HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 291/3/L301    most recent 00153.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Guidot, D. M. Articles by Matthay, M. A. Search for Related Content PubMed PubMed Citation Articles by Guidot, D. M. Articles by Matthay, M. A.

EB2006 SYMPOSIUM REPORT

Integrating acute lung injury and regulation of alveolar fluid clearance

¹Emory University School of Medicine, Atlanta, Georgia; ²Northeastern Ohio Universities College of Medicine, Rootstown, Ohio; ³Northwestern University Feinberg School of Medicine, Chicago, Illinois; and ⁴University of California at San Francisco School of Medicine and the Cardiovascular Research Institute, San Francisco, California

ABSTRACT

The acute respiratory distress syndrome (ARDS) is characterized by non-cardiogenic pulmonary edema and flooding of the alveolar air spaces with proteinaceous fluid. ARDS develops in response to inflammatory stresses including sepsis, trauma, and severe pneumonia, and despite aggressive critical care management, it still has a mortality of 30–50%. At the time of its original description in 1967, relatively little was known about the specific mechanisms by which the alveolar epithelium regulated lung fluid balance. Over the last 20 years, substantial advances in our understanding of the alveolar epithelium have provided major new insights into how molecular and cellular mechanisms regulate the active transport of solutes and fluid across the alveolar epithelium under both normal and pathological conditions. Beginning with the elucidation of active sodium transport as a major driving force for the transport of water from the air space to the interstitium, elegant work by multiple investigators has revealed a complex and integrated network of membrane channels and pumps that coordinately regulates sodium, chloride, and water flux in both a cell- and condition-specific manner. At the Experimental Biology Meeting in San Francisco on April 4, 2006, a symposium was held to discuss some of the most recent advances. Although there is still much to learn about the mechanisms that impair normal alveolar fluid clearance under pathological conditions, the compelling experimental findings presented in this symposium raise the prospect that we are now poised to test and develop therapeutic strategies to improve outcome in patients with acute lung injury.

I. USING SMALL INTERFERING RNA IN WHOLE LUNG: -ADRENERGIC STIMULATION OF ENAC

Alveolar fluid clearance (AFC) occurs secondary to vectorial sodium transport across the alveolar epithelium where sodium enters alveolar epithelial cells presumably through apical ENaC and is extruded by basolateral Na-K-ATPases (27, 28). The fairly specific ENaC blocker amiloride inhibits a significant fraction of unstimulated and stimulated AFC (27, 28). Also, -adrenoceptor (AR) agonists that increase intracellular cAMP levels can stimulate AFC (27, 28). In our studies (25), we determined the involvement of ENaC in both baseline and AR-stimulated AFC in rats by specific gene knockdown using the novel RNA interference technology. We used small interfering RNA (siRNA)-generating plasmid DNA (pDNA) vectors constructed and generated against rat ENaC to investigate ENaC involvement in AFC. Of the four pDNA vectors we generated and tested, pSi-4 was the most effective at silencing lung-specific expression of ENaC. Message for ENaC was undetectable in pSi-4-pretreated lungs, regardless of condition, but was not affected in pSi-0-pretreated lungs (scramble siRNA-generating pDNA vector; Fig. 1, A and B). Alveolar epithelial type II (ATII) cells were then isolated 24 h after in vivo pSi-4 pretreatment and ENaC was undetectable; thus ATII cell ENaC expression was attenuated after pSi-4 instillation (Fig. 1C). We determined that pSi-4-pretreatment reduced baseline AFC by 30%, whereas the AR agonist terbutaline failed to increase AFC after pSi-4 pretreatment (Fig. 1D). There existed a dose-response relationship that supported a specific effect from pSi-4 pretreatment on ENaC knockdown. We tested for specificity and found no changes in ENaC expression or ₁-Na-K-ATPase expression, and ENaC knockdown was organ specific. The most remarkable finding of this study was the fact that only terbutaline-stimulated AFC was fully sensitive to ENaC silencing. When using amiloride as an inhibitor of AFC, amiloride typically inhibits 40–70% (13, 27, 28, 33, 36, 43) of both stimulated and baseline AFC. The apparent discrepancy suggests that there are two separate mechanisms: one that may not rely on ENaC entirely, although is amiloride sensitive and responsible for baseline AFC, and a second that relies fully on ENaC and is responsible for terbutaline-stimulated AFC. Another possibility is that amiloride did not inhibit all ENaC due to loss of amiloride from the distal air spaces after instillation, thus generating a potentially low amiloride concentration. We used amiloride at a concentration of 10^–3 M, which in fact may be considered a fairly high amiloride concentration. Even after significant leak and protein binding (43), the expected active air space amiloride concentration would still be high at 10^–4 M. Thus we believe that the vast majority of amiloride-sensitive ENaC would be inhibited by this amiloride concentration. This relationship is further supported by RT-PCR analysis of ENaC mRNA and Western blot analysis of ENaC protein where ENaC expression was attenuated by pSi-4 pretreatment regardless of later terbutaline treatment. Thus AR stimulation of AFC depends critically on ENaC presence in the lung, whereas baseline AFC seems to be less ENaC dependent.

