Modification of sodium transport and alveolar fluid clearance by hypoxia: mechanisms and physiological implications.

Abstract

In order for gas exchange to occur optimally, the alveoli must remain open and free from fluid. In utero, the fetal lung is filled with fluid which is removed shortly after birth, mainly because active reabsorption of sodium ions (Na ) across the alveolar epithelium creates an osmotic force favoring reabsorption of alveolar fluid (1, 2). The classic studies from Dr. Matthay’s laboratory showing reabsorption of intratracheally instilled isotonic fluid or plasma from the alveolar spaces of adult anesthetized animals, and the partial inhibition of this process by amiloride and ouabain, implied that adult alveolar epithelial cells are also capable of actively transporting sodium (Na ) ions (reviewed in Ref. 3). In the adult lung, active Na reabsorption plays an important role in limiting the degree of alveolar edema in pathologic conditions in which the alveolar epithelium has been damaged. For example, blocking Na transport increased lung water in rats exposed to hyperoxia (4). Conversely, intratracheal instillation of adenoviral vectors containing copies of the Na ,K -ATPase genes increased survival of rats exposed to hyperoxia (5). Patients with acute lung injury who were able to concentrate alveolar protein (as a result of active Na reabsorption) had a better prognosis than those that did not (6, 7). Presently, it has not been definitely established whether or not active Na transport also plays an important role in maintaining the normal alveoli free of fluid. Additional insight into the nature and regulation of transport pathways has been derived from electrophysiologic studies in freshly isolated and cultured alveolar type II (ATII) cells: Na ions diffuse passively into ATII cells through apically located amiloride-sensitive, amilorideinsensitive, and cGMP-gated cation channels with conductances of 4–25 pS (8, 9) and are extruded across the basolateral membranes by the ouabain-sensitive Na ,K -ATPase (10). To preserve neutrality, chloride (Cl ) ions move from the apical to the basolateral compartments either through the paracellular junctions and/or through chloride channels located in alveolar epithelial cells (11, 12). In situ hybridization studies identified the presence of two of the three subunits of the cloned epithelial Na channel ( ENaC and ENaC) in the alveolar region of both fetal and adult lungs (13). Currently there is controversy as to whether ENaC per se or ENaC-type channels (i.e., channels with biophysical properties distinct from those of ENaC) are the main pathways for Na entry into ATII cells (14). There have been numerous studies attempting to identify whether decreased alveolar fluid clearance (AFC) contributes to alveolar edema formation in a variety of pathophysiologic conditions. The results of several studies suggest that severe alveolar hypoxia results in decreased AFC and Na transport ( see Table 1). This is of major interest because alveolar hypoxemia may be encountered in a variety of pathologic conditions including hypoventilation, obstructive lung disease, and ascent to high altitude (15). To investigate the mechanisms responsible for the downregulation of AFC during hypoxia, Vivona and colleagues exposed rats to physiologic levels of hypoxia (8% O 2 for up to 24 h) and measured AFC in situ and ENaC and Na ,K -ATPase mRNA and protein in isolated ATII cells (16). They reported that alveolar hypoxia decreased both the total and amiloride-sensitive portion of AFC and that these changes were ameliorated by intratracheal instillation of a 2 agonist. Surprisingly, levels of -ENaC and 1 and 1 -Na ,K -ATPase in ATII cells remained unchanged. These findings are highly significant because not only do they provide new insight into the mechanism of edema formation during ascent to high altitude, but they also highlight a potential therapeutic strategy to decrease edema and improve gas exchange. Furthermore, the results of these studies clearly point out that it is not always possible to extrapolate changes in function from biochemical and molecular biology measurements. The methodology of measuring AFC in vivo was introduced by Matthay and coworkers almost twenty years ago (17). In this set of experiments, AFC was measured in nonventilated rats with cardiac arrest. At first glance, this seems contradictory to the basic premise, namely that alveolar fluid clearance depends on the presence of an energy-requiring Na ,K -ATPase. However, previous studies have shown that constant levels of AFC can be maintained for brief periods of time following cessation of ventilation ( Received in original form August 23, 2001 )