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Eur Respir J 2002; 20:1299-1313
Copyright ©ERS Journals Ltd 2002

Alveolar epithelial fluid transport in acute lung injury: new insights

C. Sartori and M.A. Matthay

Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA

CORRESPONDENCE: M.A. Matthay, Cardiovascular Research Institute, 505 Parnassus Avenue, HSW-825, University of California San Francisco, San Francisco, CA, 94143-0130, USA

Keywords: acute respiratory distress syndrome, ß2-adrenergic agonists, alveolar fluid clearance, pulmonary oedema

Received: March 18, 2002
Accepted April 16, 2002

Abstract

Pulmonary oedema is a life-threatening condition that frequently leads to acute respiratory failure. From a physiological perspective, pulmonary oedema develops either because of an increase in lung vascular hydrostatic pressure or an increase in lung vascular permeability. Resolution of alveolar oedema depends on the active removal of salt and water from the distal air spaces of the lung across the distal lung epithelial barrier.

Much has been learned about the molecular and cellular basis for oedema fluid reabsorption, including the role of apical ion transporters for sodium (epithelial sodium channel) and chloride (cystic fibrosis transmembrane conductance regulator), as well as the central importance of the sodium pump. The rate of fluid clearance can be upregulated by both catecholamine-dependent and -independent mechanisms.

Injury to the alveolar epithelium can disrupt the integrity of the alveolar barrier or downregulate ion transport pathways, thus, reducing net alveolar fluid reabsorption and enhancing the extent of alveolar oedema. Endogenous catecholamines upregulate alveolar fluid clearance in several experimental models of acute lung injury, but this upregulation may be short term and insufficient to counterbalance alveolar flooding. There is new evidence, however, that pharmacological treatment with ß2-adrenergic agonists and/or epithelial growth factors may influence a more sustained stimulation of alveolar fluid reabsorption and in turn facilitate recovery from experimental pulmonary oedema. Similar results have been achieved experimentally by gene transfer to enhance the abundance of sodium transporters in the alveolar epithelium.

Clinical studies show that impaired alveolar fluid transport mechanisms contribute to the development, severity and outcome of pulmonary oedema in humans. Very recent data suggest that mechanisms that augment transepithelial sodium transport and enhance the clearance of alveolar oedema may lead to more effective prevention or treatment for some types of pulmonary oedema.

Pulmonary oedema is a life-threatening condition resulting from an imbalance between forces driving fluid into the airspaces and biological mechanisms for its removal. Although, for many years, Starling forces (hydrostatic and protein osmotic pressures) were thought to play a major role in maintaining the alveolar space free of fluid 1, there is now strong evidence that active ion transport across the alveolar epithelium creates an osmotic gradient that leads to water reabsorption both during the perinatal period 2–4 and in the adult lung 5. The present article reviews 1) new insights into the basic mechanisms regulating vectorial transport of salt and water across the alveolar epithelium of normal adult lung; 2) summarises current understanding of the role of transport mechanisms in the setting of experimental acute lung injury (ALI); 3) describes current pharmacological interventions designed to upregulate alveolar fluid clearance; and 4) considers how this new knowledge regarding salt and water transport in the alveolar epithelium in pathological conditions may be relevant to human clinical medicine.

Sodium and water transport across the normal respiratory epithelium

The epithelial sodium channel and sodium/potassium adenosine triphosphatase
Results from several studies indicate that sodium can enter the apical membranes of alveolar epithelial cells through amiloride-sensitive cation channels, such as the amiloride-sensitive epithelial sodium channel (ENaC) 6–8, and is then transported across the basolateral membrane into the interstitium by the ouabain-inhibitable sodium/potassium adenosine triphosphatase (Na+/K+-ATPase) 8, 9. The pathway for chloride transport has not been worked out but recent studies have begun to explore this issue 10. Water follows passively, probably through water channels (the aquaporins (AQPs) 11, 12), although the presence of these water channels is not required for maximal alveolar epithelial fluid transport in the lung 13.

In situ hybridisation studies, as well as Northern blot analyses, have identified the presence of messenger ribonucleic acid (mRNA) encoding all three subunits of the ENaC in alveolar epithelial cells both in vivo and in vitro 14–20. The physiological importance of the {alpha}-subunit of the ENaC in the lung has been demonstrated in a mouse model in which the {alpha}-subunit gene was deleted. These {alpha}-ENaC-knockout mice were unable to clear liquid from their lungs during the perinatal period, developed respiratory distress and died within 40 h of birth 2. Recent studies of alveolar epithelial transport indicate that 80–90% of basal alveolar fluid clearance is amiloride-inhibitable in adult mice, suggesting that the ENaC may indeed be the predominant cation channel in that species. However, in other species such as sheep 21, rats 22 and humans 23, amiloride only inhibits 40–50% of basal alveolar fluid clearance (fig. 1Go). Therefore, either modifications of the ENaC or non-ENaC channels may be involved in active sodium transport in species other than the mouse 24. Consistent with this hypothesis, patch-clamp studies in rat alveolar epithelial cells have failed to identify the classical amiloride-sensitive sodium channel in alveolar epithelial cells, suggesting that apical sodium entry may also be mediated by other cation channels with different single channel conductance 18, 19.



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  		Fig. 1.— Alveolar fluid clearance at baseline ({square}) and after intratracheal amiloride instillation () in different animal species. Important interspecial differences in basal alveolar fluid clearance rates have been identified. The slowest have been measured in dogs, intermediate in sheep and goats, and highest in rabbits and rats, and most recently in mice. The basal alveolar fluid clearance rate in the human lung has been difficult to estimate, but, based on the isolated nonperfused human lung model, appears to be intermediate to fast. Although, in most other species, humans included, amiloride inhibits at best 50% of alveolar fluid clearance, this amiloride sensitivity reaches almost 90% in mice, suggesting a unique major contribution of the apical sodium channels in this species.

 
Several other cation channels have been identified in alveolar type II cells 18. One of these, the nonselective cation channel, can be inhibited by amiloride, further suggesting that, in parallel with the ENaC, it could contribute to sodium transport across the alveolar epithelium 25, 26. Molecular characterisation of these other channels is needed.

Na+/K+-ATPase is a ubiquitous plasma membrane, ion-transporting ATPase that maintains transmembrane gradients of Na+ and K+ by pumping Na+ out of the cell and K+ into the cell against their respective concentration gradients. It is widely believed that a heterodimeric form comprising the {alpha}1- and ß1-subunits is the predominant sodium pump isoform expressed in alveolar epithelial type II cells, although expression of the {alpha}2-subunit has also been reported in rat cells 27. The catalytic {alpha}-subunit binds to and cleaves the high-energy phosphate bond of adenosine triphosphate, whereas the ß-subunit is apparently responsible for the assembly and normal insertion of the enzyme complex into the plasma membrane 28, 29. A recent review provides fuller details regarding the possible interaction and cellular localisation of the ENaC and Na+/K+-ATPase 30.

Regulation of alveolar transepithelial sodium transport
Studies in vitro have indicated that there is usually parallel independent regulation of apically localised sodium transport processes and basolaterally located Na+/K+-ATPase in response to a variety of stimuli, including hormones, such as catecholamines, dopamine, glucocorticoids, thyroid hormone and insulin, and growth factors (fig. 2Go, table 1Go). The intracellular sodium concentration appears to be responsible, in certain cases, for the coupling of the sodium pump and cation channel activities 31, 32.



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  		Fig. 2.— Schematic representation of the possible transporters involved in ion and water transport in alveolar cells. ENaC: apical amiloride-sensitive epithelial sodium channel; CFTR: cystic fibrosis transmembrane conductance regulator; Na+/K+-ATPase: sodium/potassium adenosine triphosphatase.

 

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  		Table 1 Summary of possible mechanisms of regulation of ion and water transport in the lung

 
Catecholamine-dependent mechanisms
This is the most extensively studied stimulatory mechanism of transepithelial sodium transport and alveolar fluid clearance. Several in vivo studies have demonstrated that ß2-adrenergic agonists can upregulate alveolar fluid clearance in rats 33, sheep 21 and dogs 34, as well as in mice 35, 36. In most of these studies, a rise in alveolar protein concentration in the distal airspaces of the lungs provided an index of alveolar fluid clearance since alveolar fluid is removed much more rapidly than protein 37. The ß2-agonist effect is mediated in part by cyclic adenosine monophosphate (cAMP)-dependent mechanisms 38, is partially inhibited by amiloride and seems to be unrelated to the increased pulmonary blood flow simultaneously induced by these drugs 21. It is noteworthy that endogenous catecholamines do not play a major role under normal conditions, as demonstrated by the unaltered alveolar fluid clearance in adrenalectomised animals 39, as well as in studies showing no effect of ß-blockers on basal alveolar clearance in sheep 21, rats 22 and the ex vivo human lung 23.

ß2-Adrenergic agonists are effective when delivered intravenously or directly into the distal airspaces of the lung 21, 40. Although early studies indicated that the primary stimulating effect was mediated by ß2-receptors, recent work indicates that ß1 stimulation is also effective in upregulating alveolar fluid clearance 41. Consistent with these data, ß1- and ß2-receptors are present on both the apical and basolateral surface of alveolar epithelium 42.

Interestingly, some species do not respond to ß2-adrenergic agonists with an increase in alveolar fluid transport, in particular rabbits and hamsters 43, 44. Therefore, studies in the ex vivo human lung have been particularly important in establishing the response of human alveolar epithelium to ß2-adrenergic agonists. Several studies have indicated that ß2-adrenergic agonists markedly enhance the rate of alveolar fluid clearance in ex vivo human lung preparations 23, 45. The magnitude of this effect is similar to that observed in other species, with a ß2-agonist-dependent doubling of alveolar fluid clearance over the baseline level.

Proposed mechanisms for stimulation of active sodium absorption across the alveolar epithelium include increases in sodium pump {alpha}-subunit phosphorylation and quantity delivered to the basolateral cell membrane 18, 46, augmented apical sodium channel (both ENaCs and nonselective cation channels 47) abundance and open probability 8, 48, augmented {alpha}-ENaC and {alpha}1-Na+/K+-ATPase gene expression 46, and increased transport of the ENaC from the cytoplasm to the cell membrane 49.

