Transforming Growth Factor-β1 Decreases Expression of the Epithelial Sodium Channel αENaC and Alveolar Epithelial Vectorial Sodium and Fluid Transport via an ERK1/2-dependent Mechanism

Acute lung injury (ALI) is characterized by the flooding of the alveolar airspaces with protein-rich edema fluid and diffuse alveolar damage. We have previously reported that transforming growth factor-β1 (TGF-β1) is a critical mediator of ALI after intratracheal administration of bleomycin or Escherichia coli endotoxin, at least in part due to effects on lung endothelial and alveolar epithelial permeability. In the present study, we hypothesized that TGF-β1 would also decrease vectorial ion and water transport across the distal lung epithelium. Therefore, we studied the effect of active TGF-β1 on 22Na+ uptake across monolayers of primary rat and human alveolar type II (ATII) cells. TGF-β1 significantly reduced the amiloride-sensitive fraction of 22Na+ uptake and fluid transport across monolayers of both rat and human ATII cells. TGF-β1 also significantly decreased αENaC mRNA and protein expression and inhibited expression of a luciferase reporter downstream of the αENaC promoter in lung epithelial cells. The inhibitory effect of TGF-β1 on sodium uptake and αENaC expression in ATII cells was mediated by activation of the MAPK, ERK1/2. Consistent with the in vitro results, TGF-β1 inhibited the amiloride-sensitive fraction of the distal airway epithelial fluid transport in an in vivo rat model at a dose that was not associated with any change in epithelial protein permeability. These data indicate that increased TGF-β1 activity in the distal airspaces during ALI promotes alveolar edema by reducing distal airway epithelial sodium and fluid clearance. This reduction in sodium and fluid transport is attributable in large part to a reduction in apical membrane αENaC expression mediated through an ERK1/2-dependent inhibition of the αENaC promoter activity. Acute lung injury (ALI) is characterized by the flooding of the alveolar airspaces with protein-rich edema fluid and diffuse alveolar damage. We have previously reported that transforming growth factor-β1 (TGF-β1) is a critical mediator of ALI after intratracheal administration of bleomycin or Escherichia coli endotoxin, at least in part due to effects on lung endothelial and alveolar epithelial permeability. In the present study, we hypothesized that TGF-β1 would also decrease vectorial ion and water transport across the distal lung epithelium. Therefore, we studied the effect of active TGF-β1 on 22Na+ uptake across monolayers of primary rat and human alveolar type II (ATII) cells. TGF-β1 significantly reduced the amiloride-sensitive fraction of 22Na+ uptake and fluid transport across monolayers of both rat and human ATII cells. TGF-β1 also significantly decreased αENaC mRNA and protein expression and inhibited expression of a luciferase reporter downstream of the αENaC promoter in lung epithelial cells. The inhibitory effect of TGF-β1 on sodium uptake and αENaC expression in ATII cells was mediated by activation of the MAPK, ERK1/2. Consistent with the in vitro results, TGF-β1 inhibited the amiloride-sensitive fraction of the distal airway epithelial fluid transport in an in vivo rat model at a dose that was not associated with any change in epithelial protein permeability. These data indicate that increased TGF-β1 activity in the distal airspaces during ALI promotes alveolar edema by reducing distal airway epithelial sodium and fluid clearance. This reduction in sodium and fluid transport is attributable in large part to a reduction in apical membrane αENaC expression mediated through an ERK1/2-dependent inhibition of the αENaC promoter activity. Acute lung injury (ALI) 1The abbreviations used are: ALI, acute lung injury; ATII, alveolar type II cells; PD, potential difference; ENaC, epithelial sodium channel; ERK, extracellular-regulated protein kinase; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; GRE, glucocorticoid response element; HSC, highly selective cation channels; TGF-β1, transforming growth factor β1; SPD, spontaneous potential difference; TEC, transepithelial current. is a devastating syndrome characterized by flooding of alveolar spaces with a protein-rich exudate that impairs pulmonary gas exchange, leading to arterial hypoxemia and respiratory failure (1Ware L.B. Matthay M.A. N. Engl. J. Med. 2000; 342: 1334-1349Crossref PubMed Scopus (4492) Google Scholar). Epithelial injury can contribute to alveolar flooding, because the epithelial barrier is much less permeable under normal conditions than the endothelial barrier. Injury to alveolar epithelial cells can also disrupt normal epithelial fluid transport, impairing the removal of edema fluid from the alveolar space. Clinical studies have demonstrated that impaired alveolar fluid clearance is a characteristic feature of clinical lung injury (2Ware L.B. Matthay M.A. Am J. Respir. Crit. Care Med. 2001; 163: 1376-1383Crossref PubMed Scopus (738) Google Scholar, 3Matthay M.A. Wiener-Kronish J.P. Am. Rev. Respir. Dis. 1990; 142: 1250-1257Crossref PubMed Scopus (506) Google Scholar), but the mechanisms for this decrease in epithelial fluid transport have not been well worked out. The removal of edema fluid from the airspaces occurs via an active transport-dependent sodium concentration gradient across the distal lung epithelium. The rate-limiting step in the transport of fluid across the lung epithelium is the movement of sodium and chloride across the apical plasma membrane, specifically the movement of sodium through amiloride-sensitive and -insensitive channels (4Matthay M.A. Folkesson H.G. Clerici C. Physiol. Rev. 2002; 82: 569-600Crossref PubMed Scopus (574) Google Scholar). Among the sodium channels at the apical membrane of lung epithelial cells, amiloride-sensitive channels represent 50–60% of the sodium transport, particularly in rat and human lungs (4Matthay M.A. Folkesson H.G. Clerici C. Physiol. Rev. 2002; 82: 569-600Crossref PubMed Scopus (574) Google Scholar). Molecular identification of the in amiloride-sensitive sodium in the that and to the that a amiloride-sensitive Am. J. Physiol. PubMed Google Scholar). The critical of αENaC in the of and fluid by lung epithelial cells been by the of respiratory syndrome and of from failure to lungs of fluid J. C. PubMed Scopus Google Scholar). In and to fluid from the lungs at at a than in the PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). The of distal lung sodium and fluid transport also been associated with respiratory failure and in with acute lung injury M.A. Wiener-Kronish J.P. Am. Rev. Respir. Dis. 1990; 142: 1250-1257Crossref PubMed Scopus (506) Google the mechanisms for the of the distal lung sodium and fluid transport in acute lung injury not The transforming growth factor (TGF-β1) a critical in the of injury in the lung C. N. PubMed Scopus Google Scholar). acute lung TGF-β1 been during the of a critical in the of pulmonary M.A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). in a of expression lung we that the expression of increased after the of injury N. 2000; PubMed Scopus Google Scholar), a that the in alveolar flooding in this the is of the of the of acute lung injury in Matthay M.A. Am. J. Respir. Crit. Care Med. PubMed Scopus Google Scholar, Med. PubMed Scopus Google Scholar). In TGF-β1 the of endothelial monolayers Am. J. Physiol. Google Scholar). of and acute lung we previously that active TGF-β1 is a critical mediator of alveolar edema J. Matthay Am. J. Respir. Crit. Care Med. Scholar). In TGF-β1 increased across epithelial and endothelial mechanisms by this contribute to alveolar In to effect on the protein across the lung endothelial and epithelial TGF-β1 was to the ion channels at the apical membrane of the alveolar epithelium. a a that TGF-β1 reduced the activity of highly selective cation channels at the apical membrane of ATII cells Am. J. Respir. Crit. Care Med. 2002; Scholar). the mechanisms effects and in vivo not channels by a of the in J. Physiol. PubMed Scopus Google Scholar). We hypothesized that activation of a would decrease vectorial fluid transport across the lung epithelium by expression or of the amiloride-sensitive sodium in lung epithelial cells. We that TGF-β1 fluid alveolar epithelial sodium and fluid transport, both in vitro and in and that this effect is due to an ERK1/2-dependent of αENaC mRNA and protein in a reduction in the of αENaC at the apical of alveolar epithelial cells. of rat and human alveolar epithelial cells used for the in vitro ATII cells by and selective on rat previously reported N. Matthay M.A. J. 2001; PubMed Scopus Google Scholar). ATII cells on with a at a concentration of in and and at in a epithelial cells by with and was to the of the the ATII monolayers with an on apical cells monolayers that a transepithelial than of the of on human alveolar epithelial type II cells a of previously J. Matthay Am. J. Respir. Crit. Care Med. Scholar). alveolar type II cells from human lungs that not used by the studies indicate that lungs in both and Matthay 2002; PubMed Scopus Google Scholar). after the lungs been for at of the human lung was that of injury on the and of or The pulmonary for this was with and the distal airspaces of a with and of in a was the airspaces of of the of lung The lung was in a water for at and in the of and The fraction was through and and The was a gradient and at for to cells. The cells that at the of the and the a of type II and alveolar These cells by at for at The was in The cells in with an at for under to The was by The of human alveolar type II cells was by or by with type II from of and been than not alveolar type II cells on at a of after the cells the a transepithelial than reported for rat ATII by the of water and and from TGF-β1 was from was from at a activity of and at a concentration of and from The of the of of the and of and of the c-Jun N-terminal from of have been to in lung epithelial cells Am. J. Respir. Crit. Care Med. PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar, Am. J. Physiol. Google Scholar). a glucocorticoid been from the of was from was from and and from and αENaC by C. of and for from and with from from and the was from The a from a the luciferase under the of the αENaC promoter a the luciferase under the of a αENaC promoter with a in the glucocorticoid and a the luciferase under the of the αENaC promoter and a concentration of was the protein with the from rat ATII cells was by a of the C. C. C. Am. J. Physiol. 2001; Scholar). of was on a and to membrane by with a was in a sodium and The with αENaC and with αENaC mRNA was with a to the a with rat αENaC C. C. C. Am. J. Physiol. 2001; Scholar). mRNA was to expression to that the of was present in The of a that been by and of the rat C. C. C. Am. J. Physiol. 2001; Scholar). the for with sodium sodium and sodium The to an or to a for and was with from cells from was previously J. Matthay M.A. J. 2001; PubMed Scopus Google Scholar). of protein in and in to and αENaC was an at a and at a and with at a of and at a of and at a The protein was a and of apical membrane previously J. Physiol. 2002; PubMed Scopus Google The protein concentration of the was the to of protein to the The of was to a of from from the by to in and by and spontaneous potential apical the was from the The effect of TGF-β1 for or on of ATII was on in previously been that TGF-β1 can a of in lung epithelial cells J. PubMed Google Scholar), TGF-β1 was also to the apical or of the activity of sodium transport on the apical membrane of rat and human ATII cells was by uptake the by Am. J. Physiol. 2002; Google Scholar). after to TGF-β1 or to on both of the the cells with and at and to the for The was of and at the was with at a activity of and monolayers by with to not by the cells and to We that the not any The cells with and the in the was in a was used for of the have that the uptake was a of was in transport across rat and human ATII monolayers was previously J. Matthay J. Scholar). after rat ATII cells on and in an for of was to the apical of the and the in a of from the apical for at with in a in and of the at the to any effect of the a was from the apical of the monolayers and in a was in in vivo studies C. Folkesson H.G. Matthay M.A. J. Physiol. 2002; PubMed Scopus Google Scholar). in the in the In we to a in the fluid transport across ATII monolayers after and a inhibition of the fluid transport after to not ATII cells with of the a the luciferase under the of the αENaC promoter and a that a expression the promoter a the luciferase under the of the αENaC promoter or a the luciferase under the of a αENaC promoter with a in the rat ATII cells on and in an for cells in by with of of the cells to TGF-β1 or for or In an of or MAPK, or with or a glucocorticoid was to the to to TGF-β1 or and for luciferase activity to the a activity was for protein and reported a of the cells that but not with also with a and activity was in to that the of was and after to conditions was by an by and at in the for The was and on a at This was by the of on with an of and in a and a was the under TGF-β1 or was the through a the was the The of was to the effect of active TGF-β1 or in on the lung endothelial and alveolar epithelial to In the of distal fluid clearance was after the intratracheal administration of TGF-β1 or in the TGF-β1 and in the we have Matthay M.A. Am. J. Respir. Crit. Care Med. 2002; PubMed Scopus Google Scholar). that active TGF-β1 the airspaces lung epithelial fluid clearance at that not have any effect on the protein across this barrier. In both a decrease in lung epithelial fluid transport and in lung endothelial and epithelial to the dose of active TGF-β1 for studies was that we the effect of active TGF-β1 on the in vivo vectorial lung epithelial fluid transport the effect of in epithelial to the of in vivo of the lung endothelial and alveolar epithelial to we used the intratracheal of a of pulmonary edema lung lung water was on the lung Matthay M.A. Am. J. Respir. Crit. Care Med. 2002; PubMed Scopus Google Scholar). after intratracheal of TGF-β1 or of in of was and at the of the after administration of plasma the lung was for of lung endothelial to plasma in the Matthay M.A. Am. J. Respir. Crit. Care Med. 2002; PubMed Scopus Google Scholar), the in the the in plasma at the of the and the in the plasma at and at the of the is the in the lungs by the the effect of TGF-β1 or on the lung epithelial to the lung was with of and the of the was epithelial to protein was distal plasma in the the in the and the in the plasma at and at the of the in studies Matthay M.A. Am. J. Respir. Crit. Care Med. 2002; PubMed Scopus Google Scholar), we distal fluid clearance by the in protein concentration a of an in normal the an in model previously Matthay M.A. Am. J. Respir. Crit. Care Med. 2002; PubMed Scopus Google Scholar). The in protein concentration a of the from the distal airspaces of the lung Matthay M.A. Am. J. Respir. Crit. Care Med. 2002; PubMed Scopus Google Scholar). with and by of the in to was the airway of of was for with after a was from the distal a was from the distal was at the with an and was with a in the the of alveolar fluid during the was the is the at and is the of the data of and used to with of was TGF-β1 and across Epithelial previously reported that active TGF-β1, at of and in the of rat ATII monolayers N. Matthay M.A. J. 2001; PubMed Scopus Google Scholar). we to of active TGF-β1 would sodium and fluid to active TGF-β1 on both of the at for significantly decreased the transepithelial across primary of rat ATII monolayers from the of transepithelial and spontaneous potential with an epithelial with This inhibition of the transepithelial across ATII monolayers TGF-β1 was on the of the TGF-β1 at a concentration of effect on the transepithelial that ion transport effect on transepithelial In of potential and transepithelial in ATII monolayers and after the of a decrease in with change in not the of ATII monolayers is by the We hypothesized that the decrease in the transepithelial was by a decrease in transepithelial ion Therefore, we the effect of TGF-β1 on the sodium uptake across the apical membrane of rat ATII cells. This the and not the transport of sodium across rat ATII TGF-β1 a decrease in sodium uptake by rat ATII cells. and studies that the decrease in sodium uptake by lung epithelial cells was for of active TGF-β1 from to and was from to after to active TGF-β1 the decrease in sodium uptake by rat ATII cells was to and by the of a concentration of that TGF-β1 amiloride-sensitive sodium uptake in cells This effect was for TGF-β1, was by a active TGF-β1, but was not an the of uptake we used a to fluid transport across monolayers of rat ATII cells J. Matthay J. Scholar). TGF-β1 decreased the fluid across rat lung epithelial monolayers by The decrease in transepithelial fluid transport after to active TGF-β1 is with the with sodium This to fluid transport in an studies have and ion uptake across lung epithelial cells. TGF-β1 in Epithelial in active TGF-β1 would in vivo fluid clearance across the distal epithelium in with of active TGF-β1 or with via a in the This dose of TGF-β1 was because a decrease in lung epithelial fluid clearance but not have any effect on the protein across this barrier. TGF-β1 a decrease in the vectorial fluid transport across the distal airspaces in TGF-β1 the amiloride-sensitive fraction of the fluid decrease in fluid clearance was was to the protein the distal airspaces in a protein with was after administration of TGF-β1 and of the that active TGF-β1 a in the of and not the lung water by the active TGF-β1 not the protein across the distal lung epithelium of TGF-β1 increased both epithelial and endothelial not indicate that active TGF-β1 in normal lungs the amiloride-sensitive fraction of the fluid transport across the distal epithelium at a dose that not the lung epithelial to TGF-β1 the of across the of of ATII studies on the effect of TGF-β1 on sodium uptake by ATII cells was to primary of human ATII cells due to the of in the of sodium uptake and to TGF-β1 for a decrease in sodium uptake across the apical membrane of human lung epithelial cells TGF-β1 the amiloride-sensitive fraction of the apical sodium decrease in sodium uptake was was with TGF-β1 data indicate that active TGF-β1 a inhibition of the vectorial movement of sodium across the apical membrane of rat and human lung epithelial monolayers and TGF-β1 αENaC and in Epithelial of demonstrated that TGF-β1 significantly the of amiloride-sensitive sodium the of was to active TGF-β1 would the αENaC and protein αENaC expression was by after to active TGF-β1 for The that TGF-β1 than a decrease in the αENaC expression with cells with active TGF-β1 reduced the αENaC protein expression in lung epithelial cells by studies from have that active TGF-β1 decreased channels at the of rat lung epithelial cells Am. J. Respir. Crit. Care Med. 2002; Scholar). studies have demonstrated that channels to the channels of the of Am. J. Physiol. 