View larger version (41K): [in this window] [in a new window]   Fig. 1. RNA interference of -epithelial Na channel (ENaC) and its effects on alveolar fluid clearance (AFC) in rats. A: representative RT-PCR gel of ENaC mRNA in the lung after pretreatment with the pSi-0 and pSi-4 plasmid DNAs (pDNAs). It is clearly shown that pSi-4 was efficient in silencing ENaC after pDNA pretreatment, as pSi-4 dramatically reduced ENaC mRNA. B: densitometric analysis of ENaC protein in the lung by Western blot 24 h after pretreatment with the irrelevant small interfering RNA (siRNA; pSi-0) and the active siRNA (pSi-4) generating pDNAs during baseline, unstimulated conditions, and terbutaline-stimulated conditions. pSi-4 pretreatment dramatically reduced ENaC protein expression by 80%. *P < 0.05, compared to pSi-0. C: representative RT-PCR gel of ENaC in alveolar epithelial type II (ATII) cells isolated 24 h after in vivo pretreatment with the irrelevant siRNA (pSi-0) and the active siRNA (pSi-4) generating pDNAs. In vivo pSi-4 pretreatment attenuated ENaC mRNA expression in ATII cells compared with ENaC mRNA expression in pSi-0-pretreated ATII cells, thus indicating an alveolar exposure to the siRNA-generating pDNAs after the intratracheal instillations. D: amiloride sensitivity of AFC during baseline unstimulated and terbutaline-stimulated conditions 24 h after pretreatment with the irrelevant pDNA (pSi-0) or the specific ENaC siRNA-generating pDNA (pSi-4). pSi-4 pretreatment attenuated the amiloride sensitivity of both unstimulated and terbutaline-stimulated AFC. *P < 0.05, compared to controls not treated with amiloride. BP, base pairs; OD, optical density; STD, standards.