Other reports indicate that, in the airways, cystic fibrosis transmembrane conductance regulator (CFTR) can regulate the ENaC 50. This hypothesis has gained new strength recently. Indeed, indirect stimulation of transcellular sodium movement by stimulation of an apical chloride conductance in the presence of ß2-agonists or cAMP has been reported by different groups 10, 51, 52. This hypothesis suggests that a critical factor in upregulating fluid clearance might be chloride, rather than simply transepithelial sodium absorption. Consistent with this possibility, preliminary data suggest that ß2-agonist stimulation of alveolar fluid clearance is absent in mutant mice deficient in the CFTR channel and in in situ lung of wildtype mice instilled with the chloride channel inhibitor, glibenclamide 53.

Sodium channels and sodium pump activity in the plasma membrane can be regulated by other mechanisms, including acute regulation by covalent or allosteric modification, and acute intracellular trafficking between the endoplasmic reticulum, intracellular endosomal pools and the plasma membrane 49. Colchicine, which impairs intracellular microtubular transport of proteins from intracellular stores to the plasma membrane, inhibits the increase in Na+/K+-ATPase subunit abundance induced by ß2-agonists, suggesting that upregulation is achieved, at least in part, by recruitment of preformed ion-transporting proteins from intracellular pools to the plasma membrane 54. Recent data also indicate that ß2-agonists can increase Na+/K+-ATPase activity by insertion of increased numbers of {alpha}-subunits, recruited from late endosomes, into the plasma membrane 55.

Chronic regulation of the abundance of channels and pumps in the membrane is mediated not only by changes in channel synthesis but also by their rates of degradation. Indeed, ENaC activity appears to depend on channel stability at the membrane, a process regulated by degradation via ubiquitination 56. Finally, there is increasing evidence supporting a new, previously undiscovered, mechanism for autocrine regulation of the ENaC by a serine protease (channel-activating protease 1) expressed in kidney, gut, lung, skin and ovary 57. The mechanisms underlying these latter processes are not yet known.

Vasoactive agents and hormones
Dobutamine markedly upregulates alveolar epithelial fluid clearance in rats by stimulating ß2-receptors 40, whereas dopamine upregulates alveolar fluid transport by stimulating the dopaminergic D1 receptor 54, 58.

Glucocorticoids and thyroid hormone increase respiratory transepithelial sodium transport during the foetal and perinatal period in several animal species 59, 60. Recent observations suggests that these hormones may modulate ENaC and Na+/K+-ATPase gene expression in the lung 15, 17 and also play a significant role in upregulating fluid clearance in adult animals 61.

Insulin can cause increased sodium transport across cultured alveolar type II cells, especially when added to the basolateral membrane 62, by increasing the open probability of ENaCs 63. There is also some data showing that oestrogens may increase ENaC expression 64. However, it is not clear whether the concentrations needed to increase sodium transport in vitro occur in the lung interstitium in vivo.

Other catecholamine-independent mechanisms
In addition to the well-studied effects of ß2-adrenergic agonists, several catecholamine-independent pathways can increase the rate of alveolar fluid clearance. Incubation of epidermal growth factor with isolated alveolar type II cells for 24–48 h increases their capacity to transport sodium 65; it also upregulates alveolar fluid clearance in rats 66. Keratinocyte growth factor (KGF), an important alveolar epithelial type II cell mitogen, induces a similar effect, primarily by stimulating alveolar type II cell proliferation 67–69. In a recent study, one dose of KGF (5 mg·kg body weight–1) produced sustained upregulation of alveolar fluid clearance over 5 days in rats 67. Interestingly, addition of terbutaline, a ß2-adrenergic agonist, further accelerated the rate of alveolar fluid clearance by 50% per hour. Transforming growth factor-{alpha} (TGF-{alpha}) can increase alveolar fluid clearance acutely in anaesthetised ventilated rats 70. Interestingly, since cAMP levels were only minimally increased in alveolar type II cells isolated from rats exposed to TGF-{alpha}, it is possible that the TGF-{alpha} effect may be mediated by an alternative signal transduction pathway that does not require elevation of cAMP levels. Since the effect was inhibited by genistein, the mechanism may involve a tyrosine kinase pathway 71.

Downregulation of alveolar fluid transport can occur with reactive oxygen or nitrogen species or with severe hypoxia. Reactive oxygen/nitrogen at concentrations similar to the one potentially released by activated macrophages downregulates the activity of alveolar type II cell sodium channels 71, 72 as well as amiloride-sensitive currents in oocytes injected with ENaCs 73. Similar effects have been observed in alveolar type II cells exposed to hypoxia for 12–18 h (see below) 74.

Initial immunocytochemical evidence in situ demonstrated apical sodium channels and Na+/K+-ATPase were present in type II cells, but not in type I cells 75. From these observations, it was initially inferred that alveolar transport was only regulated by type II cells 7, 76 and distal airway epithelial cells 77, 78. Based on more recent data, however, this hypothesis may need to be re-evaluated. New data show that freshly isolated type I cells express subunits of both Na+/K+-ATPase and the amiloride-sensitive ENaC, suggesting that this cell type might also play a role in active vectorial ion and water transport 79, 80. Moreover, freshly isolated type I cells exhibited the highest known water permeability of any mammalian cell type, thereby probably explaining the very high water permeability of the lung 11.

Role of water channels in alveolar water homeostasis
Water transport across the alveolar epithelial barrier occurs during fluid absorption from the alveolar spaces because a miniosmotic gradient is created by the vectorial transport of sodium, and perhaps chloride, that results in water absorption across the alveolar epithelium. Water permeabilities have been measured across several of the major barriers in lung 81. Osmotically-driven water movement across pulmonary epithelial barriers in the lung is fast 82, 83, weakly temperature-dependent and inhibited by mercurials 84.

Four specialised water-transporting proteins, AQPs, have been localised in lung to date: AQP1 in microvascular endothelia and some pneumocytes; AQP3 in basal cells of the nasopharynx, trachea and large airways; AQP4 at the basolateral membrane of airway epithelium; and AQP5 at the apical membrane of type I alveolar epithelial cells 85. In order to define the role of AQP water channels in water transport across the various barriers in the intact lung, each of the four lung AQPs has been deleted in mice by targeted gene disruption 13, 85. Deletion of AQP1 or AQP5 produced an ~10-fold decrease in osmotically driven water transport between the airspace and capillary compartments 86, 87, thus, demonstrating major roles in osmotically driven water movement across the alveolar endothelial and epithelial barriers, respectively. AQP1 deletion also caused a moderate decrease in isosmolar transcapillary water movement in response to a modest increase in lung vascular pressure 86. AQP4 deletion alone had little effect on airspace-to-capillary water permeability, but studies comparing water permeability in AQP1 null mice versus AQP1/AQP4 double-knockout mice showed a small but significant contribution of the distal airways to lung water permeability 88. Interestingly, and most importantly, isosmolar alveolar fluid clearance was not affected by AQP1 or AQP5 deletion, even under conditions in which the clearance rate was maximised by pretreatment with isoproterenol and KGF 13. Consistent with these observations, recent studies show no effect of AQP1, AQP4 or AQP5 deletion, alone or in combination, on the formation or clearance of lung oedema following lung injury from hyperoxia, thiourea or acid instillation 13.

Thus, although the precise role of AQPs in lung physiology remains uncertain, the studies to date demonstrate that active isosmolar alveolar fluid clearance in the newborn or adult lung does not require lung water channels. Current studies are focused on the possible role of AQPs in movement of water across the conducting airways of the lung.

Fluid transport across the respiratory epithelium in acute lung injury

Two separate barriers form the alveolar/capillary barrier, the microvascular endothelium and the alveolar epithelium. The acute phase of ALI/acute respiratory distress syndrome (ARDS) is characterised by the influx of protein-rich oedema fluid into the airspaces as a consequence of increased permeability of the alveolar/capillary barrier 89. The severity and outcome of ALI depends in part on the balance between vascular endothelial and/or alveolar epithelial injuries and their repair mechanisms. The importance of endothelial injury and increased vascular permeability to the formation of pulmonary oedema in this disorder is well established. The critical importance of epithelial injury to both the development of and recovery from alveolar flooding has recently become better recognised 90–92.

Several observations confirm that transepithelial sodium transport plays a major role in the clearance of fluid from the airspace not only under normal conditions but also during experimental lung injury. First, as already explained, {alpha}-ENaC-deficient mice die shortly after birth due to lung oedema 2. Transgenic expression of {alpha}-ENaC in {alpha}-ENaC (-/-) mice rescues the lethal pulmonary phenotype 93, but results in a subclinical defect of transepithelial sodium transport. This defect is associated with an ~50% lower rate of alveolar fluid clearance and significantly greater hypoxia- and thiourea-induced pulmonary oedema 94. Secondly, instillation of phenamil (an irreversible blocker of epithelial sodium channels) into the lungs of rats exposed to hyperoxia resulted in a significant increase in extravascular lung fluid volume 95. Thirdly, systemic administration of amiloride facilitates the development of thiourea-induced pulmonary oedema in mice (unpublished data). Finally, pharmacological stimulation of this transport facilitates recovery from lung injury in several experimental models of ALI (discussed below).

Upregulation of alveolar fluid transport in acute lung injury
Many different experimental animal models of ALI have been established. Several of these have been used to study the mechanisms regulating transepithelial sodium and water transport in such pathological conditions. In many but not all of the existing in vitro and in vivo models of ALI, sodium and fluid transport is upregulated. This interesting finding is well established in conditions such as some models of hyperoxia 48, 96–100, thiourea-induced injury 101, haemorrhagic shock 102, septic shock 103 and neurogenic pulmonary oedema 104.

Besides a possible, but not yet confirmed, direct stretch-sensitive mechanism in the alveolar wall for detecting volume overload 105, the major underlying mechanism responsible for such stimulation appears to be increased endogenous release of catecholamines (for example, as in the case of short-term studies of septic and hypovolaemic shock in rats 102, 103 or in the early phase of neurogenic pulmonary oedema 104). Consistent with this hypothesis, adrenalectomy reduces alveolar fluid clearance and facilitates thiourea-induced pulmonary oedema in lung injury models (unpublished data).

Alternatively, new evidence suggests that cytokines can stimulate sodium uptake and net alveolar fluid clearance in injured lung. For example, instillation of exotoxin A from Pseudomonas aeruginosa or endotoxin from Escherichia coli into the distal airspaces of rats can stimulate alveolar fluid clearance by a catecholamine-independent pathway 106, 107. The mechanisms of the endotoxin effect may depend on release of tumour necrosis factor-{alpha}, since a monoclonal antibody directed against tumour necrosis factor-{alpha} inhibited the increase in alveolar fluid clearance that occurred 24 h after development of Gram-negative bacterial pneumonia in the rat lung 108.