2001; PubMed Google the of was to active TGF-β1 would decrease the expression of αENaC protein at the apical in apical membrane αENaC protein was by to active TGF-β1 for decreased the of protein by that an was not in the of apical membrane but was in the data that active TGF-β1 both αENaC expression and αENaC protein expression at the apical membrane of rat ATII cells, for the inhibition by TGF-β1 of the amiloride-sensitive fraction of the vectorial sodium transport across the lung epithelium. TGF-β1 and across Epithelial via an ERK1/2-dependent studies have that activation of the can αENaC expression J. 2000; PubMed Scopus Google Scholar). TGF-β1 been to in we to inhibition of αENaC expression and uptake in rat ATII cells was mediated by ERK1/2. with an of the of the decrease in sodium uptake across rat ATII cells In with an of the and of MAPK, or with a of the c-Jun N-terminal not the inhibition of sodium uptake active TGF-β1 the of and in rat lung epithelial cells, an effect by with or of of the previously been that the activation of the a of the of the αENaC by promoter activity J. 2000; PubMed Scopus Google Scholar). rat ATII cells with a the luciferase under the of the αENaC promoter and a the cells to TGF-β1 or for In an of JNK, or was to the to to TGF-β1 or cells and luciferase activity was for and reported a of the cells that but not with also with a and activity was in to that the of was and not The that active TGF-β1 decreased the activity of the αENaC promoter by an effect that was by with the of the In with the of or of the c-Jun N-terminal not the inhibition of αENaC promoter activity in lung epithelial cells αENaC expression in alveolar epithelial cells via to the glucocorticoid on the αENaC promoter C. C. C. Am. J. Physiol. 2001; and in vivo vectorial fluid transport across the lung epithelial barrier H.G. Matthay M.A. J. Physiol. 2000; PubMed Scopus Google Scholar). of αENaC in lung epithelial cells through an ERK1/2-dependent J. 2000; PubMed Scopus Google Scholar). the of was to active TGF-β1 would the of αENaC via an ERK1/2-dependent inhibition of the present on the αENaC ATII cells with a the luciferase under the of the αENaC promoter or with a the luciferase under the of a αENaC promoter with a in the also with a and activity was in to that the of was and not The that active TGF-β1 decreased the αENaC promoter activity by an effect that was by to This effect was not in lung epithelial cells with a that not to of response to was also by the monolayers with a glucocorticoid the cells to TGF-β1 not the αENaC promoter activity in cells that have been with In with an of the and of or with a of the c-Jun N-terminal not the inhibition of the αENaC promoter activity in lung epithelial cells the luciferase activity after with the the of the in cells that not The TGF-β1 a critical in the of injury in the lung C. N. PubMed Scopus Google Scholar). ALI, TGF-β1 been during the of a critical in the of pulmonary M.A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). We have reported that the activation of TGF-β1 in the distal of the lung is a critical step in the of pulmonary edema after intratracheal administration of bleomycin or coli in N. Matthay M.A. J. 2001; PubMed Scopus Google Scholar). TGF-β1 increased alveolar epithelial after activation by the epithelial this from pulmonary edema after of bleomycin N. Matthay M.A. J. 2001; PubMed Scopus Google Scholar). These indicate that active TGF-β1 contribute to the of alveolar edema in impaired alveolar epithelial sodium and fluid transport to pulmonary we hypothesized that the activation of the associated with a decrease in the vectorial ion and water transport across the distal lung epithelium. The of demonstrated that active TGF-β1, at much than to epithelial significantly decreased uptake across the apical membrane of rat and human distal lung epithelial cells, that active TGF-β1 the of apical ion channels in sodium uptake by cells. These by fluid transport across both rat and human ATII monolayers after to active inhibition of the transepithelial across ATII monolayers was TGF-β1 was on the of the This is in with from that have that TGF-β1 can a of the of in lung epithelial cells J. PubMed Google Scholar). studies in the of that active TGF-β1 inhibited or of the amiloride-sensitive fraction of sodium uptake by cells. demonstrated that the amiloride-sensitive in lung epithelial cells is Among the αENaC to a critical in fluid in the distal airspaces of the the of in indicate that αENaC respiratory and after because of to fluid from the airspaces J. C. PubMed Scopus Google Scholar). In and to fluid from the lungs at at a than in the PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). We the inhibition of the vectorial epithelial ion and fluid transport by active TGF-β1 was to a decrease in αENaC and protein expression in lung epithelial cells. of rat ATII cells to TGF-β1 for significantly decreased αENaC and protein expression in cells. TGF-β1 inhibited of the apical membrane expression of by the of This is in with the that TGF-β1 inhibited the amiloride-sensitive uptake by lung epithelial cells and that the expression of at the ATII apical membrane for of the amiloride-sensitive sodium uptake by cells. a demonstrated a in amiloride-sensitive sodium transport at the apical membrane of cells with the and an in expression at the apical membrane of cells J. Physiol. 2002; PubMed Scopus Google Scholar). the mechanisms by TGF-β1 amiloride-sensitive sodium transport and αENaC expression in lung epithelial the activation of a of that to the in response to activation of and downstream effects through expression of In can also and J. 2001; PubMed Scopus Google Scholar). In the study, TGF-β1 was to in rat ATII but the inhibition of the the inhibition of amiloride-sensitive sodium with of studies that have reported that the activation of αENaC and protein expression in epithelial lung epithelial cells J. 2000; PubMed Scopus Google Scholar). In the activation of the been associated with a of αENaC expression in cells Am. J. Physiol. Scholar). the mechanisms by the activation of αENaC expression in lung epithelial studies have that the activation of the activity of the αENaC the of an with inhibited the activity the αENaC promoter via ERK1/2-dependent and in cells, an alveolar epithelial J. 2000; PubMed Scopus Google Scholar). In this inhibition of the αENaC promoter via the of αENaC promoter activity J. 2000; PubMed Scopus Google Scholar), been to of the of the αENaC promoter C. C. C. Am. J. Physiol. 2001; Scholar). that TGF-β1 inhibited the in αENaC promoter activity that the effect of TGF-β1 on αENaC expression in primary lung epithelial cells by a These not the of of of αENaC by TGF-β1, or data indicate that TGF-β1 decreased the membrane expression of αENaC than the αENaC protein that TGF-β1 also the well the of αENaC at the studies have reported that protein expression at the apical membrane of lung epithelial cells by conditions that for acute lung or Wiener-Kronish J.P. Folkesson H.G. Matthay M.A. J. PubMed Scopus Google Scholar, C. Matthay M.A. Clerici C. J. 2002; PubMed Scopus Google Scholar). is associated with a decrease in the membrane expression of the the αENaC protein C. Matthay M.A. Clerici C. J. 2002; PubMed Scopus Google Scholar), sodium uptake across cells by the of to the membrane J. Physiol. 2002; PubMed Scopus Google Scholar). Therefore, studies to TGF-β1 and of at the membrane of lung epithelial cells. In in vivo that active TGF-β1 is a critical mediator of alveolar edema and epithelial in in vivo of acute lung injury N. Matthay M.A. J. 2001; PubMed Scopus Google Scholar). We to TGF-β1 also in vivo alveolar fluid clearance in Consistent with in vitro results, we that active TGF-β1 in normal lungs inhibited the amiloride-sensitive fraction of the fluid transport across the distal epithelium at a dose that not the lung epithelial to the in vivo data from both studies indicate that active TGF-β1 promotes the of alveolar edema by lung epithelial to protein and by the active fluid removal from the airspaces by the lung epithelium. is the of active TGF-β1 in human clinical studies that the is of the and of the of acute lung injury in Matthay M.A. Am. J. Respir. Crit. Care Med. PubMed Scopus Google Scholar, Med. PubMed Scopus Google Scholar). Clinical studies of the of TGF-β1 in the of ALI in a a of the of active TGF-β1 in the fluid from of the of ALI, was in Am. J. Respir. PubMed Scopus Google Scholar). These data that activation of TGF-β1 also an in the of acute lung injury in In the of the that increased TGF-β1 activity in the distal airspaces during ALI promotes alveolar edema by reducing distal epithelial sodium and fluid clearance. This reduction in sodium and fluid transport is attributable in large part to a decrease in apical membrane αENaC expression in lung epithelial cells mediated through an ERK1/2-dependent inhibition of the αENaC promoter activity. Clinical studies have demonstrated that impaired alveolar fluid clearance is a characteristic feature of clinical lung injury (2Ware L.B. Matthay M.A. Am J. Respir. Crit. Care Med. 2001; 163: 1376-1383Crossref PubMed Scopus (738) Google Scholar, 3Matthay M.A. Wiener-Kronish J.P. Am. Rev. Respir. Dis. 1990; 142: 1250-1257Crossref PubMed Scopus (506) Google Scholar). the inhibition of alveolar fluid clearance occurs at a concentration than the to lung epithelial to and active TGF-β1 is present the airspaces of during the of ALI Am. J. Respir. PubMed Scopus Google Scholar), activation of TGF-β1 in the distal airspaces is to a critical for impaired fluid clearance in with We for

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