ALI presents a unique physiological challenge to the alveolar epithelium. To facilitate optimal gas exchange, the epithelium must rapidly remove any excess fluid that accumulates in its alveolar spaces (19, 32). The alveolar flooding and compromise of gas exchange that ensue in conditions such as ARDS represent a pathological extreme of a failure to maintain proper airway fluid balance and account for a significant burden of morbidity and mortality worldwide (29). Extensive research done in the last two decades has shown that precise regulation of the alveolar surface fluid layer is achieved through vectorial transport of solutes between the alveolar surface and interstitial spaces, with active sodium transport across the alveolar epithelium generating the osmotic force for movement of water (26). However, gaps still exist in our understanding of how this fine balance is achieved in vivo. In particular, ATI cells constitute 95% of the alveolar surface area, but their role in ion transport is not completely clear (24). If there are significant differences between the transport characteristics of ATI cells and ATII cells, the current paradigm describing alveolar fluid clearance will need to be modified (5, 18, 22, 37). We have recently identified a number of ion transport pathways in ATI cells (see Fig. 2) making it reasonable to propose that the entire alveolar epithelium composed of ATI and ATII cells participates in alveolar fluid homeostasis (21). ATI cells have similar numbers of highly selective channels and nonselective channels and many more cyclic nucleotide-gated (CNG) channels per patch compared with ATII cells. However, since the cell surface area of ATI to ATII cells is of the order of >40:1, ATI cells possess many more sodium channels than ATII cells. The significant number of functional CNG channels that can be detected in ATI cells, but not in ATII cells, may account for some if not all of amiloride-insensitive alveolar salt and water transport. However, CFTR channels in ATI cells are seen much less frequently than in ATII cells and may represent the rate-limiting step for augmented salt transport by these cells. The precise role of chloride channels and potassium channels observed in ATI cells but not in ATII cells needs to be determined. Overall, based on the complement of functional channels we can identify in the two cell types, we believe that they play a complementary role in alveolar fluid clearance, with ATI cells mediating basal salt and fluid clearance and ATII cells responsible for augmented transport. In addition, significant differences exist in how salt transport is regulated in the two cell types, and the response to various endogenous and exogenous agents known to alter ion transport may be determined primarily by the complement of receptors each cell expresses and the intracellular signaling pathways activated by the interaction of these receptors with appropriate agonists (16). Ultimately, the ability of the alveolar epithelium to respond to sudden changes in fluid flux such as those accompanying ALI will be contingent on the coordinated response of ATI and ATII cells.

View larger version (20K): [in this window] [in a new window]   Fig. 2. The new paradigm for alveolar salt transport. Sodium (Na+) is absorbed from the apical surface of both ATI and ATII cells via ENaC, both highly selective channels (HSC) and nonselective channels (NSC channels), and via cyclic nucleotide-gated channels (CNGC; seen only in ATI cells). Electroneutrality is conserved with chloride (Cl–) movement through the cystic fibrosis transmembrane conductance regulator (CFTR) or through chloride channels (CLC) in ATI and ATII cells and/or paracellularly through tight junctions. In ATII cells, -adrenergic agonists activate both ENaC and CFTR; in contrast, ENaC is activated in ATI and ATII cells by dopamine, but CFTR is not. Purines inhibit ENaC in ATII cells, but their effect on ENaC in ATII cells is yet to be determined. Na+ is transported from the basal surface of both cell types into the interstitial space by Na+-K+-ATPase. Potassium (K+) may be transported from alveolar epithelial cells via K+ channels located on the apical surface of ATI cells or through potential-dependent basolateral K+ channels in ATII cells. CNGC are alternative pathways for the movement of Na+ that would be amiloride insensitive; functional CNGC can be found only in ATI cells and could also serve as a pathway for calcium (Ca2+) entry into the cells. If the net ion movement is from the apical surface to the interstitium, an osmotic gradient would be created, which would in turn direct water transport in the same direction, either through aquaporins (AQP) or by diffusion.