Proliferation of alveolar epithelial type II cells provides another catecholamine-independent mechanism for accelerating fluid transport across the alveolar epithelial barrier as shown in the subacute phase of bleomycin-injured rat lungs 109. This mechanism may be very important as it can result in sustained upregulation of alveolar fluid clearance 67.

Finally, there may also be an oxidant-dependent mechanism that can increase the sodium transport capacity of individual type II cells exposed to hyperoxia for several days 48, 110, although not all studies of hyperoxia have demonstrated this effect 9, 96.

Downregulation of alveolar fluid transport in acute lung injury
In contrast, conditions associated with lung injury may downregulate transepithelial sodium transport. Hypoxia affects respiratory epithelial function 111 and inhibits transepithelial sodium transport in alveolar type II cells in vitro 74 and in ex vivo lungs 23 by impairing both amiloride-sensitive and -insensitive sodium transport. Moreover, exposure to prolonged hypoxia has been shown to decrease both nasal potential difference 112 and alveolar fluid clearance and Na+/K+-ATPase hydrolytic activity in rats 113. Recent in vivo work shows that hypoxia downregulates alveolar fluid clearance in rats by 50% but {alpha}-ENaC expression and mRNA levels are modestly upregulated, not downregulated 114. Interestingly, terbutaline increased alveolar fluid clearance to high levels, suggesting that perhaps cAMP agonists increase insertion of ENaC into the cell membrane of type II cells, as proposed by Snyder 49.

Ventilator-associated lung injury decreases the ability of the lung to clear oedema in rats. Moreover, sodium pump activity in alveolar type II cells isolated from rats with ventilator-associated lung injury is significantly downregulated compared with control animals 115. The mechanisms involved are not clear but may involve an increase in lung endothelial and epithelial paracellular permeability and/or downregulation of alveolar transport proteins.

Release of nitric oxide (NO) by activated alveolar macrophages can contribute to inhibition of sodium transport in lung injury models associated with airways inflammation 18, 71, 116, 117. Interestingly, administration of NO inhibitors can reverse the effect of pulmonary hypotension on downregulation of alveolar fluid clearance in rats 118. Finally, oxidants can also downregulate in vivo alveolar fluid clearance, as shown by Modelska et al. 119 and recently by Sakuma et al. 120.

Even when lung endothelial injury occurs, the alveolar epithelial barrier may remain normally impermeable to protein and retain a normal or upregulated fluid transport capacity 92, 121 with confinement of the oedema to the pulmonary interstitium 122. However, more severe systemic and pulmonary endothelial injury may be associated with a marked increase in epithelial permeability to protein and inability to transport fluid from the airspaces of the lung which, in turn, lead to alveolar flooding. The inability to remove excess fluid from the airspaces in these conditions may be related to both a marked increase in paracellular permeability due to injury to the epithelial tight junctions and loss or inhibition (NO or other oxidants) of the transport capacity of the alveolar epithelium. In some cases, epithelial integrity may recover rapidly (e.g. after parenteral oleic acid administration) 123 or gradually (e.g. bleomycin-induced lung injury) 109. In other cases, however, the injury to the epithelial barrier is so severe that its function is compromised and recovery may not occur (e.g. severe acid aspiration-induced lung injury) 124.

Effect of pharmacological stimulation of alveolar fluid clearance on experimental acute lung injury
During ALI/ARDS, the ability to remove alveolar fluid rapidly is associated with improved oxygenation, shorter duration of mechanical ventilation and increased likelihood of survival 125–127. The alveolar epithelium is remarkably resistant to injury, particularly compared to the adjacent lung endothelium 122. Even when mild-to-moderate alveolar epithelial injury occurs, the capacity of the alveolar epithelium to transport salt and water is often preserved 92. As discussed earlier, several mechanisms may result in upregulation of the fluid transport capacity of the distal pulmonary epithelium. However, this upregulation may not be sufficient to counterbalance alveolar flooding. Therefore, efforts to attenuate the lung endothelial injury and alveolar epithelial injury 128 are as important as treatments that might enhance the reabsorptive capacity of the alveolar epithelium. This section reviews pharmacological catecholamine-dependent and -independent interventions that can accelerate the resolution of alveolar oedema 8, 10, 12, 98, 100, 129.

Catecholamine-dependent mechanisms
ß2-Agonists are attractive as therapeutic agents because they are already in widespread clinical use and have minimal side-effects, even in critically ill patients 130. Treatment with ß2-agonists may also increase the secretion of surfactant and perhaps exert an anti-inflammatory effect, thus, helping to restore the vascular permeability of the lung 131, 132.

The previously discussed upregulation of alveolar fluid clearance by endogenous ß-adrenergic stimulation has been clearly demonstrated in several clinically relevant animal models. In addition to endogenous upregulation, there is growing evidence that alveolar fluid clearance can be further stimulated by exogenous ß-adrenergic therapy in the presence of lung injury 98, 129, 133.

In experimental hydrostatic pulmonary oedema, ß2-agonists can accelerate the resolution of alveolar oedema 134, 135. In sheep, aerosolised salmeterol resulted in effective treatment, with high concentrations of the drug in the alveolar oedema fluid 135. ß2-Adrenergic agonists have also been reported to augment the rate of alveolar epithelial fluid transport in rats in the presence of moderate lung injury due to hyperoxia 98, 129,133 and to restore the ability of the rat lung to clear oedema in ventilator-associated lung injury. In the latter studies, disruption of the cell's microtubular transport system by colchicine inhibited this stimulatory effect 133.

In contrast, following prolonged haemorrhagic shock in rats, reactive oxygen species can inhibit the response of alveolar epithelium to ß2-agonist stimulation 119. This suggests that, under certain circumstances, the epithelium may not respond to ß2-agonist stimulation because of extensive injury and loss of alveolar type II cells or because of a reactive effect of the inflammatory environment on the normal ability of type II cells to increase alveolar fluid clearance.

Growth factors
Since acute injury to alveolar epithelial type I cells frequently causes denudation of the alveolar epithelium 91, 136, an additional approach to hastening the resolution of ALI and ARDS would be to accelerate re-epithelialisation of the alveolar barrier 137.

The provision of a new epithelial barrier with alveolar type II cells may have beneficial effects in addition to restoration of the air-liquid interface. Indeed, the rate of alveolar epithelial fluid clearance in the subacute phase of bleomycin-induced ALI in rats was increased by >100% over baseline levels 109. The enhanced alveolar fluid clearance depended mainly on the extensive proliferation of alveolar epithelial type II cells.

Recent information suggests that hepatocyte growth factor (HGF) and KGF are major mitogens for alveolar epithelial type II cells. Intratracheal pretreatment of rats with KGF before induction of lung injury with radiation 138, thiourea 68, 139, bleomycin 138, 140, 141, hyperoxia 142–144 or acid instillation 145 decreased the severity of lung injury and overall mortality. This effect required high doses of the growth factor delivered by the intratracheal route and the maximal effect occurred only after 48–72 h. After 48 h, however, KGF produces sustained upregulation of alveolar fluid clearance for several days 67.

The mechanism of protection is thought to be due to an increase in alveolar fluid transport secondary to increased numbers of alveolar type II cells even though other mechanisms (including cytoprotection 142, 145, antioxidant effect 146, increased release of surface-active material 147 and, perhaps, reduction of lung endothelial injury 148, 149) may play additive roles.

Interestingly, the combination of KGF and ß2-agonist treatment results in additive upregulation of alveolar fluid clearance 150. This suggests that there may be mechanisms for providing both short-term (ß2-agonists) and longer-term (growth factor) upregulation of alveolar fluid transport that might hasten the resolution of clinical pulmonary oedema.

Gene therapy
Several experimental studies have demonstrated that alveolar oedema clearance may correlate with Na+/K+-ATPase activity in both normal and acutely injured animal lungs 21, 58, 96, 98, 151. Thus, another potential approach to increasing sodium transport and alveolar fluid reabsorption would be to overexpress the Na+/K+-ATPase gene in the alveolar epithelium.

Accordingly, overexpression (via adenoviral gene transfer) of the ß1- or {alpha}2-subunit increased sodium pump expression and function in the adult rat lung 152, 153. Furthermore, pretreatment of the lungs was associated with increased survival in rats exposed to hyperoxia for 64 h 154 or in mice exposed to thiourea 155. Surprisingly, for unknown reasons, overexpression of the catalytic ({alpha}1) subunit of the pump did not induce a similar effect 152.

Gene transfer technology 156 or transgenic overexpression 39 has also been used to overexpress the ß2-adrenergic receptor. This method has been shown to stimulate liquid clearance from the normal lung by increasing sensitivity to endogenous catecholamines in rats and mice 39, 156. However, preliminary data suggest that ß2-agonist-stimulated alveolar fluid clearance is not markedly different in these animals compared to their wild-type littermates, and that this upregulated clearance may not be sufficient to prevent pulmonary oedema induced by hyperoxia in mice (N. Fukuda, Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA, personal communication). Further studies are needed to assess whether sufficient downregulation of ß-receptors occurs in clinically relevant exposures to justify gene therapy with ß2-receptors to the alveolar epithelium.

Alveolar epithelial transport: clinical medicine

The study of the role of alveolar epithelial sodium and water transport in human clinical medicine is a new area of research. Although only limited data exist, currently available results confirm that active alveolar epithelial transport plays a critical role in maintaining lung fluid balance in humans (table 2Go).


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  		Table 2 Potential clinical applications of treatments designed to enhance the resolution of alveolar oedema

 
Several approaches have been used to assess such importance in clinical medicine. First, in the ex vivo human lung, standard agonists and antagonists 23, 45, 159, 160 have been employed to demonstrate that active alveolar transepithelial sodium transport in the human lung is inhibited by amiloride and/or ouabain and stimulated by ß2-adrenergic agonists. Furthermore, this transport is preserved in resected human lungs that are exposed to rewarming after severe hypothermia (7°C) 159. Secondly, the cellular content and protein composition of samples of undiluted oedema fluid collected from mechanically ventilated patients with ALI/ARDS have been compared to those of appropriate control samples collected from ventilated patients with hydrostatic pulmonary oedema. Thus, markers of endothelial and epithelial lung injury have been detected and their appearance correlated with clinical outcome 90, 136. Thirdly, alveolar fluid clearance has been measured in patients with ALI/ARDS and compared to control patients with hydrostatic pulmonary oedema. Fourthly, in vivo respiratory transepithelial sodium transport has been evaluated by measurement of nasal transepithelial potential difference (a marker of this transport in the distal airways) in a small number of patients with defined clinical diseases such as neonatal respiratory distress syndrome and high-altitude pulmonary oedema.

