Abstract
Acute lung injury leading to acute respiratory distress (ARDS) is a global health concern. ARDS patients have significant pulmonary inflammation leading to flooding of the pulmonary alveoli. This prevents normal gas exchange with consequent hypoxemia and causes mortality. A thin fluid layer in the alveoli is normal. The maintenance of this thin layer results from fluid movement out of the pulmonary capillaries into the alveolar interstitium driven by vascular hydrostatic pressure and then through alveolar tight junctions. This is then balanced by fluid reabsorption from the alveolar space mediated by transepithelial salt and water transport through alveolar cells. Reabsorption is a two-step process: first, sodium enters via sodium-permeable channels in the apical membranes of alveolar type 1 and 2 cells followed by active extrusion of sodium into the interstitium by the basolateral Na+, K+-ATPase. Anions follow the cationic charge gradient and water follows the salt-induced osmotic gradient. The proximate cause of alveolar flooding is the result of a failure to reabsorb sufficient salt and water or a failure of the tight junctions to prevent excessive movement of fluid from the interstitium to alveolar lumen. Cytokine- and chemokine-induced inflammation can have a particularly profound effect on lung sodium transport since they can alter both ion channel and barrier function. Cytokines and chemokines affect alveolar amiloride-sensitive epithelial sodium channels (ENaCs), which play a crucial role in sodium transport and fluid reabsorption in the lung. This review discusses the regulation of ENaC via local and systemic cytokines during inflammatory disease and the effect on lung fluid balance.
Highlights
The maintenance of a thin fluid layer on the surface of the alveolar epithelium is critical for respiration
This review focuses on the primary physiological mechanisms required to maintain and regulate this layer and is an overview of the pathophysiological mechanisms of cytokine-mediated ENaC regulation in the lung (Figure 1)
The regulation of ENaC via hormones and G-proteincoupled receptors (GPCRs) is not a primary focus of this review, but we briefly review ENaC activation and regulation via steroids since their actions often interact with the activities of cytokines and chemokines
Summary
The maintenance of a thin fluid layer on the surface of the alveolar epithelium is critical for respiration. Probably because monogenetic disorders often alter ENaC trafficking, much of the focus has examined how regulation of the number of channels at the apical membrane of alveolar epithelial cells can alter Na+ transport. High levels of pulmonary inflammation causing airway tight junction damage that compromise alveolar barrier function is a primary cause of epithelial injury [55].
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