Bench-to-bedside review: the role of the alveolar epithelium in the resolution of pulmonary edema in acute lung injury

Abstract

Clearance of pulmonary edema fluid is accomplished by active ion transport, predominantly by the alveolar epithelium. Various ion pumps and channels on the surface of the alveolar epithelial cell generate an osmotic gradient across the epithelium, which in turn drives the movement of water out of the airspaces. Here, the mechanisms of alveolar ion and fluid clearance are reviewed. In addition, many factors that regulate the rate of edema clearance, such as catecholamines, steroids, cytokines, and growth factors, are discussed. Finally, we address the changes to the alveolar epithelium and its transport processes during acute lung injury (ALI). Since relevant clinical outcomes correlate with rates of edema clearance in ALI, therapies based on our understanding of the mechanisms and regulation of fluid transport may be developed.

Figure 1

The distal airway epithelium contains alveolar type I and type II cells and Clara cells, which possess various pumps and channels that achieve clearance of edema fluid. Sodium is transported through channels on the apical membrane and extruded from the cell by the Na⁺/K⁺-ATPase located on the basolateral membrane. This transport generates a sodium gradient that drives the transport of water, which is accomplished in part through water channels. AQP, aquaporin; CFTR, cystic fibrosis transmembrane conductance regulator; CNG, cyclic nucleotide-gated; ENaC, epithelial Na⁺channel. From Matthay and coworkers [3], with permission from the American Physiological Society.

Figure 2

Catecholamines stimulate alveolar fluid clearance – an effect that can be inhibited by β-blockers or amiloride. This suggests that the mechanism by which catecholamines upregulate fluid transport is mediated by β-adrenergic receptors and depends on the transport of sodium through epithelial sodium channels. From Sakuma and coworkers [17], with permission from the American Thoracic Society.

Figure 3

In severe acute lung injury (ALI) the alveolar epithelium is damaged to such an extent that epithelial repair is needed before fluid clearance can be achieved. In contrast, in mild ALI the epithelium and its transport functions are spared, and so pharmacologic stimulation of fluid clearance is possible. If epithelial cell proliferation occurs after injury, either endogenously or due to the administration of mitogens such as keratinocyte growth factor, then fluid clearance may be enhanced. From Berthiaume and coworkers [93], with permission from Thorax.

Figure 4

In patients with acute lung injury, the rate of edema clearance correlates with important clinical outcomes such as survival. From Ware and Matthay [49], with permission from the American Thoracic Society.