Patients with ALI usually have pulmonary edema leading to gas exchange impairment, which results in significant morbidity and mortality. Starling forces regulate edema formation during lung injury; however, the lung ability to clear edema is dependent on active sodium transport where sodium enters the cell via apical ENaC and is extruded by the basolateral Na-K-ATPase, with water following the sodium gradient (32). The Na-K-ATPase, a membrane protein critically important for the maintenance of the ion gradients required for cell homeostasis, consists of a catalytic -subunit and a regulatory -subunit. Active sodium and potassium transport by this protein is responsible for 20–80% of the cell’s resting metabolic rate and 30% of cellular ATP consumption. Exposure of the alveolar epithelium to hypoxic conditions has significant adverse effects on epithelial function (20). Important observations have been made over the recent past on the effects of acute hypoxia on alveolar epithelial function. We propose that during hypoxia, the cell senses the lack of oxygen, and via a complex signaling process involving mitochondrial reactive oxygen species (ROS) and the ubiquitin system, regulates its adaptive response by stabilizing hypoxia-inducible factor-1 (6, 17, 38). This in turn leads to activation of transcription factors that ultimately induce protection against hypoxia. In parallel, the ubiquitin system regulates a decrease in cellular Na-K-ATPase activity during hypoxia as generation of mitochondrial ROS activate PKC- and consequent phosphorylation and ubiquitination of the Na pump (9, 10). These steps ultimately promote endocytosis of the pump from the plasma membrane into intracellular pools, and if hypoxia persists, the degradation of the pump at the plasma membrane (Fig. 3). Further work is needed to better understand the effects of hypoxia on alveolar epithelial function and to design optimal therapeutic strategies to prevent these deleterious effects.

View larger version (22K): [in this window] [in a new window]   Fig. 3. Proposed schema by which hypoxia leads to internalization and degradation of the alveolar epithelial Na-K-ATPase pump. Reactive oxygen species (ROS) generated by mitochondria in response to hypoxia activate PKC-, which phosphorylates the pump and thereby initiates a series of steps that ultimately leads to internalization and degradation of the pump by the ubiquitin system.

IV. TRANSFORMING GROWTH FACTOR- AND ALI

The cytokine transforming growth factor-1 (TGF-1) belongs to a family of proteins that includes three members: TGF-1, TGF-2, and TGF-3. Stored as a nonactive protein in the extracellular space by its binding to latent-associated peptide (LAP), TGF-1 can be activated by mild protein denaturation, oxidants, several classes of proteases, or thrombospondin-1. Furthermore, two integrins have been shown to activate TGF-1 in the lung. The _v6-integrin activates TGF-1 via an inside-out signal that results in the presentation of active TGF-1 to its receptors in a paracrine fashion without the release of free active TGF-1. In contrast, the _v8-integrin activates TGF-1 by presenting LAP to metalloproteinases that degrade LAP and release free active TGF-1 (reviewed in Ref. 39).

TGF-1 has multiple roles in the lung that include, but are not limited to, development, cell proliferation, immunity, and cancer. After ALI, TGF-1 has been most thoroughly evaluated during the late phases of tissue repair where it plays a critical role in the development of pulmonary fibrosis (40). However, recent experimental evidence indicates that the expression levels of several TGF-1-inducible genes are dramatically increased before the development of alveolar flooding caused by exposure to bleomycin (23) or nickel (42). In vitro, TGF-1 directly increases the permeability of lung endothelial and epithelial monolayers (3, 8, 35). In vivo, active TGF-1 is a critical mediator of alveolar edema induced by bleomycin, Escherichia coli endotoxin (35), or nickel (42). Furthermore, TGF-1 inhibits alveolar epithelial sodium and fluid transport, both in vitro and in vivo, via an ERK1/2-dependent repression of ENaC mRNA and protein expression (13). Finally, TGF-1 potentiates Fas-induced lung epithelial cell apoptosis (15), inhibits surfactant release (2), and induces the expression of the plasminogen activator inhibitor by distal epithelial cells (4), three important mechanisms associated with lung epithelial dysfunction in ALI (41).

