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
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.
Keywords: 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.
(Received in original form January 27, 2005; accepted in final form March 9, 2005)
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: [email protected]
Proc Am Thorac Soc Vol 2. pp 202–205, 2005
DOI: 10.1513/pats.200501-006AC
Internet address: www.atsjournals.org
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).
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␣ and the
hypoxia insensitive subunit HIF-1␤. During normoxia, HIF-1␣
is polyubiquinated and targeted for proteosomal degradation by
the E3 ligase von Hippel-Lindau (VHL) protein complex. VHL
binding to HIF-1␣ is dependent on hydroxylation of proline
residues within HIF-1␣ and the hydroxylation reaction is oxygen
dependent. Thus, during hypoxia VHL fails to bind HIF-1␣,
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
Jain and Sznajder: Hypoxia in Alveolar Epithelium
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.
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
203
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.
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 move-
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.
204
ment 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 ␤2-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
␤-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,KATPase (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-␨, 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
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 2 2005
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.
Conflict of Interest Statement : Neither author has a financial relationship with a
commercial entity that has an interest in the subject of this manuscript.
References
1. Ouiddir A, Planes C, Fernandes I, VanHesse A, Clerici C. Hypoxia upregulates activity and expression of the glucose transporter GLUT1 in
alveolar epithelial cells. Am J Respir Cell Mol Biol 1999;21:710–718.
2. Suzuki S, Noda M, Sugita M, Ono S, Koike K, Fujimura S. Impairment
of transalveolar fluid transport and lung Na(⫹)-K(⫹)-ATPase function by hypoxia in rats. J Appl Physiol 1999;87:962–968.
3. Suzuki S, Sugita M, Noda M, Tsubochi H, Fujimura S. Effects of intra-
Jain and Sznajder: Hypoxia in Alveolar Epithelium
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
alveolar oxygen concentration on alveolar fluid absorption and metabolism in isolated rat lungs. Respir Physiol 1999;115:325–332.
Semenza GL. Regulation of mammalian O2 homeostasis by hypoxiainducible factor 1. Annu Rev Cell Dev Biol 1999;15:551–578.
Heerlein K, Schulze A, Hotz L, Bartsch P, Mairbaurl H. Hypoxia decreases cellular ATP-demand and inhibits mitochondrial respiration
of A549 cells. Am J Respir Cell Mol Biol 2005;32:44–51.
Simon LM, Robin ED, Raffin T, Theodore J, Douglas WH. Bioenergetic
pattern of isolated type II pneumocytes in air and during hypoxia. J
Clin Invest 1978;61:1232–1239.
Pham I, Uchida T, Planes C, Ware LB, Kaner R, Matthay MA, Clerici
C. Hypoxia upregulates VEGF expression in alveolar epithelial cells
in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 2002;283:
L1133–L1142.
Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza
GL. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 1996;16:4604–4613.
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara
JM, Lane WS, Kaelin WG Jr. HIFalpha targeted for VHL-mediated
destruction by proline hydroxylation: implications for O2 sensing. Science 2001;292:464–468.
Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ,
Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex
by O2-regulated prolyl hydroxylation. Science 2001;292:468–472.
Schroedl C, McClintock DS, Budinger GR, Chandel NS. Hypoxic but
not anoxic stabilization of HIF-1alpha requires mitochondrial reactive
oxygen species. Am J Physiol Lung Cell Mol Physiol 2002;283:L922–
L931.
Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxiainduced transcription. Proc Natl Acad Sci USA 1998;95:11715–11720.
Vaux EC, Metzen E, Yeates KM, Ratcliffe PJ. Regulation of hypoxiainducible factor is preserved in the absence of a functioning mitochondrial respiratory chain. Blood 2001;98:296–302.
Chandel NS, Budinger GR, Choe SH, Schumacker PT. Cellular respiration during hypoxia. Role of cytochrome oxidase as the oxygen sensor
in hepatocytes. J Biol Chem 1997;272:18808–18816.
Matthay MA, Wiener-Kronish JP. Intact epithelial barrier function is
critical for the resolution of alveolar edema in humans. Am Rev Respir
Dis 1990;142:1250–1257.
Karhausen J, Ibla JC, Colgan SP. Implications of hypoxia on mucosal
barrier function. Cell Mol Biol (Noisy-le-grand) 2003;49:77–87.
Furuta GT, Turner JR, Taylor CT, Hershberg RM, Comerford K, Narravula S, Podolsky DK, Colgan SP. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function
during hypoxia. J Exp Med 2001;193:1027–1034.
Wodopia R, Ko HS, Billian J, Wiesner R, Bartsch P, Mairbaurl H.
Hypoxia decreases proteins involved in epithelial electrolyte transport
in A549 cells and rat lung. Am J Physiol Lung Cell Mol Physiol
2000;279:L1110–L1119.
Vivona ML, Matthay M, Chabaud MB, Friedlander G, Clerici C. Hypoxia
reduces alveolar epithelial sodium and fluid transport in rats: reversal
by beta-adrenergic agonist treatment. Am J Respir Cell Mol Biol 2001;
25:554–561.
Matthay MA, Folkesson HG, Verkman AS. Salt and water transport
across alveolar and distal airway epithelia in the adult lung. Am J
Physiol 1996;270:L487–L503.
Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD,
Rossier BC. Amiloride-sensitive epithelial Na⫹ channel is made of
three homologous subunits. Nature 1994;367:463–467.
Sakuma T, Okaniwa G, Nakada T, Nishimura T, Fujimura S, Matthay
MA. Alveolar fluid clearance in the resected human lung. Am J Respir
Crit Care Med 1994;150:305–310.
Brochiero E, Dagenais A, Prive A, Berthiaume Y, Grygorczyk R. Evidence of a functional CFTR Cl(-) channel in adult alveolar epithelial
cells. Am J Physiol Lung Cell Mol Physiol 2004;287:L382–L392.
McCann JD, Welsh MJ. Basolateral K⫹ channels in airway epithelia: II.
Role in Cl- secretion and evidence for two types of K⫹ channel. Am
J Physiol 1990;258:L343–L348.
Crandall ED, Matthay MA. Alveolar epithelial transport. Basic science
to clinical medicine. Am J Respir Crit Care Med 2001;163:1021–1029.
205
26. Song Y, Fukuda N, Bai C, Ma T, Matthay MA, Verkman AS. Role of
aquaporins in alveolar fluid clearance in neonatal and adult lung, and
in oedema formation following acute lung injury: studies in transgenic
aquaporin null mice. J Physiol 2000;525:771–779.
27. Hackett PH. Mountain sickness: prevention, recognition and treatment.
New York: American Alpine Club; 1980.
28. Maggiorini M, Melot C, Pierre S, Pfeiffer F, Greve I, Sartori C, Lepori
M, Hauser M, Scherrer U, Naeije R. High-altitude pulmonary edema
is initially caused by an increase in capillary pressure. Circulation 2001;
103:2078–2083.
29. Scherrer U, Sartori C, Lepori M, Allemann Y, Duplain H, Trueb L,
Nicod P. High-altitude pulmonary edema: from exaggerated pulmonary hypertension to a defect in transepithelial sodium transport. Adv
Exp Med Biol 1999;474:93–107.
30. Gowen CW Jr, Lawson EE, Gingras J, Boucher RC, Gatzy JT, Knowles
MR. Electrical potential difference and ion transport across nasal
epithelium of term neonates: correlation with mode of delivery, transient tachypnea of the newborn, and respiratory rate. J Pediatr 1988;
113:121–127.
31. Sartori C, Duplain H, Lepori M, Egli M, Maggiorini M, Nicod P, Scherrer
U. High altitude impairs nasal transepithelial sodium transport in
HAPE-prone subjects. Eur Respir J 2004;23:916–920.