Pulmonary oedema fluid studies
Several studies have compared the concentrations of different biologically active substances in pulmonary oedema fluid collected from patients with ARDS versus controls with hydrostatic pulmonary oedema. These studies indicate that, in patients with ALI, oedema fluid concentrations of several substances are increased compared to control subjects.

For example, the concentration of intercellular adhesion molecule-1 (ICAM-1), an adhesion molecule found in high concentrations on the alveolar endothelium and epithelium and released in soluble form into the alveolar space in the setting of lung injury, was two-fold higher in the pulmonary oedema fluid of ALI patients than in that of control patients with hydrostatic oedema 161. In contrast, plasma concentrations of ICAM-1 were similar in both groups, suggesting that this substance is released directly into the alveolar space when the lungs are injured. Also, preliminary data indicate that high pulmonary oedema fluid levels of ICAM-1 were associated with impaired alveolar fluid clearance and prolonged duration of assisted ventilation 161.

Similarly, the concentration of biologically active HGF (but not KGF) was seven-fold higher in the oedema fluid than in the plasma of patients with ALI. Moreover, the oedema fluid concentration of HGF was higher in patients with ALI than in those with hydrostatic pulmonary oedema 162, and higher oedema fluid levels of HGF were associated with higher mortality in patients with ALI.

Soluble TGF-{alpha} is also present, in biologically significant concentrations, in the pulmonary oedema fluid of patients with ALI but not those with hydrostatic pulmonary oedema. The concentrations of TGF-{alpha} in pulmonary oedema have potent in vivo and in vitro effects on alveolar epithelial sodium transport and alveolar epithelial cell mobility 163.

The clinical significance of these and other recently discovered (such as leukotriene D4, leukotriene B4, substance P, interleukin-8, interleukin-6, fibroblast-associated (Fas; CD95)/Fas-ligand (CD95L) 164 and HTI-56 (a new integral membrane antigen specific for alveolar epithelial type I cells 136) increased oedema fluid concentrations are still unknown. However, their role in injuring or repairing the alveolar epithelial barrier in patients with ALI, their utility as possible markers of respiratory epithelial injury and their potential contribution in the development of multiorgan failure secondary to ARDS are currently being studied 90.

Alveolar fluid clearance in patients
Two properties of the epithelial barrier can be assessed clinically. First, since the epithelial barrier is normally impermeable to protein, the ratio of oedema fluid to plasma protein concentration is a good index of epithelial permeability 34, 126. Secondly, since the concentration of protein in alveolar fluid reflects net clearance of alveolar fluid, the measurement of protein concentration in sequential alveolar oedema fluid samples provides a useful estimate of the ability of the epithelial barrier to remove alveolar oedema fluid. With this method, it has been shown that clearance of alveolar fluid can occur surprisingly early and is often apparent within the first few hours after intubation and initiation of mechanical ventilation in patients with either hydrostatic or increased permeability oedema 125, 126, 165.

In one study, ~40% of patients with ARDS were able to reabsorb some of the alveolar oedema fluid within 12 h after intubation 126. These patients showed more rapid recovery from respiratory failure and lower mortality. In contrast, patients with no evidence of net reabsorption of alveolar oedema fluid in the first 12 h following ALI experienced protracted respiratory failure and higher mortality 125, 126. A recent study has extended these initial findings to a larger number of patients 127.

In contrast, 75% of 65 mechanically ventilated patients with severe hydrostatic pulmonary oedema showed intact alveolar fluid clearance. In this study, impaired alveolar fluid clearance was associated with lower arterial pH and higher Simplified Acute Physiology Score II at the time of oedema fluid sampling. Both of these factors may be markers of systemic hypoperfusion, which has been reported to impair alveolar epithelial fluid transport by oxidant-mediated mechanisms in experimental models 119. Conversely, administration of ß2-agonist (albuterol) had a positive predictive value of 85% for the presence of intact alveolar fluid clearance, although this finding did not reach statistical significance. Finally, intact alveolar fluid clearance was associated with a greater improvement in oxygenation at 24 h, along with a trend towards shorter duration of mechanical ventilation and lower hospital mortality 166.

Intact and rapid alveolar fluid clearance was also found in a group of patients with ischaemia/reperfusion pulmonary oedema after lung transplantation, confirming that a functionally intact alveolar epithelium may be preserved despite clinically severe reperfusion lung injury. Furthermore, alveolar epithelial fluid transport was preserved in most patients despite evidence of marked lung endothelial injury with a substantial increase in alveolar-capillary barrier permeability. Intact alveolar fluid clearance was correlated with less histological injury, rapid resolution of hypoxaemia, more rapid resolution of radiographic infiltrates, and a trend towards a shorter duration of mechanical ventilation and a shorter intensive care unit stay 165.

Finally, since intact alveolar fluid clearance is a favourable prognostic finding in lung transplant patients with reperfusion pulmonary oedema 165, alveolar fluid clearance and degree of pulmonary oedema were measured in 13 human lungs rejected for transplantation. Interestingly, alveolar fluid transport was intact in the majority of lungs studied, suggesting that many of these lungs might have functioned well had they been used in transplantation 167.

Nasal potential difference
Newborn infants with either transient tachypnoea 168 or neonatal distress syndrome 169 demonstrate a lower nasal potential difference, a marker of transepithelial sodium transport across the epithelium in the distal airways 170, 171. In these patients, the nasal potential difference is reduced weakly by amiloride. These results suggest that impairment of sodium absorption across the respiratory epithelia of very premature infants may be one factor contributing to the pathogenesis of neonatal respiratory distress syndrome.

Other investigators hypothesised that a similar mechanism may contribute to susceptibility to pulmonary oedema in adults. High-altitude pulmonary oedema (HAPO) was chosen as a paradigm of pulmonary oedema because it occurs in predisposed, but otherwise healthy, subjects, making it possible to study underlying mechanisms in the absence of drugs or cardiac dysfunction 172. At low altitude, the nasal potential difference was ~30% lower in HAPO-prone than in HAPO-resistant subjects. Amiloride superfusion induced a significantly smaller decrease in nasal potential difference in HAPO-prone than in HAPO-resistant subjects. These findings provide the first evidence for genetic impairment of respiratory transepithelial sodium and water transport, at least in part related to ENaC dysfunction, in a human form of pulmonary oedema 173. However, the ENaC may not be the only important cation channel facilitating alveolar fluid clearance 26, 160.

Pharmacological stimulation of alveolar fluid clearance
Since impaired alveolar epithelial function and blunted alveolar fluid clearance mechanisms contribute to the development and persistence of pulmonary oedema in humans, another important question is whether pharmacological interventions intended to stimulate alveolar sodium transport might be beneficial for the clearance of pulmonary oedema, not only in animal models but also in humans. The preliminary data on this issue, from a recent placebo-controlled clinical study, suggest that this might be true. In this study, inhalation of the lipid-soluble ß2-agonist, salmeterol, prevented the development of HAPO in predisposed subjects, providing evidence that the impairment in respiratory transepithelial fluid transport in these subjects 173 may be reversed by administration of a ß2-adrenergic agonist 157.

Conclusion

In considering the potential use of ß2-adrenergic agonist therapy for hastening the resolution of alveolar oedema in patients, the method of drug delivery is important. In one experimental study in sheep, a lipid-soluble ß2-agonist, salmeterol, was delivered via a simple nebuliser, similar to the method used for aerosolisation in ventilated, critically ill patients. Interestingly, 5 mg salmeterol resulted in a high concentration (10–6 M) in alveolar oedema fluid, even 3 h after administration of the aerosolised salmeterol 135. This concentration was at the plateau of the dose/response curve based on ex vivo human lung studies 45. Recent data show similar or even higher concentrations of albuterol are present in the undiluted oedema fluid of mechanically ventilated patients with ARDS after a single inhalation by standard aerosolisation 174. Therefore, these results indicate that aerosolisation of a ß2-agonist may be sufficient to provide therapeutic concentrations of ß2-adrenergic agonists in the distal airspaces of the lung. An alternative delivery route could be the intravenous route, although the potential for unwanted haemodynamic side-effects would be greater. Another important issue to consider when using ß2-adrenergic agonists is the occurrence of possible downregulation of ß-receptors with a diminishing therapeutic effect over time 175. However, recently published studies demonstrated no evidence of downregulation when high doses of adrenalin were delivered to rats over a period of 4 h 158.

In addition to ß2-adrenergic agonists, other treatments, such as stimulation of alveolar fluid clearance by gene therapy and/or stimulation of alveolar type II cell proliferation by growth factors, should be further evaluated experimentally. Gene therapy may provide a novel approach for the treatment of pulmonary oedema. Short-term expression may be sufficient for clinical benefit. However, several questions should be addressed before its clinical use can be evaluated. The required levels of expression, the speed of onset, and the thresholds for beneficial effect and duration are still to be defined. The potential of increasing inflammation in response to viral vectors in an already damaged lung and the possibility of development of a secondary systemic injury may limit its beneficial effects. The efficacy of transfection and expression and its benefit need to be established when administered after injury occurs. Further, it is important to determine whether transfection of type I or type II alveolar epithelial cells, or both, is important for upregulation of alveolar fluid clearance. Finally, the optimal delivery method in pulmonary gene therapy remains to be determined. It is also possible that the time course of viral transfection may prohibit its use in the acute setting. However, it may have clinical implications for the therapy of longer-term, volume-overload states such as congestive hearth failure or the pretreatment of donor lungs to prevent development of reperfusion pulmonary oedema.

Is there potential value in using growth factors to stimulate the proliferation of alveolar type II cells in the clinical setting? There are concerns about their short- and long-term efficacy, potential side-effects, and the possible induction of epithelial dysplasia. Since glucocorticoids can upregulate alveolar fluid clearance experimentally 61, 176, 177, the potential clinical value of this therapy in patients with pulmonary odema due to ALI may deserve further evaluation. However, enthusiasm for this approach has been diminished, in part by clinical studies demonstrating that acute treatment with high doses of glucocorticoids has no beneficial effect on outcome in the early acute phase of clinical ALI 178, 179. Furthermore, the potential deleterious effects of glucocorticoids on host susceptibility to infection make this form of therapy less attractive, at least as a targeted approach to upregulating alveolar fluid clearance. Nevertheless, a large prospective National Institutes of Health study is evaluating the effects of glucocorticoid therapy in patients with persistent ARDS as a follow-up to the studies of Meduri and co-workers 180, 181.

In conclusion, the value of therapies to enhance alveolar fluid clearance in patients with acute lung injury and/or other forms of pulmonary oedema, ultimately, will need to be demonstrated by evidence of improved clinical outcomes, such as decreased duration of mechanical ventilation and/or decreased mortality 137.

Footnotes

Previous articles in this series: No. 1: Baldacci S, Omenaas E, Oryszczyn MP. Allergy markers in respiratory epidemiology. Eur Respir J 2001; 17: 773–790. No. 2: Antó JM, Vermeire P, Vestbo J, Sunyer J. Epidemiology of chronic obstructive pulmonary disease. Eur Respir J 2001; 17: 982–994. No. 3: Cuvelier A, Muir J-F. Noninvasive ventilation and obstructive lung diseases. Eur Respir J 2001; 17: 1271–1281. No. 4: Wysocki M, Antonelli M. Noninvasive mechanical ventilation in acute hypoxaemic respiratory failure. Eur Respir J 2001; 18: 209–220. No. 5: Østerlind K. Chemotherapy in small cell lung cancer. Eur Respir J 2001; 18: 1026–1043. No. 6: Jaakkola M.S. Environmental tobacco smoke and health in the elderly. Eur Respir J 2002; 19: 172–181. No. 7: Hollings N, Shaw P. Diagnostic imaging of lung cancer. Eur Respir J 2002; 19: 722–742. No. 8: Künzli N. The public health relevance of air pollution abatement. Eur Respir J 2002; 20: 198–209. No. 9: D'Amato G, Liccardi G, D'Amato M, Cazzola M. Outdoor air pollution, climatic changes and allergic bronchial asthma. Eur Respir J 2002; 20: 763–776. No. 10: Pelosi P, Brazzi L, Gattinoni L. Prone position in acute respiratory distress syndrome. Eur Respir J 2002; 20: 1017–1028. Back

References

  1. Staub NC. Pulmonary edema. Physiol Rev 1974;54:678–811.[Free Full Text]
  2. Hummler E, Barker P, Gatzy J, et al. Early death due to defective neonatal lung liquid clearance in {alpha}-ENaC-deficient mice. Nat Genet 1996;12:325–328.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  3. O'Brodovich H, Hannam V, Seear M, Mullen JBM. Amiloride impairs lung water clearance in newborn guinea pigs. J Appl Physiol 1990;68:1758–1762.[Abstract/Free Full Text]
  4. Folkesson HG, Norlin A, Baines DL. Salt and water transport across the alveolar epithelium in the developing lung: correlations between function and recent molecular biology advances. Int J Mol Med 1998;2:515–531.[Web of Science][Medline] [Order article via Infotrieve]
  5. Matthay MA, Flori HR, Conner ER, Ware LB. Alveolar epithelial fluid transport: basic mechanisms and clinical relevance. Proc Assoc Am Physicians 1998;110:496–505.[Web of Science][Medline] [Order article via Infotrieve]
  6. Basset G, Crone C, Saumon G. Fluid absorption by rat lung in situ: pathways for sodium entry in the luminal membrane of alveolar epithelium. J Physiol 1987;384:325–345.[Abstract/Free Full Text]
  7. Goodman BE, Fleischer RS, Crandall ED. Evidence for active Na+ transport by cultured monolayers of pulmonary alveolar epithelial cells. Am J Physiol 1983;245:C78–C83.
  8. Matalon S, Benos DJ, Jackson RM. Biophysical and molecular properties of amiloride-inhibitable Na+ channels in alveolar epithelial cells. Am J Physiol 1996;271:L1–L22.
  9. Sznajder JI, Olivera WG, Ridge KM, Rutschman DH. Mechanisms of lung liquid clearance during hyperoxia in isolated rat lungs. Am J Respir Crit Care Med 1995;151:1519–1525.[Abstract]
  10. Jiang X, Ingbar DH, O'Grady SM. Adrenergic stimulation of Na+ transport across alveolar epithelial cells involves activation of apical Cl– channels. Am J Physiol 1998;275:C1610–C1620.
  11. Dobbs L, Gonzales R, Matthay MA, Carter EP, Allen L, Verkman AS. Highly water-permeable type I alveolar epithelial cells confer high transalveolar water permeability between the airspace and vasculature in rat lung. Proc Natl Acad Sci USA 1998;95:2991–2996.[Abstract/Free Full Text]
  12. Matthay MA, Folkesson HG, Clenci C. Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev 2002;82:569–600.[Abstract/Free Full Text]
  13. 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.[Abstract/Free Full Text]
  14. Michaut P, Planes C, Escoubet B, Clement A, Amiel C, Clerici C. Rat lung alveolar type II cell line maintains sodium transport characteristics of primary culture. J Cell Physiol 1996;169:78–86.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  15. O'Brodovich H, Canessa C, Ueda J, Rafii B, Rossier BC, Edelson J. Expression of the epithelial Na+ channel in the developing rat lung. Am J Physiol 1993;265:C491–C496.
  16. McDonald FJ, Snyder PM, McCray PB Jr, Welsh MJ. Cloning, expression, and tissue distribution of a human amiloride-sensitive Na+ channel. Am J Physiol 1994;266:L728–L734.
  17. Tchepichev S, Ueda J, Canessa C, Rossier BC, O'Brodovich H. Lung epithelial Na channel subunits are differentially regulated during development and by steroids. Am J Physiol 1995;269:C805–C812.
  18. Matalon S, O'Brodovich H. Sodium channels in alveolar epithelial cells: molecular characterization, biophysical properties, and physiological significance. Annu Rev Physiol 1999;61:627–661.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  19. Jain L, Chen XJ, Malik B, Al Khalili O, Eaton DC. Antisense oligonucleotides against the {alpha}-subunit of ENaC decrease lung epithelial cation-channel activity. Am J Physiol 1999;276:L1046–L1051.
  20. Gaillard D, Hinnrasky J, Coscoy S, et al. Early expression of ß- and {gamma}-subunits of epithelial sodium channel during human airway development. Am J Physiol 2000;278:L177–L184.
  21. Berthiaume Y, Staub NC, Matthay MA. ß-Adrenergic agonists increase lung liquid clearance in anesthetized sheep. J Clin Invest 1987;79:335–343.
  22. Jayr C, Garat C, Meignan M, Pittet JF, Zelter M, Matthay MA. Alveolar liquid and protein clearance in anesthetized ventilated rats. J Appl Physiol 1994;76:2636–2642.[Abstract/Free Full Text]
  23. 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.[Abstract]
  24. Bonny O, Chraibi A, Loffing J, et al. Functional expression of a pseudohypoaldosteronism type I mutated epithelial Na+ channel lacking the pore-forming region of its {alpha} subunit. J Clin Invest 1999;104:967–974.[Web of Science][Medline] [Order article via Infotrieve]
  25. Feng ZP, Clark RB, Berthiaume Y. Identification of nonselective cation channels in cultured adult rat alveolar type II cells. Am J Respir Cell Mol Biol 1993;9:248–254.
  26. Junor RW, Benjamin AR, Alexandrou D, Guggino SE, Walters DV. A novel role for cyclic nucleotide-gated cation channels in lung liquid homeostasis in sheep. J Physiol 1999;520:255–260.[Abstract/Free Full Text]
  27. Ridge KM, Rutschman DH, Factor P, Katz AI, Bertorello AM, Sznajder JL. Differential expression of Na-K-ATPase isoforms in rat alveolar epithelial cells. Am J Physiol 1997;273:L246–L255.
  28. Blanco G, DeTomaso AW, Koster J, Xie ZJ, Mercer RW. The {alpha}-subunit of the Na,K-ATPase has catalytic activity independent of the ß-subunit. J Biol Chem 1994;269:23420–23425.[Abstract/Free Full Text]
  29. McDonough AA, Geering K, Farley RA. The sodium pump needs its ß subunit. FASEB J 1990;4:1598–1605.[Abstract]
  30. Berthiaume Y, Lesur O, Dagenais A. Treatment of adult respiratory distress syndrome: plea for rescue therapy of the alveolar epithelium. Thorax 1999;54:150–160.[Free Full Text]
  31. Rokaw MD, Sarac E, Lechman E, et al. Chronic regulation of transepithelial Na+ transport by the rate of apical Na+ entry. Am J Physiol 1996;270:C600–C607.
  32. Middleton JP. Direct regulation of the Na,K pump by signal transduction mechanisms. Miner Electrolyte Metab 1996;22:293–302.[Web of Science][Medline] [Order article via Infotrieve]
  33. Crandall ED, Heming TA, Palombo RL, Goodman BE. Effects of terbutaline on sodium transport in isolated perfused rat lung. J Appl Physiol 1986;60:289–294.[Abstract/Free Full Text]
  34. Berthiaume Y, Broaddus VC, Gropper MA, Tanita T, Matthay MA. Alveolar liquid and protein clearance from normal dog lungs. J Appl Physiol 1988;65:585–593.[Abstract/Free Full Text]
  35. Garat C, Carter EP, Matthay MA. New in situ mouse model to quantify alveolar epithelial fluid clearance. J Appl Physiol 1998;84:1763–1767.[Abstract/Free Full Text]
  36. Fukuda N, Folkesson HG, Matthay MA. Relationship of interstitial fluid volume to alveolar fluid clearance in mice: ventilated vs. in situ studies. J Appl Physiol 2000;89:672–679.[Abstract/Free Full Text]
  37. Berthiaume Y, Albertine KH, Grady M, Fick G, Matthay MA. Protein clearance from the air spaces and lungs of unanesthetized sheep over 144 h. J Appl Physiol 1989;67:1887–1897.[Abstract/Free Full Text]
  38. Goodman BE, Anderson JL, Clemens JW. Evidence for regulation of sodium transport from airspace to vascular space by cAMP. Am J Physiol 1989;257:L86–L93.
  39. Fukuda N, Mcgraw DW, Liggert SB, Folkesson HG, Matthay MA. Overexpression of the ß-2 adrenergic receptor in alveolar type II cells upregulates alveolar epithelial fluid transport in mice. FASEB J 2000;14:A129.
  40. Tibayan FA, Chesnutt AN, Folkesson HG, Eandi J, Matthay MA. Dobutamine increases alveolar liquid clearance in ventilated rats by ß-2 receptor stimulation. Am J Respir Crit Care Med 1997;156:438–444.[Abstract/Free Full Text]
  41. Norlin A, Finley N, Abedinpour P, Folkesson HG. Alveolar liquid clearance in the anesthetized ventilated guinea pig. Am J Physiol 1998;274:L235–L243.
  42. Carstairs JR, Nimmo AJ, Barnes PJ. Autoradiographic visualization of ß-adrenoceptor subtypes in human lung. Am Rev Respir Dis 1985;132:541–547.[Web of Science][Medline] [Order article via Infotrieve]
  43. Smedira N, Gates L, Hastings R, et al. Alveolar and lung liquid clearance in anesthetized rabbits. J Appl Physiol 1991;70:1827–1835.[Abstract/Free Full Text]
  44. Effros RM, Mason GR, Hukkanen J, Silverman P. Reabsorption of solutes and water from fluid-filled rabbit lungs. Am Rev Respir Dis 1987;136:669–676.[Web of Science][Medline] [Order article via Infotrieve]
  45. Sakuma T, Folkesson HG, Suzuki S, Okaniwa G, Fujimura S, Matthay MA. ß-Adrenergic agonist stimulated alveolar fluid clearance in ex vivo human and rat lungs. Am J Respir Crit Care Med 1997;155:506–512.[Abstract]
  46. Minakata Y, Suzuki S, Grygorczyk C, Dagenais A, Berthiaume Y. Impact of ß-adrenergic agonist on Na+ channel and Na+-K+-ATPase expression in alveolar type II cells. Am J Physiol 1998;275:L414–L422.
  47. Tohda H, Foskett JK, O'Brodovich H, Marunaka Y. Cl– regulation of a Ca(2+)-activated nonselective cation channel in ß-agonist-treated fetal distal lung epithelium. Am J Physiol 1994;266:C104–C109.
  48. Yue G, Russell WJ, Benos DJ, Jackson RM, Olman MA, Matalon S. Increased expression and activity of sodium channels in alveolar type II cells of hyperoxic rats. Proc Natl Acad Sci USA 1995;92:8418–8422.[Abstract/Free Full Text]
  49. Snyder PM. Liddle's syndrome mutations disrupt cAMP-mediated translocation of the epithelial Na(+) channel to the cell surface. J Clin Invest 2000;105:45–53.[Web of Science][Medline] [Order article via Infotrieve]
  50. Stutts MJ, Canessa CM, Olsen JC, et al. CFTR as a cAMP-dependent regulator of sodium channels. Science 1995;269:847–850.[Abstract/Free Full Text]
  51. Reddy MM, Light MJ, Quinton PM. Activation of the epithelial Na+ channel (ENaC) requires CFTR Cl– channel function. Nature 1999;402:301–304.[CrossRef][Medline] [Order article via Infotrieve]
  52. Inglis SK, Corboz MR, Taylor AE, Ballard ST. Regulation of ion transport across porcine distal bronchi. Am J Physiol 1996;270:L289–L297.
  53. Fang X, Fukuda N, Barbry P, Sartori C, Verkman AS, Matthay MA. Novel role for CFTR in fluid absorption from the distal airspaces of the lung. J Gen Physiol 2002;119:199–207.[Abstract/Free Full Text]
  54. Saldias FJ, Lecuona E, Comellas AP, Ridge KM, Sznajder JI. Dopamine restores lung ability to clear edema in rats exposed to hyperoxia. Am J Respir Crit Care Med 1999;159:626–633.[Abstract/Free Full Text]
  55. 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.
  56. Staub O, Gautschi I, Ishikawa T, et al. Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. EMBO J 1997;16:6325–6336.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  57. Vallet V, Chraibi A, Gaeggeler HP, Horisberger JD, Rossier BC. An epithelial serine protease activates the amiloride-sensitive sodium channel. Nature 1997;389:607–610.[CrossRef][Medline] [Order article via Infotrieve]
  58. Barnard ML, Olivera WG, Rutschman DM, Bertorello AM, Katz AI, Sznajder JI. Dopamine stimulates sodium transport and liquid clearance in rat lung epithelium. Am J Respir Crit Care Med 1997;156:709–714.[Abstract/Free Full Text]
  59. Barker PM, Walters DV, Markiewicz M, Strang LB. Development of the lung liquid reabsorptive mechanism in fetal sheep: synergism of triiodothyronine and hydrocortisone. J Physiol 1991;433:435–449.[Abstract/Free Full Text]
  60. Barker PM, Markiewicz M, Parker KA, Walters DV, Strang LB. Synergistic action of triiodothyronine and hydrocortisone on epinephrine-induced reabsorption of fetal lung liquid. Pediatr Res 1990;27:588–591.[Web of Science][Medline] [Order article via Infotrieve]
  61. Folkesson HG, Norlin A, Wang Y, Abedinpour P, Matthay MA. Dexamethasone and thyroid hormone pretreatment upregulate alveolar epithelial fluid clearance in adult rats. J Appl Physiol 2000;88:416–424.[Abstract/Free Full Text]
  62. Sugahara K, Freidenberg GR, Mason RJ. Insulin binding and effects on glucose and transepithelial transport by alveolar type II cells. Am J Physiol 1984;247:C472–C477.
