Resolution of pulmonary edema. Thirty years of progress

Abstract

In the last 30 years, we have learned much about the molecular, cellular, and physiological mechanisms that regulate the resolution of pulmonary edema in both the normal and the injured lung. Although the physiological mechanisms responsible for the formation of pulmonary edema were identified by 1980, the mechanisms that explain the resolution of pulmonary edema were not well understood at that time. However, in the 1980s several investigators provided novel evidence that the primary mechanism for removal of alveolar edema fluid depended on active ion transport across the alveolar epithelium. Sodium enters through apical channels, primarily the epithelial sodium channel, and is pumped into the lung interstitium by basolaterally located Na/K-ATPase, thus creating a local osmotic gradient to reabsorb the water fraction of the edema fluid from the airspaces of the lungs. The resolution of alveolar edema across the normally tight epithelial barrier can be up-regulated by cyclic adenosine monophosphate (cAMP)-dependent mechanisms through adrenergic or dopamine receptor stimulation, and by several cAMP-independent mechanisms, including glucocorticoids, thyroid hormone, dopamine, and growth factors. Whereas resolution of alveolar edema in cardiogenic pulmonary edema can be rapid, the rate of edema resolution in most patients with acute respiratory distress syndrome (ARDS) is markedly impaired, a finding that correlates with higher mortality. Several mechanisms impair the resolution of alveolar edema in ARDS, including cell injury from unfavorable ventilator strategies or pathogens, hypoxia, cytokines, and oxidative stress. In patients with severe ARDS, alveolar epithelial cell death is a major mechanism that prevents the resolution of lung edema.

Figure 1.

Resolution of pulmonary edema. (A) Bilateral alveolar opacities consistent with extensive alveolar edema in an intubated and ventilated patient. (B) Marked resolution of the bilateral pulmonary opacities in the same patient over a 24-hour period. (C) Standard hematoxylin and eosin–stained section, demonstrating alveolar edema with pink fluid filling most of the alveoli. (D) Normal air-filled alveoli, indicting reabsorption of alveolar edema fluid.

Figure 2.

(A) Normal alveolar fluid clearance pathways. The interstitial, capillary, and alveolar compartments are shown with edema fluid in the alveolus. Type I and II cells are indicated. Apical channels on type I and II cells for absorption of sodium (Na⁺) are shown, including the epithelial sodium channel (ENaC), as well as other apical sodium channels, including nonselective cation channels (NCC), cyclic nucleotide–gated channels (CNG), and other selective cation channels (SCC). Chloride (Cl^–) is shown crossing the alveolar epithelium either by a transcellular or a paracellular route, the latter possibly facilitated by claudins. Water (H₂O) is shown crossing through an aquaporin (AQP) channel or by an intercellular route. Note that the basolaterally located sodium/potassium ATPase pump (Na/K-ATPase) is shown on both type I and II cells. The large purple arrows in the interstitium indicate that after alveolar edema fluid is absorbed into the interstitium, the fluid moves to the lung lymphatics for clearance, which are present in the extraalveolar interstitium. (B) Up-regulated clearance pathways. Shown here are mechanisms by which the rate of alveolar fluid clearance can be increased by exogenous or endogenous factors. The best described mechanism involves cyclic adenosine monophosphate (cAMP), which is an intracellular messenger, stimulated by activation of β receptors on alveolar type I and II cells, which stimulates adenyl cyclase, which increases intracellular cAMP. cAMP can be stimulated by endogenous elevations of epinephrine or exogenous dobutamine or epinephrine. Other mechanisms for increased clearance include dopamine, thyroid hormone, corticosteroids, and growth factors, in particular keratinocyte growth factor. Note in B that the quantity of alveolar edema fluid has declined in the presence of accelerated alveolar fluid clearance. CFTR = cystic fibrosis transmembrane conductance regulator.

Figure 3.

Impaired alveolar fluid clearance. Shown are some of the clinically relevant mechanisms that decrease the rate of alveolar fluid clearance in patients with acute respiratory disease syndrome. Note that type I and type II alveolar epithelial cell necrosis is shown. This is an important mechanism because of the loss of epithelial barrier function and the ability to generate net alveolar epithelial sodium and fluid clearance. The other factors and mechanisms shown are discussed in text.