=5

Figure 1: (A) Schematic model of the normal alveolus (left) and the injured alveolus (right) with edema formation in inflammatory lung disease. In pulmonary inflammation, the epithelial and endothelial barrier become disrupted leading to influx of protein-rich edema fluid and migration of neutrophils from the vasculature into the alveolar space. In the air space, alveolar macrophages secrete proinflammatory cytokines that stimulate chemotaxis and activate neutrophils which in turn produce and release further cytokines. (B) Distribution of epithelial ion transporter and proposed mechanism of alveolar fluid clearance (AFC) (left) and secretion (right). In alveolar type II and presumably also type I cells, AFC is mediated through apical Na+ entry by sodium channels like epithelial Na+ channel (ENac), sodium-coupled amino acid transporter (SNATs), and sodium glucose transporter (SGLT). Basolateral extrusion is driven by Na+-K+-ATPase and sodium hydrogen exchanger (NHE). Water and Cl− follow for electroneutrality. In pulmonary edema, ENaC and probably other sodium transporter are inhibited generating a gradient for Na+ influx via basolateral NKCC1. Cl− enters in cotransport with Na+, and exits along an electrochemical gradient on the apical side through CFTR, resulting in Cl−-driven fluid secretion and formation of lung edema.
Mentions: In the intact lung, AFC constantly moves fluid from the alveolar space across the epithelial barrier into the interstitial space. Na+ is actively absorbed on the apical side of alveolar epithelial cells, which is mediated by several sodium channels (Figure 1), most notably the amiloride-sensitive ENaC (9), the sodium glucose transporter (SGLT) (10, 11) and the sodium-coupled neutral amino acid transporter (SNAT) (12–14). On the basolateral surface, Na+ extrusion to the interstitial space is driven through the Na+-K+-ATPase (8) and the Na+/H+ antiporter (15). For electroneutrality and osmotic balance, Cl− and water follow the electrochemical gradient partly paracellularly and partly through aquaporins (specifically aquaporin 5) (16) and chloride channels, predominantly CFTR (17). Although it was thought that channels and transporter are primarily expressed in ATII cells, recent data demonstrated that ATI cells contain ENaC, CFTR, and the Na+-K+-ATPase suggesting a role for ATI cells in alveolar fluid transport (9, 18).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus