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INVITED REVIEW

Mechanisms of pulmonary edema clearance

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

	ABSTRACT

TOP ABSTRACT ALVEOLAR EPITHELIUM REGULATION OF ALVEOLAR FLUID... INHIBITION OF ALVEOLAR FLUID... FUTURE DIRECTIONS CONCLUSIONS GRANTS REFERENCES

 
The mechanisms of pulmonary edema resolution are different from those regulating edema formation. Absorption of excess alveolar fluid is an active process that involves vectorial transport of Na⁺ out of alveolar air spaces with water following the Na⁺ osmotic gradient. Active Na⁺ transport across the alveolar epithelium is regulated via apical Na⁺ and chloride channels and basolateral Na-K-ATPase in normal and injured lungs. During lung injury, mechanisms regulating alveolar fluid reabsorption are inhibited by yet unclear pathways and can be upregulated by pharmacological means. Better understanding of the mechanisms that regulate edema clearance may lead to therapeutic interventions to improve the ability of lungs to clear fluid, which is of clinical significance.

acute lung injury; acute respiratory distress syndrome; alveolar epithelium; alveoli lung

View larger version (53K): [in this window] [in a new window]   Fig. 1. Lung edema is cleared by active Na+ transport where Na+ moves vectorially across the alveolo-capillary barrier mostly via apical Na+ channels and basolaterally located Na-K-ATPase with water following isosmotically the Na+ gradient. AQPS, aquaporins; ENaC, amiloride-sensitive epithelial Na+ channel; ONaC; amiloride-insensitive Na+ channel; OCl–, other chloride channels.

	ALVEOLAR EPITHELIUM

TOP ABSTRACT ALVEOLAR EPITHELIUM REGULATION OF ALVEOLAR FLUID... INHIBITION OF ALVEOLAR FLUID... FUTURE DIRECTIONS CONCLUSIONS GRANTS REFERENCES

Under normal conditions, the alveolo-capillary barrier has a very low permeability to solutes (69, 186). Tight junctions are critical for the alveolar epithelial barrier function as they connect adjacent epithelial cells and modulate dynamic permeability via distinct ion-selective channels and pores (73, 168). The diffusion of solutes across the alveolar epithelium is much slower than through the intercellular junctions of the adjacent lung capillaries (75, 167, 170, 177). Radii of the pores for small solute movement across the alveolar epithelium and pulmonary capillary endothelium have been estimated to be 0.6–1.0 and 4–5.8 nm, respectively (43, 44). As such, most of the resistance to albumin flux across the alveolo-capillary barrier is due to alveolar epithelium, which has a higher reflection coefficient for proteins than the capillary endothelium (69, 167, 186).

Transepithelial osmotic gradient created by the active Na⁺ transport represents the major driving force for water reabsorption. Sodium enters the alveolar epithelial cell via amiloride-sensitive and -insensitive channels in the apical surface, and then it is "pumped out" via the basolateral surface into the lung interstitium and the pulmonary circulation by the Na-K-ATPase.

Among two types of epithelial cells, the AT2 cell has been better studied. Previously, it was thought that the AT2 cell is responsible for the majority of the vectorial transport of Na⁺ across the alveolar epithelial barrier (56, 68, 109, 110, 114, 123, 154). However, recently, an important role for AT1 cell in vectorial Na⁺ transport has been demonstrated, and it appears that the ₂ Na-K-ATPase isozyme expressed mostly in AT1 cells is responsible for 60% of Na⁺ transport (23, 89, 154, 155). Freshly isolated AT1 cells have the highest osmotic permeability to water of any mammalian cell, possibly contributed by aquaporin (AQP)-5 (46). Similar to Na-K-ATPase, there is evidence for the presence of all three subunits of epithelial Na⁺ channel (ENaC) in AT1 cells (22). This new evidence strongly supports the role of the AT1 cells in vectorial ion transport.

In addition to alveolar epithelial cells, distal airway epithelium may also contribute to fluid clearance (2, 7, 25, 26, 82, 202). Supporting evidence for the contribution of distal airways includes active Na⁺ absorption by Clara cells and regulation by cystic fibrosis transmembrane conductance regulator (CFTR) (190, 191), but because of their smaller surface area, distal airways probably contribute to a smaller degree to the overall fluid reabsorption (2, 7, 25, 26, 82).

Apical Sodium Channels

Transepithelial Na⁺ transport at the apical surface of alveolar epithelial cells is mediated predominantly by amiloride-sensitive Na⁺ channels (ENaC) and also in part by other, less well-characterized cationic channels (16). The ENaC consists of three subunits, -, -, and -ENaC (31, 119) and is widely distributed in epithelia such as lung, kidney, and colon. The ENaCs are expressed along the respiratory tract epithelia as well as in the apical surface of alveolar epithelial cells (28, 52, 113, 150) usually as a tetramer made of two -, one -, and one -subunit or a much larger complex made of nine subunits (3 from each subunit) (58, 96, 176). In Xenopus oocyte studies, amiloride-sensitive sodium transport was detected when only -ENaC was injected; however, maximal transport required the presence of all three subunits (32, 122). Whereas highly selective channels (HSCs) are composed of -, -, and -subunits, nonselective channels (NSCs) are composed of -subunit alone and moderately selective channels are some combination of -subunit with and (83, 84). The HSC has a high Na⁺/K⁺ selectivity (Na⁺/K⁺ permeability ratio >40), is insensitive to Ca²⁺, and has a conductance of 4–6 pS. The NSC has equal permeability for both Na⁺ and K⁺ (Na⁺/K⁺ 1.5) with a conductance of 21–28 pS. It is voltage dependent, Ca²⁺ activated (at high doses), and completely inhibited by 1 µM amiloride (53).

The importance of ENaC in fluid transport is supported by studies in transgenic mice with targeted deletions of ENaC subunits. In both animal and human lungs, the expression of -ENaC is greater than that of - and -subunits (35, 38, 41, 83, 111, 117, 123, 137, 166, 185, 187). Mice with targeted deletion of -ENaC die with pulmonary edema within 40 h of birth (78). Mice lacking - or -ENaC are able to clear fluid out of alveolar space, albeit at a lower rate compared with wild type. On the other hand, these animals die from hyperkalemia due to abnormal handling of electrolytes in the kidneys (8, 118).

Amiloride-Insensitive Sodium Channels

Lack of complete inhibition of Na⁺ transport in the alveolar epithelial cells by amiloride suggests the presence of amiloride-insensitive pathways contributing to alveolar fluid reabsorption (85, 135, 136, 174). The impact of amiloride-sensitive Na⁺ channel on Na⁺ transport in the lungs is species dependent. Whereas amiloride inhibits up to 90% of sodium transport in mice, the relative contribution of ENaC to alveolar fluid clearance is smaller (40–60%) in other species such as rats, sheep, rabbits, and human lung. There are also differences within the same species. For example, while only 20% of fluid clearance is amiloride insensitive in CD-1 mice, it is 40% in C57Bl6 mice (76).

Among these, cyclic nucleotide-gated cation channels (CNG) have been suggested to play a role in fluid absorption in distal lung epithelia (90, 92, 171). Cyclic guanosine monophosphate is the second messenger for CNG channels, and they are inhibited by dichlorobenzamyl and L-cis-diltiazem (171). One of the three isoforms of CNG, CNG1 channel, is widely distributed in human epithelial cells and expressed in the lung, particularly in distal airway and alveolar epithelia (45).

Another pathway for amiloride-insensitive fluid transport is the Na⁺-glucose transporter, which is inhibited by phloridzin (13). However, luminal glucose does not have any effect on fluid transport in mice (80). Similar to Na⁺-glucose, the role of other cotransporters (i.e., Na⁺-amino acid) is yet to be defined.

Chloride Channel

Apical membrane chloride channels have functional and pharmacological properties similar to those of CFTR. The CFTR is a cAMP-regulated Cl^– channel expressed on the apical surface of airway and alveolar epithelial cells (133). Gating of CFTR is tightly regulated by the phosphorylation of the regulatory domain via cAMP and activation of PKA (64).

Activation of CFTR increases the amiloride-sensitive fluid absorption (51). Although lack of CFTR gene (targeted deletion of F508 –/–) does not appear to affect lung fluid homeostasis at baseline, it is important in the regulation of fluid clearance during hydrostatic pulmonary edema (51). Lack of increase in alveolar fluid clearance in response to -agonists suggests the interdependency between CFTR and ₂-adrenergic receptors (₂ARs) and importance of CFTR in cAMP-mediated regulation of fluid clearance (51, 129).

Na-K-ATPase

The sodium pump (Na-K-ATPase) located on the basolateral surface of the alveolar epithelial cell transports ions by consuming ATP and pumping Na⁺ out of the cell in exchange for potassium influx to maintain Na⁺ and potassium gradients across the plasma membrane. The basolateral membrane location of the Na-K-ATPase is crucial for alveolar fluid reabsorption where the vectorial Na⁺ transport is followed by water in an isosmolar manner.

The Na,K-ATPase is expressed in both AT1 and AT2 cells (23, 89, 138, 154, 169). It is a heterodimeric protein composed of an - and a -subunit. The -subunit cleaves high-energy phosphate bonds and has the catalytic site for the exchange of intracellular Na⁺ for extracellular K⁺ (172). The -subunit is a smaller glycosylated transmembrane protein that appears to control the heterodimer assembly and insertion into the plasma membrane (120). Both subunits are required for a functional Na-K-ATPase (39, 120). Interestingly, overexpression of the ₁- or the ₂-subunit increases Na-K-ATPase expression and thus alveolar fluid clearance in adult rats and fetal alveolar epithelial cells (50, 152, 154, 188). The short-term regulation of Na-K-ATPase activity is regulated by the changes in Na-K-ATPases at the plasma membrane via recruitment of the Na⁺ pump proteins from intracellular compartments via dephosphorylation and phosphorylation events involving protein phosphatase 2A PKC and Rho-associated kinase (18–20, 39, 100, 101, 153). Long-term regulation of the Na-K-ATPase is elicited by stimulation of dopaminergic (D_2A) and ₂ARs via transcription and translational mechanisms (71, 72, 144, 145).

Aquaporins

Transcellular water channels or AQPs have been localized to the lung (193). In mice and rats, AQP-1 is expressed in both the apical and basolateral membrane of endothelial cells and fibroblasts (95), and AQP-3, AQP-4, and AQP-5 are found on both apical and basolateral membranes at different locations of respiratory tract epithelium (94). In the human respiratory system, AQP-5 is expressed in the apical surface of alveolar AT1 cells and in the nasopharyngeal epithelium, and AQP-3 is expressed at the apical membrane of columnar epithelial, basal, and AT2 cells (97).

Studies in transgenic mice with targeted deletions of AQPs have suggested that AQPs are not essential for alveolar fluid clearance (193). A limitation of these and other transgenic mice studies is that while absence of AQPs did not limit the rate of fluid clearance from the alveoli, compensatory mechanisms could have taken place. It is also possible that AQPs may be important in regulation of cell volume, especially of alveolar AT1 cell (77) and of fluid secretion from mucus-secreting cells (104).

	REGULATION OF ALVEOLAR FLUID ABSORPTION

TOP ABSTRACT ALVEOLAR EPITHELIUM REGULATION OF ALVEOLAR FLUID... INHIBITION OF ALVEOLAR FLUID... FUTURE DIRECTIONS CONCLUSIONS GRANTS REFERENCES

 
Although active Na⁺ transport appears to be the primary mechanism by which catecholamines regulate lung edema clearance across alveolar epithelium, stimulation of Cl^– uptake may also contribute to alveolar fluid clearance (87, 88, 114, 139).

-Adrenergic Receptor-Mediated Regulation

Both endogenous and exogenous catecholamines stimulate alveolar fluid reabsorption in newborn and adult animals via activation of -adrenergic receptors (ARs) (17, 27, 33, 37, 57, 85, 107, 136, 146, 156, 161). Similar to catecholamines, both nonspecific AR agonists and those specific for ₂AR, such as salmeterol and terbutaline, increase fluid reabsorption of rat (85), dog (15), guinea pig (135), mice (62, 65, 80), and human lungs (156, 157). Interestingly, AR stimulation does not increase alveolar fluid clearance in rabbits and hamsters (174).

Both ₁ARs and ₂ARs are present in the membrane of AT2 cells (11, 49). The AR-mediated increase in alveolar fluid clearance is due to the upregulation of ENaC, chloride channel, and Na-K-ATPase (20, 67, 85, 111, 130, 135, 146, 180) (Fig. 2). The cAMP serves as the second messenger for the stimulatory effects of AR agonists (14), regulating ENaC open-state probability (108, 110, 180) and increasing protein abundance of ENaC and Na-K-ATPases at the plasma membrane (21, 29, 54, 88, 175), which leads to increased Na⁺ transport across the alveolar epithelial cells (6, 10, 17–20, 39, 48, 159, 163). These effects can occur within 1 min via highly regulated translocation of Na⁺ pump proteins due to phosphorylation of the intermediary cytoskeletal proteins and RhoA kinase (20, 34, 100). Interestingly, activation of ARs also increases Na-K-ATPase long term (>24 h) (145) via increased translation of the Na-K-ATPase (144) and ENaC (40) via PKA- and PKC-induced phosphorylation of cAMP-responsive elements and posttranscriptional regulation via MAPK/ERK and rapamycin-sensitive pathways (144, 145). Overexpression of ₂AR increases alveolar fluid clearance in transgenic mice (121) and in mice and rats with adenoviral-mediated overexpression of ₂AR (48, 130).

View larger version (23K): [in this window] [in a new window]   Fig. 2. Simulation of 2-adrenergic receptors increases pulmonary edema clearance by increasing alveolar epithelial ion (Na+ and Cl–) transport via upregulation of epithelial Na+ channels, cystic fibrosis transmembrane conductance regulator, and Na-K-ATPase. AC, adenylyl cyclase; 2AR, 2-adrenergic receptor; EGFR, epithelial growth factor receptor; ENaC, epithelial Na+ channel; G, G protein; mTOR, mammalian target of rapamycin; MEK, mitogen-activated protein/extracellular signal-regulated kinase kinase; PI3K, phosphatidylinositol 3'-kinase; PKA, protein kinase A; P70s6K, 70-kDa ribosomal protein S6 kinase.

The ₂AR-mediated upregulation of active alveolar Na⁺ transport makes exogenous ₂-agonist use a promising therapeutic option for management of pulmonary edema (131). However, receptor desensitization remains a well-known limitation of this therapy (131). Desensitization includes loss of signaling upon subsequent engagement by agonists (homologous desensitization), downregulation of membrane-bound receptors, and inhibition/alteration of downstream effector pathways (heterologous desensitization).

Although these processes have been extensively studied in myocytes and airway smooth muscle cells, recently, more data regarding desensitization of alveolar ₂AR became available. Morgan and colleagues (127, 128) have reported that sustained infusion of high-dose isoproterenol (400 µg·kg^–1·h^–1) impairs ₂-agonist-induced alveolar active Na⁺ transport in rats; however, other groups using albuterol have noted downregulation of receptor number but not loss of effect on alveolar active Na⁺ transport (165). More interestingly, Morgan and colleagues have shown that sustained, high-dose albuterol infusion diminishes adenylyl cyclase and PKA activity, providing the first evidence of heterologous receptor desensitization in the alveolar epithelium (128).

Other Mechanisms of Edema Clearance Regulation

There are several AR-independent mechanisms that may contribute to fluid clearance in distal air spaces (Table 1). Catecholamines and -adrenergic agonists may upregulate alveolar active Na⁺ transport and increase edema clearance independent of AR stimulation (4). Among other AR-independent mechanisms are dopamine, hormones such as glucocorticoids and mineralocorticoids, and cellular growth factors such as epidermal growth factor (EGF), transforming growth factor- (TGF-), fibroblast growth factor-10 (FGF-10), keratinocyte growth factor (KGF), hepatocyte growth factor, thyroid hormone, and leukotriene D₄ (LTD₄) (1, 9, 10, 12, 42, 47, 59, 81, 103, 112, 132, 150, 173, 184, 187, 189, 198, 199).

View larger version (25K): [in this window] [in a new window]   Fig. 3. Dopamine increases alveolar fluid clearance in lungs via activation of D1 receptor (D1R; short term) and D2 receptor (D2R; long term).

Lung epithelial cells express mineralocorticoid receptors as well as 11--hydroxysteroid dehydrogenase, an enzyme responsible for conversion of corticosterone into 11-dehydrocorticosterone. Similar to other epithelial cells, aldosterone increased the number of highly selective channels (84) and alveolar fluid clearance by increasing mRNA and ₁ and ₁ Na-K-ATPase proteins in AT2 cells (142).

Growth factors. Several growth factors including EGF, TGF-, KGF, and FGF-10 have been reported to regulate alveolar fluid clearance. For example, EGF increased both ₁ and ₁ Na-K-ATPase mRNA and protein and increased lung liquid clearance (42, 184). EGF did not change in ENaC subunits but induced nonselective cation channels in cultured AT2 cells (42, 91). The TGF- increased cAMP activity and alveolar fluid clearance via increased tyrosine kinase, which is stimulated by both EGF and TGF- (59, 112, 132). KGF, a heparin-binding growth factor, has been shown to increase alveolar fluid clearance as a mitogen for AT2 cells (195). Pretreatment with KGF prevented ventilator-induced lung injury as well as hydrostatic pulmonary edema (198, 199). Although hyperplasia of AT2 cells appears to be the major mechanism of KGF-mediated increase in alveolar fluid clearance, it may also contribute to the increased expression of ENaC and Na-K-ATPase (3, 24). FGF-10 is also a potent mitogen of alveolar epithelial cells. It is structurally similar to KGF and has short-term (15 min) effects on alveolar epithelial cells by increasing Na-K-ATPase activity via Grb2-SOS/Ras/MAPK pathway (189).

Cysteine leukotriene levels are elevated during acute lung injury in animals and may play a role in upregulation of alveolar active Na⁺ transport. LTD₄ increased alveolar fluid clearance by upregulating Na-K-ATPase activity (173). Last, exogenous thyroid hormone administration, particularly 3,3',5-triiodo-L-thyronine, increases active Na⁺ transport by stimulation of Na-K-ATPase (103).

	INHIBITION OF ALVEOLAR FLUID REABSORPTION

TOP ABSTRACT ALVEOLAR EPITHELIUM REGULATION OF ALVEOLAR FLUID... INHIBITION OF ALVEOLAR FLUID... FUTURE DIRECTIONS CONCLUSIONS GRANTS REFERENCES

 
In several models of lung injury, the ability of the lungs to clear alveolar fluid is impaired, which is particularly relevant to clinical situations, as described by Ware and Matthay (197). Although the lung epithelium is relatively more resistant to injury than the endothelium (126), alveolar fluid clearance, which is a marker of alveolar epithelial cell function, is altered during both hydrostatic pulmonary edema (5, 160, 192) and various models of acute lung injury (61, 98, 102, 125, 179).

Hydrostatic Pulmonary Edema

Mechanisms of pulmonary edema clearance have been reported to be impaired in animal models of hydrostatic pulmonary edema independently of the mechanisms regulating edema formation (5, 160, 192). Elevation of left atrial pressure decreased alveolar fluid clearance via increased atrial natriuretic peptide (ANP) (30, 141). Lung serves as a target organ for ANP as well as a site of synthesis and has the highest tissue concentration of binding sites for ANP (74, 149). Some patients with cardiogenic pulmonary edema may have clearance rates >3% per hour (192) due to elevated levels of catecholamines, which may mask the deleterious effects of ANP released in response to left atrial hypertension (30), the presence of circulatory ouabain-like substances (55), and regional hypoxia. In ex vivo lung models, acute elevation of left atrial pressure inhibits active Na⁺ transport possibly by decreasing the number of Na-K-ATPase at the basolateral membrane of alveolar epithelial cells (5, 6, 160).

Acute Lung Injury

Alveolar fluid clearance mechanisms are inhibited in several models of lung injury even when the injury to the distal lung epithelium is not associated with gross disruption of the alveolo-capillary barrier (140, 183). Most patients with noncardiogenic pulmonary edema have impaired ability to clear alveolar fluid (197). However, those who clear edema rapidly (a minority of these patients) have better outcomes (116, 181, 182, 196, 197). However, in some models of lung injury, the lung's capacity to clear fluid out of alveolar air spaces can be upregulated (146). The increase in alveolar fluid clearance is usually mediated by surges of endogenous catecholamines acting on ARs as reported during hemorrhagic shock (124), bacterial pneumonia (151), and subacute models such as moderate hyperoxia (66, 183). Whereas increase in alveolar fluid clearance is mediated by ARs during hemorrhagic shock, increase in Na⁺ transport across alveolar epithelium during bacterial pneumonia appears to depend on tumor necrosis factor-, which may have a direct effect on ENaC (63, 151).

More severe lung injury is associated with decreased fluid clearance out of the alveoli. For example, the effects of bacterial sepsis on alveolar fluid clearance depend on the extent of the lung injury. Although alveolar fluid clearance is enhanced if the alveolar epithelium is intact, it is significantly reduced when injury is associated with alveolar flooding. Similar to bacterial sepsis models of lung injury, acid aspiration (125), smoke inhalation (98), ventilator-associated lung injury (61, 102), and reperfusion injury after lung transplantation (179) are also associated with decreased alveolar fluid clearance.

The effect of hyperoxia on alveolar fluid clearance depends on the duration and the degree of hyperoxia. In the model of acute hyperoxic lung injury (100% O₂ for 64 h), Na-K-ATPase activity and clearance are decreased (143). In contrast to hypoxia (39, 194) and acute hyperoxia, subacute hyperoxic lung injury (85% O₂ for 7 days) is associated with an increase in active Na⁺ transport and edema clearance due to the upregulation of amiloride-sensitive apical Na⁺ channels and alveolar epithelial Na-K-ATPases (183, 204).

Hypoxia impairs active Na⁺ transport across the alveolar epithelium (36, 39, 106, 194) and inhibits ENaC and Na-K-ATPase activity (36, 39, 105, 106, 147, 148, 194, 203). Short-term severe hypoxia inhibits Na-K-ATPase activity by phosphorylating the Na⁺ pump, triggering it to endocytose via generation of mitochondrial reactive oxygen species activating atypical PKC- (39). Prolonged hypoxia promotes degradation of the Na⁺ pump via the ubiquitin/proteosome pathway (unpublished observations).

Persistence of lung edema in patients with lung injury is due to both increased permeability of the alveolo-capillary barrier and decreased ability of the alveolar epithelium to clear edema. Although some of the excess edema fluid is removed via the pleura and the lung lymphatic systems, active Na⁺ transport from the alveoli into the pulmonary circulation is the major pathway for removal of alveolar edema, which is cleared even in the absence of pulmonary blood flow in ex vivo models (70, 86, 158).

TGF-1 directly increases the permeability of endothelial and epithelial cell monolayers (79, 201), which appears to be dose and time dependent. TGF-1 at low concentrations (5- to 10-fold lower than what is required to increase alveolar epithelial permeability) has been shown to decrease alveolar epithelial fluid transport by inhibiting ENaC via MAPK, ERK1/2 pathway (60). However, these results contrast those from another study that showed an increase in alveolar Na⁺ transport in response to TGF-1 (201). It is noteworthy that the increase in alveolar Na⁺ transport occurred after 72 h, suggesting that the increase in alveolar fluid clearance in response to TGF-1 may represent an adaptive mechanism in response to increased permeability.

	FUTURE DIRECTIONS

TOP ABSTRACT ALVEOLAR EPITHELIUM REGULATION OF ALVEOLAR FLUID... INHIBITION OF ALVEOLAR FLUID... FUTURE DIRECTIONS CONCLUSIONS GRANTS REFERENCES

 
The understanding of the mechanisms of pulmonary edema clearance has advanced significantly since the report by Matthay et al. (115), who in 1982 demonstrated that alveolar fluid was reabsorbed via an active metabolic process. Initially, it was proposed that alveolar epithelial type 2 cells solely effected active Na⁺ transport; however, more recently it been shown that AT1 cells (which cover >90% of the alveolar epithelial surface area) contribute 60% to active Na⁺ transport and thus alveolar fluid reabsorption. Further studies are warranted to better evaluate the role of AT1 cells and the distal airway epithelium as well as the role of chloride channels and their regulation.

	CONCLUSIONS

TOP ABSTRACT ALVEOLAR EPITHELIUM REGULATION OF ALVEOLAR FLUID... INHIBITION OF ALVEOLAR FLUID... FUTURE DIRECTIONS CONCLUSIONS GRANTS REFERENCES

 
The mechanisms of resolution of pulmonary edema are different from those of edema formation. Resolution of excess alveolar fluid is an active metabolic process that involves vectorial transport of Na⁺ out of alveolar air spaces with water following the osmotic gradient. Regulation of Na⁺ transport across alveolar epithelium is mediated by apical Na⁺ and chloride channels and basolateral Na-K-ATPases. Mechanisms that maintain the alveoli free of edema may be impaired during acute lung injury. Understanding these mechanisms is of importance for the development of novel therapeutic strategies to resolve lung edema and normalize the alveolar epithelial function.

	GRANTS

TOP ABSTRACT ALVEOLAR EPITHELIUM REGULATION OF ALVEOLAR FLUID... INHIBITION OF ALVEOLAR FLUID... FUTURE DIRECTIONS CONCLUSIONS GRANTS REFERENCES

 
This work was supported by National Heart, Lung, and Blood Institute Grants HL-48129, HL-65161, and PO1–71643 (J. I. Sznajder), American Heart Association, American Lung Association, American Lung Association of Metropolitan Chicago, and Northwestern Memorial Foundation (G. M. Mutlu).

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. I. Sznajder, Pulmonary and Critical Care Medicine, Northwestern Univ. Medical School, 240 E. Huron, McGaw 2300, Chicago, IL 60611 (e-mail: j-sznajder{at}northwestern.edu)

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