  63. Tohda H, Marunaka Y. Insulin-activated amiloride-blockable nonselective cation and Na+ channels in the fetal distal lung epithelium. Gen Pharmacol 1995;26:755–763.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  64. Sweezey N, Tchepichev S, Gagnon S, Fertuck K, O'Brodovich H. Female gender hormones regulate mRNA levels and function of the rat lung epithelial Na channel. Am J Physiol 1998;274:C379–C386.
  65. Borok Z, Hami A, Danto SI, Lubman RL, Kim KJ, Crandall ED. Effects of EGF on alveolar epithelial junctional permeability and active sodium transport. Am J Physiol 1996;270:L559–L565.
  66. Sznajder JI, Ridge KM, Yeates DB, Ilekis J, Olivera W. Epidermal growth factor increases lung liquid clearance in rat lungs. J Appl Physiol 1998;85:1004–1010.[Abstract/Free Full Text]
  67. Wang Y, Jayr C, Folkesson HG, Matthay MA. Alveolar epithelial fluid transport can be upregulated simultaneously in rats by two different mechanisms. Chest 1999;116:Suppl. 1, 98S–100S.[Free Full Text]
  68. Guery BP, Mason CM, Dobard EP, Beaucaire G, Summer WR, Nelson S. Keratinocyte growth factor increases transalveolar sodium reabsorption in normal and injured rat lungs. Am J Respir Crit Care Med 1997;155:1777–1784.[Abstract]
  69. Borok Z, Danto SI, Dimen LL, Zhang XL, Lubman RL. Na(+)-K(+)-ATPase expression in alveolar epithelial cells: upregulation of active ion transport by KGF. Am J Physiol 1998;274:L149–L158.
  70. Folkesson HG, Pittet JF, Nitenberg G, Matthay MA. Transforming growth factor-{alpha} increases alveolar liquid clearance in anesthetized ventilated rats. Am J Physiol 1996;271:L236–L244.
  71. Guo Y, Duvall MD, Crow JP, Matalon S. Nitric oxide inhibits Na+ absorption across cultured alveolar type II monolayers. Am J Physiol 1998;274:L369–L377.
  72. Ding JW, Dickie J, O'Brodovich H, et al. Inhibition of amiloride-sensitive sodium-channel activity in distal lung epithelial cells by nitric oxide. Am J Physiol 1998;274:L378–L387.
  73. Duvall MD, Zhu S, Fuller CM, Matalon S. Peroxynitrite inhibits amiloride-sensitive Na+ currents in Xenopus oocytes expressing {alpha} ß {gamma}-rENaC. Am J Physiol 1998;274:C1417–C1423.
  74. Planes C, Friedlander G, Loiseau A, Amiel C, Clerici C. Inhibition of Na-K-ATPase activity after prolonged hypoxia in an alveolar epithelial cell line. Am J Physiol 1996;271:L70–L78.
  75. Schneeberger EE, McCarthy KM. Cytochemical localization of Na+-K+-ATPase in rat type II pneumocytes. J Appl Physiol 1986;60:1584–1589.[Abstract/Free Full Text]
  76. Mason RJ, Williams MC, Widdicombe JH, Sanders MJ, Misfeldt DS, Berry LC Jr. Transepithelial transport by pulmonary alveolar type II cells in primary culture. Proc Natl Acad Sci USA 1982;79:6033–6037.[Abstract/Free Full Text]
  77. Ballard ST, Schepens SM, Falcone JC, Meininger GA, Taylor AE. Regional bioelectric properties of porcine airway epithelium. J Appl Physiol 1992;73:2021–2027.[Abstract/Free Full Text]
  78. Al Bazzaz FJ. Regulation of Na and Cl transport in sheep distal airways. Am J Physiol 1994;267:L193–L198.
  79. Borok Z, Liebler J, Lubman R, et al. Sodium transport proteins are expressed by rat alveolar epithelial type I cells. Am J Physiol 2002; (In press)
  80. Johnson M, Widdicombe J, Allen P, Barbry P, Dobbs L. Alveolar epithelial type I cells contain transport proteins and transport sodium, supporting an active role for type I cells in regulation of lung liquid homeostasis. Proc Natl Acad Sci USA 2002; (In press)
  81. Verkman AS. Role of aquaporin water channels in kidney and lung. Am J Med Sci 1998;316:310–320.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  82. Folkesson HG, Kheradmand F, Matthay MA. The effect of salt water on alveolar epithelial barrier function. Am J Respir Crit Care Med 1994;150:1555–1563.[Abstract]
  83. Folkesson HG, Matthay MA, Hasegawa H, Kheradmand F, Verkman AS. Transcellular water transport in lung alveolar epithelium through mercury-sensitive water channels. Proc Natl Acad Sci USA 1994;91:4970–4974.[Abstract/Free Full Text]
  84. Carter EP, Matthay MA, Farinas J, Verkman AS. Transalveolar osmotic and diffusional water permeability in intact mouse lung measured by a novel surface fluorescence method. J Gen Physiol 1996;108:133–142.[Abstract/Free Full Text]
  85. Verkman AS, Yang B, Song Y, Manley GT, Ma T. Role of water channels in fluid transport studied by phenotype analysis of aquaporin knockout mice. Exp Physiol 2000;85:233S–241S.[Abstract]
  86. Bai C, Fukuda N, Song Y, Ma T, Matthay MA, Verkman AS. Lung fluid transport in aquaporin-1 and aquaporin-4 knockout mice. J Clin Invest 1999;103:555–561.[Web of Science][Medline] [Order article via Infotrieve]
  87. Ma T, Fukuda N, Song Y, Matthay MA, Verkman AS. Lung fluid transport in aquaporin-5 knockout mice. J Clin Invest 2000;105:93–100.[Web of Science][Medline] [Order article via Infotrieve]
  88. Song Y, Ma T, Matthay MA, Verkman AS. Role of aquaporin-4 in airspace-to-capillary water permeability in intact mouse lung measured by a novel gravimetric method. J Gen Physiol 2000;115:17–27.
  89. Pugin J, Verghese G, Widmer MC, Matthay MA. The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. Crit Care Med 1999;27:304–312.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  90. Pittet JF, Mackersie RC, Martin TR, Matthay MA. Biological markers of acute lung injury: prognostic and pathogenetic significance. Am J Respir Crit Care Med 1997;155:1187–1205.[Web of Science][Medline] [Order article via Infotrieve]
  91. Bachofen M, Weibel ER. Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia. Am Rev Respir Dis 1977;116:589–615.[Web of Science][Medline] [Order article via Infotrieve]
  92. Wiener-Kronish JP, Albertine KH, Matthay MA. Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin. J Clin Invest 1991;88:864–875.
  93. Hummler E, Barker P, Talbot C, et al. A mouse model for the renal salt-wasting syndrome pseudohypoaldosteronism. Proc Natl Acad Sci USA 1997;94:11710–11715.[Abstract/Free Full Text]
  94. Egli M, Sartori C, Duplain H, et al. Impaired alveolar fluid clearance and augmented susceptibility to lung edema in mice with defective amiloride sensitive sodium transport. FASEB J 2000;14:A127.
  95. Yue G, Matalon S. Mechanisms and sequelae of increased alveolar fluid clearance in hyperoxic rats. Am J Physiol 1997;272:L407–L412.
  96. Olivera W, Ridge K, Wood LD, Sznajder JI. Active sodium transport and alveolar epithelial Na-K-ATPase increase during subacute hyperoxia in rats. Am J Physiol 1994;266:L577–L584.
  97. Olivera WG, Ridge KM, Sznajder JI. Lung liquid clearance and Na,K-ATPase during acute hyperoxia and recovery in rats. Am J Respir Crit Care Med 1995;152:1229–1234.[Abstract]
  98. Lasnier JM, Wangensteen OD, Schmitz LS, Gross CR, Ingbar DH. Terbutaline stimulates alveolar fluid resorption in hyperoxic lung injury. J Appl Physiol 1996;81:1723–1729.[Abstract/Free Full Text]
  99. Carter EP, Wangensteen OD, O'Grady SM, Ingbar DH. Effects of hyperoxia on type II cell Na-K-ATPase function and expression. Am J Physiol 1997;272:L542–L551.
  100. Saldias FJ, Comellas A, Ridge KM, Lecuona E, Sznajder JI. Isoproterenol improves ability of lung to clear edema in rats exposed to hyperoxia. J Appl Physiol 1999;87:30–35.[Abstract/Free Full Text]
  101. Zuege D, Suzuki S, Berthiaume Y. Increase of lung sodium-potassium-ATPase activity during recovery from high-permeability pulmonary edema. Am J Physiol 1996;271:L896–L909.
  102. Pittet JF, Brenner TJ, Modelska K, Matthay MA. Alveolar liquid clearance is increased by endogenous catecholamines in hemorrhagic shock in rats. J Appl Physiol 1996;81:830–837.[Abstract/Free Full Text]
  103. Pittet JF, Wiener-Kronish JP, McElroy MC, Folkesson HG, Matthay MA. Stimulation of lung epithelial liquid clearance by endogenous release of catecholamines in septic shock in anesthetized rats. J Clin Invest 1994;94:663–671.
  104. Lane SM, Maender KC, Awender NE, Maron MB. Adrenal epinephrine increases alveolar liquid clearance in a canine model of neurogenic pulmonary edema. Am J Respir Crit Care Med 1998;158:760–768.[Abstract/Free Full Text]
  105. Waters CM, Ridge KM, Sunio G, Venetsanou K, Sznajder JI. Mechanical stretching of alveolar epithelial cells increases Na(+)-K(+)- ATPase activity. J Appl Physiol 1999;87:715–721.[Abstract/Free Full Text]
  106. Garat C, Rezaiguia S, Meignan M, et al. Alveolar endotoxin increases alveolar liquid clearance in rats. J Appl Physiol 1995;79:2021–2028.[Abstract/Free Full Text]
  107. Pittet JF, Hashimoto S, Pian M, McElroy MC, Nitenberg G, Wiener-Kronish JP. Exotoxin A stimulates fluid reabsorption from distal airspaces of lung in anesthetized rats. Am J Physiol 1996;270:L232–L241.
  108. Rezaiguia S, Garat C, Delclaux C, et al. Acute bacterial pneumonia in rats increases alveolar epithelial fluid clearance by a tumor necrosis factor-{alpha}-dependent mechanism. J Clin Invest 1997;99:325–335.[Web of Science][Medline] [Order article via Infotrieve]
  109. Folkesson HG, Nitenberg G, Oliver BL, Jayr C, Albertine KH, Matthay MA. Upregulation of alveolar epithelial fluid transport after subacute lung injury in rats from bleomycin. Am J Physiol 1998;275:L478–L490.
  110. Nici L, Dowin R, Gilmore-Hebert M, Jamieson JD, Ingbar DH. Upregulation of rat lung Na-K-ATPase during hyperoxic injury. Am J Physiol 1991;261:L307–L314.
  111. Clerici C, Matthay MA. Hypoxia regulates gene expression of alveolar epithelial transport proteins. J Appl Physiol 2000;88:1890–1896.[Abstract/Free Full Text]
  112. Tomlinson LA, Carpenter TC, Baker EH, Bridges JB, Weil JV. Hypoxia reduces airway epithelial sodium transport in rats. Am J Physiol 1999;277:L881–L886.
  113. 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.[Abstract/Free Full Text]
  114. Vivora ML, Matthay MA, Blot-Chabaud M, Friedlander G, Clerici C. Hypoxia reduces alveolar epithelial sodium and fluid transport in rats in vivo: reversal by ß-2 adrenergic agonist treatment. Am J Respir Cell Mol Biol 2001;25:554–561.[Abstract/Free Full Text]
  115. Lecuona E, Saldias F, Comellas A, Ridge K, Guerrero C, Sznajder JI. Ventilator-associated lung injury decreases lung ability to clear edema in rats. Am J Respir Crit Care Med 1999;159:603–609.[Abstract/Free Full Text]
  116. Matthay MA, Geiser T, Matalon S, Ischiropoulos H. Oxidant-mediated lung injury in the acute respiratory distress syndrome. Crit Care Med 1999;27:2028–2030.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  117. Olivera W, Ridge K, Wood LD, Sznajder JI. ANF decreases active sodium transport and increases alveolar epithelial permeability in rats. J Appl Physiol 1993;75:1581–1586.[Abstract/Free Full Text]
  118. Pittet JF, Lu M, Morris DG, Matthay MA. Reactive nitrogen species inhibit alveolar epithelial fluid transport after hemorrhagic shock in rats. J Immunol 2001;166:6301–6310.[Abstract/Free Full Text]
  119. Modelska K, Matthay MA, Brown LA, Deutch E, Lu LN, Pittet JF. Inhibition of ß-adrenergic-dependent alveolar epithelial clearance by oxidant mechanisms after hemorrhagic shock. Am J Physiol 1999;276:L844–L857.
  120. Sakuma T, Tsukano C, Ishigaki M, et al. Lung deflation impairs alveolar epithelial fluid transport in ischemic rabbit and rat lungs. Transplantation 2000;69:1785–1793.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  121. Guidot DM, Modelska K, Lois M, et al. Ethanol ingestion via glutathione depletion impairs alveolar epithelial barrier function in rats. Am J Physiol 2000;279:L127–L135.
  122. Pittet JF, Wiener-Kronish JP, Serikov V, Matthay MA. Resistance of the alveolar epithelium to injury from septic shock in sheep. Am J Respir Crit Care Med 1995;151:1093–1100.[Abstract]
  123. Wiener-Kronish JP, Broaddus VC, Albertine KH, Gropper MA, Matthay MA, Staub NC. Relationship of pleural effusions to increased permeability pulmonary edema in anesthetized sheep. J Clin Invest 1988;82:1422–1429.
  124. Folkesson HG, Matthay MA, Hebert CA, Broaddus VC. Acid aspiration-induced lung injury in rabbits is mediated by interleukin-8-dependent mechanisms. J Clin Invest 1995;96:107–116.
