1Institut National de la Santé et de la Recherche Médicale U 426, Faculté Xavier Bichat, Université Paris 7, Paris, France; and 2Cardiovascular Research Institute, University of California, San Francisco, California 94143
THE CYTOKINE TRANSFORMING GROWTH FACTOR-1 (TGF-
1) plays a critical role in the resolution of tissue injury in multiple organs, including the lung. The role of TGF-
1 in the development of pulmonary fibrosis has been demonstrated in several reports by evaluating the later stages of tissue repair after bleomycin administration. For example, the role of TGF-
1 in bleomycin-induced lung fibrosis was demonstrated by recent evidence that mice deficient either in integrin
v
6, which locally activates TGF-
1, or in Smad3, which transduces TGF-
signals from the cell membrane to the nucleus, are protected from pulmonary fibrosis (2).
In mice, the early phase of bleomycin-induced lung injury is similar to human acute lung injury, which is characterized by alveolar flooding with a protein-rich exudate. Interestingly, TGF-inducible genes, such as procollagen III, were dramatically increased as early as 2 days after the induction of lung injury, suggesting that activation of TGF-1 is an early event that could be important in bleomycin-induced alveolar flooding. The crucial role of TGF-
1 in the bleomycin-induced alveolar edema was recently demonstrated by Pittet et al. (2). These investigators showed that 5 days after intratracheal administration of bleomycin, there was an increase in lung permeability to protein and in the extravascular water content of the lung in wild-type mice, but not in mice lacking the integrin
v
6. This protective effect was reproduced in wild-type mice after pharmacological inhibition of TGF-
1. The integral role of TGF-
1 in the increase of alveolar epithelial permeability was also strengthened by in vitro experiments demonstrating that addition of TGF-
1 to alveolar epithelial cells elicited a dose-dependent decrease of transepithelial resistance. At present, the mechanisms by which TGF-
1 decreased transepithelial resistance are not fully elucidated. In a previous report, Pittet et al. (2) attributed this effect to the depletion of intracellular glutathione. However, a possible role of TGF-
1 on tight junctional complex, as previously reported in epithelial renal cells (4), could not be excluded.
The study from Willis et al., one of the current articles in focus (Ref. 5, see p. L1192 in this issue), also reports that, in vitro, TGF-1 directly modulates ion conductance and active transport in rat lung alveolar epithelial cells. Addition of TGF-
1 from day 0-6 increased transcellular active Na+ transport as evaluated by the amiloride and ouabain components of short-circuit current. This effect was associated with an increase in membrane-associated as well as total cellular Na+-K+-ATPase subunits. Interestingly, although Na+-K+-ATPase protein expression was increased, no change in
-epithelial Na+ channel (
-ENaC) protein expression was observed. However, this result did not completely exclude a role of TGF-
1 on ENaC protein expression because the investigators did not evaluate the effects of TGF-
1 on the two other ENaC subunits,
and
, which may be differentially regulated (3). The mechanism whereby TGF-
1 induced an increase in active Na+ transport in alveolar epithelial cells is not clearly elucidated since the TGF-
1-induced increase in short-circuit current was clearly dependent on the concentration, whereas the level of Na+ pump protein, which increased for the low concentrations of TGF-
1, remained stable for the highest concentrations.
Together, these studies highlight a dual role for TGF-1. TGF-
1 increases alveolar barrier permeability, thus favoring the formation of alveolar edema, and concurrently stimulates reabsorption of alveolar fluid through enhanced active ion transport. However, these effects seem to be temporally regulated. Willis et al. (5) reported that the short-term addition of TGF-
1 rapidly decreased the transepithelial resistance, whereas the increase of active Na+ transport was only observed after 72 h of TGF-
1. The differential temporal modulation of alveolar transport properties in vitro would suggest that, in vivo, the TGF-
1-induced increase in alveolar permeability perhaps preceded the upregulation of active Na+ transport. This latter effect may be considered an adaptative response to alveolar flooding that might permit the lung to reduce alveolar edema.
However, several issues need to be studied in more detail. What is the mechanism that leads to an increase in amiloride-sensitive apical Na+ transport? Are amiloride-insensitive Na+ transport proteins involved? Does TGF-1 modify the tight junctional complex-associated proteins? Also, there is a new study that indicates that TGF-
1 can decrease net alveolar epithelial fluid transport in vivo in rats and in vitro in both rat and human alveolar epithelial type II cells (1). This information, when added to the results in the Willis et al. (5) study, indicates the importance of determining the dose- and time-dependent effects of TGF-
1 as well as testing the role of TGF-
1 in the in vivo setting of the normal and injured lung. It is now clear that TGF-
1 should be further investigated for its potential role in the acute regulation of alveolar and lung fluid balance, especially in the setting of acute lung injury. Further studies will help us to answer these questions.
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