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The Proceedings of the American Thoracic Society 2:202-205 (2005)
© 2005 The American Thoracic Society

Effects of Hypoxia on the Alveolar Epithelium

Manu Jain and Jacob Iasha Sznajder

Pulmonary Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

Correspondence and requests for reprints should be addressed to Jacob I. Sznajder, M.D., Pulmonary and Critical Care Medicine, The Feinberg School of Medicine, Northwestern University, 240 E. Huron, McGaw 2-2300, Chicago, IL 60611. E-mail: j-sznajder{at}northwestern.edu

ABSTRACT

An important role of the alveolar epithelium is to contribute to the alveolocapillary barrier, secrete surfactant to lower the surface tension, and clear edema. These are energy-requiring processes for which normal oxygenation is required. There are many clinical conditions in which alveolar epithelial cells are exposed to low oxygen concentrations and although they can adapt to hypoxia, there are alterations in cellular function that can impact clinical outcomes. Hypoxic alveolar cells maintain cellular ATP content by increasing glycolytic capacity and via the hypoxia inducible factor-1 activation of a myriad of genes including the vascular endothelial growth factor. In addition, they decrease ATP utilization by downregulating the high energy consuming Na,K-ATPase activity and protein synthesis. The alveolar epithelium is in close apposition to vascular endothelium, which facilitates efficient gas exchange and provides a physical barrier between luminal and interstitial/vascular spaces. Alveolar edema clearance is an active process requiring activity of many proteins of which the amiloride-sensitive sodium channel (ENaC) and Na,K-ATPase are important contributors. Exposure to hypoxia impairs alveolar edema clearance by mechanisms that downregulate both ENaC and the Na,K-ATPase function. Other effects of hypoxia on alveolar cell function include surfactant production, disruption of cytoskeleton integrity, and the triggering of apoptosis. In summary, hypoxia has deleterious effects on the alveolar epithelium. More research needs to be done to better understand the effects of hypoxia on alveolar epithelia cell and lung function.

Key Words: alveolar barrier • hypoxia • ENaC • Na,K-ATPase • oxygen

The most important cellular role for oxygen is in ATP synthesis via the mitochondrial electron transport chain, which is termed oxidative phosphorylation. O2 is exchanged across the alveolar capillary membrane, and with normal ventilation at sea level the alveolar O2 partial pressure is about 100 mm Hg. There are, however, a number of clinical conditions under which the alveolar epithelium is exposed to much lower oxygen tensions. For example, during high-altitude ascent a decreased oxygen tension can occur as the consequence of lower barometric pressure. This can be exacerbated by the development of high-altitude pulmonary edema (HAPE), which is characterized by flooding of the alveolar spaces. More commonly, alveolar hypoxia can develop during acute lung injury, or congestive heart failure. There is abundant information on the effects of hypoxia on the pulmonary endothelium, such as hypoxic vasoconstriction and gene regulation via hypoxia inducible factor (HIF). However, relatively little is known about the effects of hypoxia on alveolar epithelial cell function. We will review alterations in alveolar epithelial cellular function in response to acute hypoxia, which has been less studied.

HYPOXIA: CELLULAR ADAPTATION

Several studies have indicated that cells tolerate hypoxia remarkably well. For example, in vitro, alveolar epithelial cells exposed to anoxia (0% O2 for 18 h), have a transient decrease in ATP content at 3 h, but this reverses and increases progressively to match normoxic controls at 18 h (1). Similarly, rats exposed to 10% oxygen for 48 h maintained their lung ATP content comparable to normoxic controls (2).

Mammalian cells are able to maintain oxidative phosphorylation down to very low oxygen concentrations. Nevertheless, as they encounter lower oxygen levels they summon mechanisms to prevent oxygen depletion and maintain cellular ATP levels in order to prevent cell death. There are two general mechanisms that cells invoke during hypoxia to prevent oxygen depletion (Figure 1). First, cells attempt to maintain ATP synthesis by increasing glycolysis (3), and upregualting vascular endothelial growth factor (VEGF) (4). The increase in VEGF stimulates angiogenesis, which increases oxygen delivery during hypoxia. Second, because a tight coupling exists between oxygen availability and ATP-requiring cellular processes, cells downregulate ATP using pathways in order to decrease cellular respiration rates and oxygen demand (5).