32. Sartori C, Allemann Y, Duplain H, Lepori M, Egli M, Lipp E, Hutter
D, Turini P, Hugli O, Cook S, et al. Salmeterol for the prevention of
high-altitude pulmonary edema. N Engl J Med 2002;346:1631–1636.
33. Bertorello AM, Ridge KM, Chibalin AV, Katz AI, Sznajder JI. Isoproterenol increases Na⫹-K⫹-ATPase activity by membrane insertion of
alpha-subunits in lung alveolar cells. Am J Physiol 1999;276:L20–L27.
34. Mairbaurl H, Wodopia R, Eckes S, Schulz S, Bartsch P. Impairment of
cation transport in A549 cells and rat alveolar epithelial cells by hypoxia. Am J Physiol 1997;273:L797–L806.
35. Planes C, Escoubet B, Blot-Chabaud M, Friedlander G, Farman N, Clerici
C. Hypoxia downregulates expression and activity of epithelial sodium
channels in rat alveolar epithelial cells. Am J Respir Cell Mol Biol
1997;17:508–518.
36. Carpenter TC, Schomberg S, Nichols C, Stenmark KR, Weil JV. Hypoxia
reversibly inhibits epithelial sodium transport but does not inhibit lung
ENaC or Na-K-ATPase expression. Am J Physiol Lung Cell Mol
Physiol 2003;284:L77–L83.
37. Dada LA, Chandel NS, Ridge KM, Pedemonte C, Bertorello AM,
Sznajder JI. Hypoxia-induced endocytosis of Na,K-ATPase in alveolar
epithelial cells is mediated by mitochondrial reactive oxygen species
and PKC-zeta. J Clin Invest 2003;111:1057–1064.
38. Comellas AP, Pesce LM, Dada LA, Lecuona E, Zacharaias A, Budinger
GS, Chandel N, Ciechanove A, Sznajder JI. Mitochodrial ROS mediate hypoxia-induced degradation on Na,K-ATPase in alveolar epithelial cells. Am J Respir Crit Care Med 2003;167:A663.
39. Qayyum I, Zubrow AB, Ashraf QM, Kubin J, Delivoria-Papadopoulos
M, Mishra OP. Nitration as a mechanism of Na⫹, K⫹-ATPase modification during hypoxia in the cerebral cortex of the guinea pig fetus.
Neurochem Res 2001;26:1163–1169.
40. Brown KR, England KM, Goss KL, Snyder JM, Acarregui MJ. VEGF
induces airway epithelial cell proliferation in human fetal lung in vitro.
Am J Physiol Lung Cell Mol Physiol 2001;281:L1001–L1010.
41. Clauss M, Weich H, Breier G, Knies U, Rockl W, Waltenberger J, Risau
W. The vascular endothelial growth factor receptor Flt-1 mediates
biological activities: implications for a functional role of placenta
growth factor in monocyte activation and chemotaxis. J Biol Chem
1996;271:17629–17634.
42. Ridge K, Ni N. Hypoxia regulates the expression of keratin 8 and 18 in
alveolar epithelial cells. Am J Respir Crit Care Med 2004;169:A213.
43. Strassberg S, Godi I, Pandya D, Dudhbhai A, Parton L. Proinflammatory
mediators amplify the apoptotic response of human lung cells during
hypoxia. Am J Respir Crit Care Med 2004;169:A797.
44. Krick S, Appel J, Haenze J, Schmidt S, Weissman NGH, Grimminger
F, Schermuly R, Seeger W, Rose F. Hypoxia syngergistically enhances
Ang II induced apoptosis in alveolar epithelial cells by the activation
of HIF-1 alpha and Ang II receptor type 1 [abstract]. Am J Respir
Crit Care Med 2003;167:A798.
45. Haddad JJ, Land SC. The differential expression of apoptosis factors in
the alveolar epithelium is redox sensitive and requires NF-kappaB
(RelA)-selective targeting. Biochem Biophys Res Commun 2000;271:
257–267.