The potential clinical relevance of these recent observations is beginning to come into focus. Earlier clinical studies had shown that the TGF-1-inducible gene, procollagen type III, is one of the earliest and best predictors of the severity of ALI in humans (7). A recent study including a small number of patients showed the presence of functionally active TGF-1 in the bronchoalveolar lavage fluid from patients within 24 h of the diagnosis of ALI, whereas none was detected in control subjects (11). Investigators at Emory University have provided strong experimental and clinical evidence supporting a pathophysiological role for TGF-1 in alcoholics. Specifically, these investigators have identified that alcohol abuse increases the risk for developing ALI approximately fourfold after sepsis (31). In experimental models they have shown that alcohol-mediated susceptibility to ALI is related to increased lung endothelial and epithelial permeability and a severe reduction in the level of glutathione in the air spaces. Recent findings from these models implicate angiotensin II-induced expression of latent TGF-1 in the lungs that, in response to a second insult such as sepsis, is rapidly activated and released into the alveolar space where it promotes permeability of the alveolar-capillary barrier (1). Figure 4 shows a proposed scheme by which activation of latent TGF-1 contributes to ALI and how both lung-specific expression of TGF-1 and its activation and release into the airway are amplified by chronic alcohol abuse. This conceptual framework provides the basis for investigating other conditions that cause chronic redox stress and therefore would be predicted to increase TGF-1 expression and activation. Together, these experimental and clinical results indicate that the activation of TGF-1 could play an important role not only in the development of lung fibrosis associated with ALI but also in the early exudative phase of this syndrome in humans.

View larger version (28K): [in this window] [in a new window]   Fig. 4. Proposed hypothetical scheme by which activation of latent transforming growth factor (TGF)-1 within the lung contributes to the pathophysiology of acute respiratory distress syndrome (ARDS) and how chronic alcohol abuse amplifies this sequence. TGF-1 is normally bound in cells or within the extracellular matrix by a latent-associated peptide that keeps it inactive (see text for details). During acute inflammatory stresses such as sepsis, TGF-1 is released and activated into the alveolar space where it contributes to acute epithelial barrier dysfunction, which is a cardinal feature of ARDS. Chronic alcohol abuse, via the sequential actions of angiotensin II and the consequent redox stress, increases both the lung-specific expression of latent TGF-1 as well as its activation and release into the alveolar space, mechanisms that may contribute to the 4-fold increased risk of ARDS observed in otherwise healthy alcoholics in response to sepsis.

Alveolar fluid clearance is a complex process that requires the coordinated transport of sodium, chloride, water, and other molecules across the normally tight epithelium barrier into the interstitial space. Although it is clear that the active transport of sodium drives a significant fraction of overall fluid clearance, it is clear that other mechanisms, including chloride transport, are involved. Recent studies that have taken an integrative physiological approach in both experimental models and in clinical studies are beginning to elucidate the critical role of alveolar fluid clearance in both health and in the response to ALI. Studies of isolated ATII cells and, more recently, ATI cells have enabled investigators to identify common as well as cell-specific mechanisms by which the lung removes excess alveolar fluid from the distal air spaces. In addition, the application of powerful techniques such as RNA interference and single-cell patch clamping in intact lung slices has advanced the field rapidly. Recent studies, including those highlighted in the four presentations in this symposium, are revealing the complex mechanisms that maintain this important and unique microenvironment.

FOOTNOTES

Address for reprint requests and other correspondence: D. M. Guidot, Atlanta VAMC (151-P), 1670 Clairmont Road, Decatur, GA 30033 (e-mail: dguidot{at}emory.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

REFERENCES

1. Bechara RI, Pelaez A, Palacio A, Joshi PC, Hart CM, Brown LA, Raynor R, and Guidot DM. Angiotensin II mediates glutathione depletion, transforming growth factor-1 expression, and epithelial barrier dysfunction in the alcoholic rat lung. Am J Physiol Lung Cell Mol Physiol 289: L363–L370, 2005.[Abstract/Free Full Text]
2. Beers MF, Solarin KO, Guttentag SH, Rosenbloom J, Kormilli A, Gonzales LW, and Ballard PL. TGF-1 inhibits surfactant component expression and epithelial cell maturation in cultured human fetal lung. Am J Physiol Lung Cell Mol Physiol 275: L950–L960, 1998.[Abstract/Free Full Text]
3. Birukova AA, Birukov KG, Adyshev D, Usatyuk P, Natarajan V, Garcia JG, and Verin AD. Involvement of microtubules and Rho pathway in TGF-1-induced lung vascular barrier dysfunction. J Cell Physiol 204: 934–947, 2005.[CrossRef][ISI][Medline]
4. Boehm JR, Kutz SM, Sage EH, Staiano-Coico L, and Higgins PJ. Growth state-dependent regulation of plasminogen activator inhibitor type-1 gene expression during epithelial cell stimulation by serum and transforming growth factor-1 . J Cell Physiol 181: 96–106, 1999.[CrossRef][ISI][Medline]
5. Borok Z, Liebler JM, Lubman RL, Foster MJ, Zhou B, Li X, Zabski SM, Kim KJ, and Crandall ED. Na transport proteins are expressed by rat alveolar epithelial type I cells. Am J Physiol Lung Cell Mol Physiol 282: L599–L608, 2002.[Abstract/Free Full Text]
6. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, and Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA 95: 11715–11720, 1998.[Abstract/Free Full Text]
7. Chesnutt AN, Matthay MA, Tibayan FA, and Clark JG. Early detection of type III procollagen peptide in acute lung injury: pathogenetic and prognostic significance. Am J Respir Crit Care Med 156: 840–845, 1997.[Abstract/Free Full Text]
8. Clements RT, Minnear FL, Singer HA, Keller RS, and Vincent PA. RhoA and Rho-kinase dependent and independent signals mediate TGF--induced pulmonary endothelial cytoskeletal reorganization and permeability. Am J Physiol Lung Cell Mol Physiol 288: L294–L306, 2005.[Abstract/Free Full Text]
9. Comellas AP, Dada LA, Lecuona E, Pesce LM, Chandel NS, Quesada N, Budinger GR, Strous GJ, Ciechanover A, and Sznajder JI. Hypoxia-mediated degradation of Na,K-ATPase via mitochondrial reactive oxygen species and the ubiquitin-conjugating system. Circul Res 98: 1314–1322, 2006.[Abstract/Free Full Text]
10. Dada LA, Chandel NS, Ridge KM, Pedemonte C, Bertorello AM, and Sznajder JI. Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-. J Clin Invest 111: 1057–1064, 2003.[CrossRef][ISI][Medline]
11. Fahy RJ, Lichtenberger F, McKeegan CB, Nuovo GJ, Marsh CB, and Wewers MD. The acute respiratory distress syndrome: a role for transforming growth factor-1. Am J Respir Cell Mol Biol 28: 499–503, 2003.[Abstract/Free Full Text]
12. Fang X, Fukuda N, Barbry P, Sartori C, Verkman AS, and Matthay MA. Novel role for CFTR in fluid absorption from the distal airspaces of the lung. J Gen Physiol 119: 199–207, 2002.[Abstract/Free Full Text]
13. Finley N, Norlin A, Baines DL, and Folkesson HG. Alveolar epithelial fluid clearance is mediated by endogenous catecholamines at birth in guinea pigs . J Clin Invest 101: 972–981, 1998.[ISI][Medline]
14. Frank J, Roux J, Kawakatsu H, Su G, Dagenais A, Berthiaume Y, Howard M, Canessa CM, Fang X, Sheppard D, Matthay MA, and Pittet JF. Transforming growth factor-1 decreases expression of the epithelial sodium channel ENaC and alveolar epithelial vectorial sodium and fluid transport via an ERK1/2-dependent mechanism. J Biol Chem 278: 43939–43950, 2003.[Abstract/Free Full Text]
15. Hagimoto N, Kuwano K, Inoshima I, Yoshimi M, Nakamura N, Fujita M, Maeyama T, and Hara N. TGF-1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. J Immunol 168: 6470–6478, 2002.[Abstract/Free Full Text]
16. Helms MN, Chen XJ, Ramosevac S, Eaton DC, and Jain L. Dopamine regulation of amiloride-sensitive sodium channels in lung cells. Am J Physiol Lung Cell Mol Physiol 290: L710–L722, 2006.[Abstract/Free Full Text]
17. Hochachka PW, Buck LT, Doll CJ, and Land SC. Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc Natl Acad Sci USA 93: 9493–9498, 1996.[Abstract/Free Full Text]
18. Jain L and Eaton DC. Alveolar fluid transport: a changing paradigm. Am J Physiol Lung Cell Mol Physiol 290: L646–L648, 2006.[Free Full Text]
19. Jain L and Eaton DC. Physiology of fetal lung fluid clearance and the effect of labor. Semin Perinatol 30: 34–43, 2006.[CrossRef][ISI][Medline]
20. Jain M and Sznajder JI. Effects of hypoxia on the alveolar epithelium. Proc Am Thor Soc 2: 202–205, 2005.
21. Johnson MD, Bao HF, Helms MN, Chen XJ, Tigue Z, Jain L, Dobbs LG, and Eaton DC. Functional ion channels in pulmonary alveolar type I cells support a role for type I cells in lung ion transport. Proc Natl Acad Sci USA 103: 4964–4969, 2006.[Abstract/Free Full Text]
22. Johnson MD, Widdicombe JH, Allen L, Barbry P, and Dobbs LG. 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 99: 1966–1971, 2002.[Abstract/Free Full Text]
23. Kaminski N, Allard JD, Pittet JF, Zuo F, Griffiths MJ, Morris D, Huang X, Sheppard D, and Heller RA. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. Proc Natl Acad Sci USA 97: 1778–1783, 2000.[Abstract/Free Full Text]
24. Kemp PJ and Kim KJ. Spectrum of ion channels in alveolar epithelial cells: implications for alveolar fluid balance. Am J Physiol Lung Cell Mol Physiol 287: L460–L464, 2004.[Abstract/Free Full Text]
25. Li T and Folkesson HG. RNA interference for ENaC inhibits rat lung fluid absorption in vivo. Am J Physiol Lung Cell Mol Physiol 290: L649–L660, 2006.[Abstract/Free Full Text]
26. Matalon S, Lazrak A, Jain L, and Eaton DC. Invited review: biophysical properties of sodium channels in lung alveolar epithelial cells. J Appl Physiol 93: 1852–1859, 2002.[Abstract/Free Full Text]
27. Matthay MA, Folkesson HG, and Clerici C. Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev 82: 569–600, 2002.[Abstract/Free Full Text]
28. Matthay MA, Folkesson HG, and Verkman AS. Salt and water transport across alveolar and distal airway epithelium in the adult lung. Am J Physiol Lung Cell Mol Physiol 270: L487–L503, 1996.[Abstract/Free Full Text]
29. Matthay MA and Zimmerman GA. Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol 33: 319–327, 2005.[Free Full Text]
30. McAuley DF, Frank JA, Fang X, and Matthay MA. Clinically relevant concentrations of ₂-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent air space fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury. Crit Care Med 32: 1470–1476, 2004.[CrossRef][ISI][Medline]
31. Moss M, Parsons PE, Steinberg KP, Hudson LD, Guidot DM, Burnham E, Eaton S, and Cotsonis G. Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock. Crit Care Med 31: 869–877, 2003.[CrossRef][ISI][Medline]
32. Mutlu GM and Sznajder JI. Mechanisms of pulmonary edema clearance. Am J Physiol Lung Cell Mol Physiol 289: L685–L695, 2005.[Abstract/Free Full Text]
33. O’Brodovich H, Hannam V, Seear M, and Mullen JB. Amiloride impairs lung water clearance in newborn guinea pigs. J Appl Physiol 68: 1758–1762, 1990.[Abstract/Free Full Text]
34. Perkins GD, McAuley DF, Thickett DR, and Gao F. The -Agonist Lung Injury Trial (BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med 173: 281–287, 2006.[Abstract/Free Full Text]
35. Pittet JF, Griffiths MJ, Geiser T, Kaminski N, Dalton SL, Huang X, Brown LA, Gotwals PJ, Koteliansky VE, Matthay MA, and Sheppard D. TGF- is a critical mediator of acute lung injury. J Clin Invest 107: 1537–1544, 2001.[ISI][Medline]
36. Pittet JF, Wiener-Kronish JP, McElroy MC, Folkesson HG, and Matthay MA. Stimulation of lung epithelial liquid clearance by endogenous release of catecholamines in septic shock in anesthetized rats . J Clin Invest 94: 663–671, 1994.[ISI][Medline]
37. Ridge KM, Olivera WG, Saldias F, Azzam Z, Horowitz S, Rutschman DH, Dumasius V, Factor P, and Sznajder JI. Alveolar type 1 cells express the ₂ Na,K-ATPase, which contributes to lung liquid clearance. Circ Res 92: 453–460, 2003.[Abstract/Free Full Text]
38. Schroedl C, McClintock DS, Budinger GR, and Chandel NS. Hypoxic but not anoxic stabilization of HIF-1 requires mitochondrial reactive oxygen species. Am J Physiol Lung Cell Mol Physiol 283: L922–L931, 2002.[Abstract/Free Full Text]
39. Sheppard D. Integrin-mediated activation of latent transforming growth factor . Cancer Metastasis Rev 24: 395–402, 2005.[CrossRef][ISI][Medline]
40. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, and Calvin D. Targeted disruption of the mouse transforming growth factor-1 gene results in multifocal inflammatory disease. Nature 359: 693–699, 1992.[CrossRef][Medline]
41. Ware LB and Matthay MA. The acute respiratory distress syndrome. N Engl J Med 342: 1334–1349, 2000.[Free Full Text]
42. Wesselkamper SC, Case LM, Henning LN, Borchers MT, Tichelaar JW, Mason JM, Dragin N, Medvedovic M, Sartor MA, Tomlinson CR, and Leikauf GD. Gene expression changes during the development of acute lung injury: role of transforming growth factor . Am J Respir Crit Care Med 172: 1399–1411, 2005.[Abstract/Free Full Text]
43. Yue G and Matalon S. Mechanisms and sequelae of increased alveolar fluid clearance in hyperoxic rats. Am J Physiol Lung Cell Mol Physiol 272: L407–L412, 1997.[Abstract/Free Full Text]