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  		Figure 1. Cells adapt to hypoxia by two general mechanisms. The first is an attempt to maintain ATP levels: cells increase glycolytic activity and angiogenesis. The second is by downregulating ATP-requiring processes such as Na,K-ATPase and protein synthesis.

 
Glycolysis is an alternative, albeit a relatively inefficient, mechanism by which cells generate ATP. Hypoxic cells can upregulate pyruvate kinase and phosphofructokinase, both glycolytic enzymes, and increase lactate production. This is consistent with the hypothesis of increased glycolysis in response to a fall in ambient oxygen levels (6). In addition, hypoxia has been shown to induce stimulation of glucose transport into cells (1) in association with a threefold increase of the glucose transporter, GLUT1, at both protein and mRNA levels. Interestingly, the increase in GLUT1 activity is HIF–dependent.

In addition to upregulating glycolysis, alveolar epithelial cells induce vascular endothelial growth factor (VEGF) (7) by the transcription factor HIF-1 during hypoxia (8). HIF-1 is a heterodimer composed of the hypoxia-sensitive subunit HIF-1{alpha} and the hypoxia insensitive subunit HIF-1ß. During normoxia, HIF-1{alpha} is polyubiquinated and targeted for proteosomal degradation by the E3 ligase von Hippel-Lindau (VHL) protein complex. VHL binding to HIF-1{alpha} is dependent on hydroxylation of proline residues within HIF-1{alpha} and the hydroxylation reaction is oxygen dependent. Thus, during hypoxia VHL fails to bind HIF-1{alpha}, allowing it to accumulate (9, 10) and increase VEGF expression and regulate approximately 100 other genes. The mechanisms by which cells sense hypoxia are being elucidated, and generation of mitochondrial reactive oxygen species (ROS) has been proposed to play a role (11, 12), though this point is controversial (13).

Cells exposed to hypoxia for 60 s do not decrease oxygen consumption (14); however, as cells are exposed to longer periods of hypoxia, oxygen consumption decreases. Oxygen consumption of A549 cells, a transformed alveolar epithelial cell line, decreases by 25% after 5 min of hypoxia (1.5% O2) and by 35% after 24 h (5). The fall in oxygen consumption is almost completely reversible after 5 min, but there is no recovery if the cells are exposed to hypoxia for 24 h. Similar results are seen in primary rat alveolar type II cells in which protein synthesis and Na,K-ATPase activity account for about 20 to 30% of total oxygen consumption (5). O2 use for protein synthesis falls an additional 30% when hypoxia is extended to 24 h, and is then not reversible. Residual oxygen consumption, that is in pathways other that Na,K-ATPase activity and protein synthesis, decreases by 28% and 61% after 5 min and 24 h of hypoxia, respectively (5).

ALVEOLAR EPITHELIAL BARRIER FUNCTION

Mucosal tissues provide a physical barrier between biological compartments, separating the luminal space from the cellular interstitium and vascular space. The close apposition between the alveolar epithelium and the vascular endothelium facilitates the efficient exchange of gases and also forms a barrier to movement of liquid and proteins from the interstitial and vascular spaces. The establishment and maintenance of a selectively permeable barrier occurs through interactions of domains between adjacent cells (e.g., adherens junctions, tight junctions) via highly regulated events that establish cell polarity (Figure 2). In addition, it confers vectorial transport properties to the epithelium, since ion transporters and other membrane proteins are asymmetrically distributed on opposing cell surfaces. Movement of ions and cells through transcellular pathways is complemented by movement of molecules via selective pores between epithelial cells. The characteristics of this paracellular pathway contribute substantially to the establishment of the epithelial permeability barrier.



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  		Figure 2. Domain interactions between tight and adherens junctions maintain a selectively permeable barrier. Desmosenes externally maintain together cells within a tissue, and internally anchor intermediate filaments.