  125. Ware LB, Matthay MA. Maximal alveolar epithelial fluid clearance in clinical acute lung injury: an excellent predictor of survival and the duration of mechanical ventilation. Am J Respir Crit Care Med 1999;159:A694.
  126. 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.[Web of Science][Medline] [Order article via Infotrieve]
  127. Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;163:1376–1383.[Abstract/Free Full Text]
  128. Modelska K, Pittet JF, Folkesson HG, Courtney BV, Matthay MA. Acid-induced lung injury. Protective effect of anti-interleukin-8 pretreatment on alveolar epithelial barrier function in rabbits. Am J Respir Crit Care Med 1999;160:1450–1456.[Abstract/Free Full Text]
  129. Garat C, Meignan M, Matthay MA, Luo DF, Jayr C. Alveolar epithelial fluid clearance mechanisms are intact after moderate hyperoxic lung injury in rats. Chest 1997;111:1381–1388.[Abstract/Free Full Text]
  130. Wright PE, Carmichael LC, Bernard GR. Effect of bronchodilators on lung mechanics in the acute respiratory distress syndrome (ARDS). Chest 1994;106:1517–1523.[Abstract/Free Full Text]
  131. Masclans JR, Barbera JA, MacNee W, et al. Salbutamol reduces pulmonary neutrophil sequestration of platelet-activating factor in humans. Am J Respir Crit Care Med 1996;154:529–532.[Abstract]
  132. Barnard JW, Seibert AF, Prasad VR, et al. Reversal of pulmonary capillary ischemia-reperfusion injury by rolipram, a cAMP phosphodiesterase inhibitor. J Appl Physiol 1994;77:774–781.[Abstract/Free Full Text]
  133. Saldias FJ, Lecuona E, Comellas AP, Ridge KM, Rutschman DH, Sznajder JI. ß-Adrenergic stimulation restores rat lung ability to clear edema in ventilator-associated lung injury. Am J Respir Crit Care Med 2000;162:282–287.[Abstract/Free Full Text]
  134. Frank JA, Wang Y, Osorio O, Matthay MA. ß-Adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats. J Appl Physiol 2000;89:1255–1265.[Abstract/Free Full Text]
  135. Campbell AR, Folkesson HG, Berthiaume Y, Gutkowska J, Suzuki S, Matthay MA. Alveolar epithelial fluid clearance persists in the presence of moderate left atrial hypertension in sheep. J Appl Physiol 1999;86:139–151.[Abstract/Free Full Text]
  136. Newman V, Gonzalez RF, Matthay MA, Dobbs LG. A novel alveolar type I cell-specific biochemical marker of human acute lung injury. Am J Respir Crit Care Med 2000;161:990–995.[Abstract/Free Full Text]
  137. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334–1349.[Free Full Text]
  138. Yi ES, Williams ST, Lee H, et al. Keratinocyte growth factor ameliorates radiation- and bleomycin-induced lung injury and mortality. Am J Pathol 1996;149:1963–1970.[Abstract]
  139. Mason CM, Guery BP, Summer WR, Nelson S. Keratinocyte growth factor attenuates lung leak induced by {alpha}-naphthylthiourea in rats. Crit Care Med 1996;24:925–931.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  140. Guo J, Yi ES, Havill AM, et al. Intravenous keratinocyte growth factor protects against experimental pulmonary injury. Am J Physiol 1998;275:L800–L805.
  141. Deterding RR, Havill AM, Yano T, et al. Prevention of bleomycin-induced lung injury in rats by keratinocyte growth factor. Proc Assoc Am Physicians 1997;109:254–268.[Web of Science][Medline] [Order article via Infotrieve]
  142. Panos RJ, Bak PM, Simonet WS, Rubin JS, Smith LJ. Intratracheal instillation of keratinocyte growth factor decreases hyperoxia-induced mortality in rats. J Clin Invest 1995;96:2026–2033.
  143. Borok Z, Mihyu S, Fernandes VF, Zhang XL, Kim KJ, Lubman RL. KGF prevents hyperoxia-induced reduction of active ion transport in alveolar epithelial cells. Am J Physiol 1999;276:C1352–C1360.
  144. Barazzone C, Donati YR, Rochat AF, et al. Keratinocyte growth factor protects alveolar epithelium and endothelium from oxygen-induced injury in mice. Am J Pathol 1999;154:1479–1487.[Abstract/Free Full Text]
  145. Yano T, Deterding RR, Simonet WS, Shannon JM, Mason RJ. Keratinocyte growth factor reduces lung damage due to acid instillation in rats. Am J Respir Cell Mol Biol 1996;15:433–442.[Abstract]
  146. Waters CM, Savla U, Panos RJ. KGF prevents hydrogen peroxide-induced increases in airway epithelial cell permeability. Am J Physiol 1997;272:L681–L689.
  147. Xu X, McCormick-Shannon K, Voelker DR, Mason RJ. KGF increases SP-A and SP-D mRNA levels and secretion in cultured rat alveolar type II cells. Am J Respir Cell Mol Biol 1998;18:168–178.[Abstract/Free Full Text]
  148. Gillis P, Savla U, Volpert OV, et al. Keratinocyte growth factor induces angiogenesis and protects endothelial barrier function. J Cell Sci 1999;112:2049–2057.[Abstract]
  149. Viget N, Guery BP, Ader F, et al. Keratinocyte growth factor protects against Pseudomonas aeruginosa-induced lung injury. Am J Physiol Lung Cell Moll Physiol 2000;279:L1199–L1209.[Abstract/Free Full Text]
  150. Wang Y, Folkesson HG, Jayr C, Ware LB, Matthay MA. Alveolar epithelial fluid transport can be simultaneously upregulated by both KGF and ß-agonist therapy. J Appl Physiol 1999;87:1852–1860.[Abstract/Free Full Text]
  151. Saldias F, Lecuona E, Friedman E, Barnard ML, Ridge KM, Sznajder JI. Modulation of lung liquid clearance by isoproterenol in rat lungs. Am J Physiol 1998;274:L694–L701.
  152. Factor P, Saldias F, Ridge K, et al. Augmentation of lung liquid clearance via adenovirus-mediated transfer of a Na,K-ATPase ß1 subunit gene. J Clin Invest 1998;102:1421–1430.[Web of Science][Medline] [Order article via Infotrieve]
  153. Azzam ZS, Ridge KM, Factor P, et al. Adenoviral mediated overexpression of the Na-K-ATPase {alpha} 2 isoform increases alveolar fluid reabsorption in rats. Am J Respir Crit Care Med 2000;161:A286.
  154. Factor P, Dumasius V, Saldias F, Sznajder JI. Adenoviral-mediated overexpression of the NA,K-ATPase ß1 subunit gene increases lung edema clearance and improves survival during acute hyperoxic lung injury in rats. Chest 1999;116:Suppl. 1, 24S–25S.[Free Full Text]
  155. Stern M, Ulrich K, Robinson C, et al. Pretreatment with cationic lipid-mediated transfer of the Na+K+-ATPase pump in a mouse model in vivo augments resolution of high permeability pulmonary oedema. Gene Ther 2000;7:960–966.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  156. Dumasius V, Sznajder JI, Azzam ZS, et al. ß2-adrenergic receptor overexpression increases alveolar fluid clearance and responsiveness to endogenous catecholamines in rats. Circ Res 2001;89:907–914.[Abstract/Free Full Text]
  157. Sartori C, Allemann Y, Duplain H, et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 2002;346:1631–1636.[Abstract/Free Full Text]
  158. Charron PD, Fawley JP, Maron MB. Effect of epinephrine on alveolar liquid clearance in the rat. J Appl Physiol 1999;87:611–618.[Abstract/Free Full Text]
  159. Sakuma T, Suzuki S, Usuda K, et al. Preservation of alveolar epithelial fluid transport mechanisms in rewarmed human lung after severe hypothermia. J Appl Physiol 1996;80:1681–1686.[Abstract/Free Full Text]
  160. Sakuma T, Takahashi K, Ohya N, Nakada T, Matthay MA. Effects of ATP-sensitive potassium channel opener on potassium transport and alveolar fluid clearance in the resected human lung. Pharmacol Toxicol 1998;83:16–22.[Web of Science][Medline] [Order article via Infotrieve]
  161. Conner ER, Ware LB, Modin G, Matthay MA. Elevated pulmonary edema fluid concentrations of soluble intercellular adhesion molecule-1 in patients with acute lung injury: biological and clinical significance. Chest 1999;116:Suppl. 1, 83S–84S.[Abstract/Free Full Text]
  162. Verghese GM, McCormick-Shannon K, Mason RJ, Matthay MA. Hepatocyte growth factor and keratinocyte growth factor in the pulmonary edema fluid of patients with acute lung injury. Biologic and clinical significance. Am J Respir Crit Care Med 1998;158:386–394.[Abstract/Free Full Text]
  163. Chesnutt AN, Kheradmand F, Folkesson HG, Alberts M, Matthay MA. Soluble transforming growth factor-{alpha} is present in the pulmonary edema fluid of patients with acute lung injury. Chest 1997;111:652–656.[Abstract/Free Full Text]
  164. Ware LB, Geiser T, Nuckton TJ, Daniel B, Matthay MA. Elevated levels of markers of apoptosis in the biological fluids of patients with early acute lung injury. Am J Respir Crit Care Med 2000;161:A380.
  165. Ware LB, Golden JA, Finkbeiner WE, Matthay MA. Alveolar epithelial fluid transport capacity in reperfusion lung injury after lung transplantation. Am J Respir Crit Care Med 1999;159:980–988.[Abstract/Free Full Text]
  166. Verghese GM, Ware LB, Matthay BA, Matthay MA. Alveolar epithelial fluid transport and the resolution of clinically severe hydrostatic pulmonary edema. J Appl Physiol 1999;87:1301–1312.[Abstract/Free Full Text]
  167. Wang Y, Ware LB, Sakuma T, Hall TS, Matthay MA. Alveolar epithelial fluid transport is preserved in human lungs rejected for transplantation. Am J Respir Crit Care Med 2000;161:A507.
  168. 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.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  169. Barker PM, Gowen CW, Lawson EE, Knowles MR. Decreased sodium ion transport across nasal epithelium of very premature infants with respiratory distress syndrome. J Pediatr 1997;130:373–377.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  170. Knowles MR, Carson JL, Collier AM, Gatzy JT, Boucher RC. Measurements of nasal transepithelial electric potential differences in normal human subjects in vivo. Am Rev Respir Dis 1981;124:484–490.[Web of Science][Medline] [Order article via Infotrieve]
  171. Knowles MR, Buntin W, Bromberg PA, Gatzy JT, Boucher RC. Measurements of transepithelial electric potential differences in the trachea and bronchi of human subjects in vivo. Am Rev Respir Dis 1982;126:108–112.[Web of Science][Medline] [Order article via Infotrieve]
  172. Scherrer U, Sartori C, Lepori M, et al. High-altitude pulmonary edema: from exaggerated pulmonary hypertension to a defect in transepithelial sodium transport. Adv Exp Med Biol 1999;474:93–107.[Web of Science][Medline] [Order article via Infotrieve]
  173. Sartori C, Lepori M, Maggiorini M, Allemann Y, Nicod P, Scherrer U. Impairment of amiloride-sensitive sodium transport in individuals susceptible to high altitude pulmonary edema. FASEB J 1998;12:A231.
  174. Atabai K, Ware LB, Snider M, et al. Aerosolized ß-2 adrenergic agonists achieve therapeutic levels in the pulmonary edema fluid of ventilated patients with acute respiratory failure. Intensive Care Med 2002;28:705–711.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  175. Fabisiak JP, Vesell ES, Rannels DE. Interactions of ß adrenergic antagonists with isolated rat alveolar type II pneumocytes. I. Analysis, characterization and regulation of specific ß adrenergic receptors. J Pharmacol Exp Ther 1987;241:722–727.[Abstract/Free Full Text]
  176. Lazrak A, Samanta A, Venetsanou K, Barbry P, Matalon S. Modification of biophysical properties of lung epithelial Na(+) channels by dexamethasone. Am J Physiol 2000;279:C762–C770.
  177. Lazrak A, Samanta A, Matalon S. Biophysical properties and molecular characterization of amiloride- sensitive sodium channels in A549 cells. Am J Physiol 2000;278:L848–L857.
  178. Sprung CL, Caralis PV, Marcial EH, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med 1984;311:1137–1143.[Abstract]
  179. Luce JM, Montgomery AB, Marks JD, Turner J, Metz CA, Murray JF. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Respir Dis 1988;138:62–68.[Web of Science][Medline] [Order article via Infotrieve]
  180. Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 1998;280:159–165.[Abstract/Free Full Text]
  181. Meduri GU. Levels of evidence for the pharmacologic effectiveness of prolonged methylprednisolone treatment in unresolving ARDS. Chest 1999;116:Suppl. 1, 116S–118S.[Free Full Text]



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