This article has been cited by other articles:

				M. Eisenhut Reduction in systemic epithelial ion transport in septicemia-related pulmonary edema due to changes in amiloride-insensitive sodium transport? Am J Physiol Lung Cell Mol Physiol, August 1, 2008; 295(2): L378 - L378. [Full Text] [PDF]

				M. A. Matthay Measurement of extravascular lung water in patients with pulmonary edema Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1021 - L1022. [Full Text] [PDF]

				M. Licker, J.-M. Tschopp, J. Robert, J.-G. Frey, J. Diaper, and C. Ellenberger Aerosolized Salbutamol Accelerates the Resolution of Pulmonary Edema After Lung Resection Chest, April 1, 2008; 133(4): 845 - 852. [Abstract] [Full Text] [PDF]

				M. A Matthay and J. Lee {beta}2 Adrenergic agonist therapy may enhance alveolar epithelial repair in patients with acute lung injury Thorax, March 1, 2008; 63(3): 189 - 190. [Full Text] [PDF]

				S. Kunzmann, C. P. Speer, A. H. Jobe, and B. W. Kramer Antenatal inflammation induced TGF-beta1 but suppressed CTGF in preterm lungs Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L223 - L231. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 291/3/L301    most recent 00153.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Guidot, D. M. Articles by Matthay, M. A. Search for Related Content PubMed PubMed Citation Articles by Guidot, D. M. Articles by Matthay, M. A.