 
Alveolar epithelial cells form a tight barrier that restricts passage of lipid-insoluble molecules between alveolar and interstitial spaces. Breach of normal barrier function often translates into development of pulmonary edema such as in patients with ARDS who present with severe hypoxemia (15). There have been specific permeability factors identified that contribute to the severity of the disease, but the role of hypoxia in the changes of epithelial barrier function are not fully understood.

In cell culture models, polarization of epithelia and maintenance of the permeability barrier depends in large part on cell–cell contact mediated by adherens and tight junctions (16). There is scant information on the effects of hypoxia on these structures in different epithelia (17). Animal experiments have failed to discern measurable effects of hypoxia on alveolar barrier function. Rats exposed to 10% oxygen have similar lung-wet-dry weight (2, 18) and permeability to large solutes (2) compared with normoxic controls. Similarly, no differences were found between hypoxic rats (8% O2 for 24 h) and normoxic controls when 125I-albumin flux was used to assess alveolar epithelial integrity (7, 19). These animal studies, however, have evaluated movement of relatively large molecules, and it is possible that permeability to smaller molecules through the epithelia barrier is affected by moderate or severe hypoxia. Alternatively, prolonged hypoxia (i.e., > 24 h) may affect more pronounced permeability changes.

HYPOXIA AND LUNG EDEMA CLEARANCE

During acute hypoxemic respiratory failure, alveoli flood with edema, thus impairing the transfer of oxygen from the airspaces into the pulmonary circulation. Transport of Na+ and edema reabsorption from alveolar spaces into interstitial and vascular spaces is critical to improving hypoxemia and restoring normal lung function. Transport of Na+ is an active process that requires sodium uptake at the apical surface of alveolar epithelial cells, predominantly via amiloride-sensitive (ENaC) (20, 21) and amiloride-insensitive (22) pathways. Apical chloride anion movement occurs via the cystic fibrosis transmembrane regulator (23) and possibly other chloride channels. At the basolateral membrane, Na+ is actively extruded against a gradient in exchange for K+ into the interstitium predominantly by Na,K-ATPase, hydrolyzing ATP in the process (24), and water follows the Na+ osmotic gradient (25), via aquaporins. However, aquaporins seem not to be rate-limiting in edema fluid clearance from the airspaces (26).

As mentioned above, HAPE is a life-threatening condition characterized by alveolar flooding and occurs in predisposed individuals at altitudes greater than 8,000 feet (27). Oxygen tensions fall dramatically during ascent to high altitude, and several reports suggest that exaggerated hypoxic pulmonary vasoconstriction plays a primary role in HAPE pathogenesis (28, 29). Recent observations suggest, however, that effects of hypoxia on the alveolar epithelium may play a role as well. Investigators have used nasal potential differences (NPD) to quantify transepithelial sodium transport in humans and feel that nasal and airway epithelia exhibit similar membrane bioelectric and ion transport properties (30). Compared with HAPE-resistant controls, individuals prone to HAPE have lower baseline NPD, which decreases further at high altitude (31). In addition, upregulation of Na,K-ATPase activity by prophylactic administration of the ß2-adrenergic agonists can decrease the incidence of HAPE in susceptible individuals (32). These findings are consistent with the hypothesis that hypoxia impairs transepithelial sodium transport in humans and that ß-adrenergic stimulation can reverse this process by upregulating Na,K-ATPase (33).

The human evidence adds to previous experimental evidence that hypoxia downregulates epithelial sodium and fluid transport. Both A549 cells and rat ATII cells in culture exhibit a fall in transcellular Na+ transport when exposed to hypoxia (34). As outlined above, transcellular movement of Na+ and water requires multiple components and hypoxia impacts virtually all of them. Exposure to severe hypoxia for 3 to 12 h inhibits Na+ channel activity as measured by amiloride-sensitive 22Na+ influx in rat ATII cells (35). Reoxygenation for 48 h restored Na+ channel activity and ENaC mRNA levels. Experiments in A549 cells suggest that the fall in ENaC activity due to hypoxia may result from fewer membrane-bound ENaC channels (18).

The mechanisms by which hypoxia downregulates Na,K-ATPase (2, 35) are better understood. Some reports have suggested that though hypoxia downregulates the plasma cell membrane Na,K-ATPase activity, it has no impact on whole cell Na,K-ATPase protein levels (19, 36). To reconcile these observations, it is worth noting that Na,K-ATPase activity can be regulated by changes in its affinity for substrates or through the traffic of Na,K-ATPase molecules between the plasma membrane and intracellular compartments (33). In A549 cells, hypoxia (1.5% O2 for 60 min) decreased Na,K-ATPase activity by promoting the endocytosis of the Na,K-ATPase protein (37). Dada and coworkers reported that during severe hypoxia, mitochondrial ROS activate PKC-{zeta}, which phosphorylates Na,K-ATPase at Serine 18 of the N-terminus and triggers endocytosis of the Na+ pump (37). This results in fewer Na,K-ATPase pumps at the plasma membrane and decreased Na,K-ATPase activity, though whole cell Na,K-ATPase protein abundance is not changed. The effects of short-term severe hypoxia (up to 1 h) are reversible upon oxygenation.

However, if cells are exposed to severe hypoxia for prolonged periods of time, the cellular pool of Na,K-ATPase does begin to fall. A549 cells exposed to severe hypoxia (1.5% O2) degrade the ATP-consuming plasma cell Na+ pumps by 50% within 2 h, while the intracellular pools of Na,K-ATPase are stable for more than 24 h of hypoxia (38). We speculate that this is an adaptive mechanism by which cells degrade first the most metabolically active Na+ pumps (i.e., those in the plasma membrane) in an effort to minimize oxygen consumption. The fall in Na,K-ATPase protein levels is prevented by ROS and proteasome/lysosome inhibitors, implicating the ubiquitin pathway and mitochondrial ROS in the degradation of the Na,K-ATPase as a mechanism of cell adaptation. Other mechanisms of hypoxia-mediated modulation of Na,K-ATPase have also been proposed. Peroxynitrite production during hypoxia has been shown to decrease activity of brain Na,K-ATPase (39).

MISCELLANEOUS EFFECTS OF HYPOXIA ON ALVEOLAR EPITHELIAL FUNCTION

There have been several other observations of the effects of hypoxia on alveolar epithelial cells that may have clinical implications. In addition to its role in angiogenesis, VEGF effects on alveolar epithelial cells may induce epithelial cell proliferation (40), increase surfactant protein production (40), and induce immune cell recruitment to the alveolar space (41). These effects would have potential implications in the development of and recovery from acute lung injury.

Hypoxia appears to disturb the cell cytoskeleton in alveolar epithelial cells, specifically intermediate filaments (42). The functional significance of this finding is not clear, but changes in the IF network could compromise desmosome function and increase permeability of the epithelial barrier.

Finally, there are preliminary reports that A549 cells may undergo apoptosis at an accelerated rate under hypoxic stress, and this effect is augmented when accompanied by inflammatory mediators (43) (e.g., IL-6 and IL-8) or angiotensin II (44). The presence of antiinflammatory (e.g., IL-1Ra and IL-10) mediators attenuated the response to hypoxia (43). In contrast to these reports is the observation that there is no increase in apoptotic or necrotic cell death of fetal alveolar type II cells when exposed to approximately 3% O2 for 24 h (45) and there was increased expression of the antiapoptotic factor Bcl-2. The reason(s) for this discrepancy are not clear. The role of hypoxia on alveolar apoptotic cell death would have clinical implications for both acute and chronic lung diseases.

SUMMARY

Exposing the alveolar epithelium to hypoxic conditions has significant adverse effects on epithelial function. Important observations have been made recently on the effects of acute hypoxia on alveolar epithelial function. We have reviewed the deleterious effects of hypoxia on transepithelial Na+ transport and thus the ability of the lungs to clear edema. There is also preliminary data on the impact of hypoxia on cellular bioenergetics, tight junctions, apoptosis, and intermediate filaments. However, not much is known about the impact of hypoxia on surfactant production, innate immune defense, or cell differentiation. Further work is needed to better comprehend the effects of hypoxia on alveolar epithelial function and to design optimal therapeutic strategies to prevent these deleterious effects.

FOOTNOTES

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form January 27, 2005; accepted in final form March 9, 2005)

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