Pulmonary oedema, the accumulation of liquid in the gas exchanging region of the lung, is a life threatening condition with many underlying causes including septic and haemorrhagic shock and ascent to high altitude. Although often attributed to disturbed pulmonary haemodynamics, it has proved difficult to form a coherent physiological model of the condition in this way and, to a large extent, this is because the passive movement of liquid is only one of the factors that determines the amount of liquid in the alveolar region. The epithelia that line the gas exchanging regions of the lung thus actively absorb Na+ from the lung lumen and this ion transport process establishes osmotic gradients that favour the continual removal of liquid from the airspaces (see review Olver et al. 2004). Earlier work by Scherrer and colleagues had shown that pulmonary hypertension did not necessarily precipitate oedema, and had provided evidence that a loss of Na+ transport capacity may allow abnormal amounts of liquid to remain in the lung and thus play a role in the development of at least some forms of pulmonary oedema (e.g. Sartori et al. 2000). This issue of TheJournal of Physiology includes new work from this group that significantly strengthens this hypothesis (Egli et al. 2004).

Pulmonary Na+ transport occurs via a mechanism in which Na+ first crosses the apical membrane by diffusing down the inwardly directed electrochemical gradient, and is then extruded from the cell by the basolateral Na+ pump. An important feature of this model is that it is the rate of apical Na+ entry that restricts the overall transport rate and this model, which can account for epithelial Na+ transport in other absorptive tissues, therefore highlights the importance of the ion channel species that allow this influx of Na+. This has now been identified as the epithelial Na+ channel, a transport protein composed of three homologous subunits (α-, β- and γ-ENaC) all of which are expressed in the lung. Moreover, mice with an artificial deletion of α-ENaC cannot clear fluid from their lungs at the time of birth and so die from hypoxia within ∼48 h (Hummler et al. 1996). Lung function is therefore critically dependent upon α-ENaC.

The new study (Egli et al. 2004) extends upon this earlier work by studying the lungs of α-ENaC ‘knock out’ mice in which the deleted mouse gene has been replaced by the corresponding rat transgene whose expression was driven by a constitutively active promoter. Although this manoeuvre did allow the mice to survive into adulthood, electrometric studies indicated that the lung and airway epithelia transported Na+ at an abnormally low rate and direct measurements of liquid transport revealed a corresponding reduction in the rate of alveolar fluid clearance. Whilst expression of the transgene had clearly rescued the lethal phenotype, there was still a substantial impairment of the lungs' capacity to transport Na+ but, despite this deficit, there was no histological evidence of oedema and the lung tissue had a normal wet/dry weight ratio. Under standard conditions it thus appears that the substantial loss of Na+ transport capacity described in this paper has no discernible effect upon lung fluid balance.

A very different picture emerged from experiments that explored the effects of either administering a large dose of thiourea, which increases vascular permeability, or exposing mice to a hyperoxic environment for 72 h. These manoeuvres are both known to cause pulmonary oedema and studies of control animals confirmed the well-documented increase in the wet/dry weight ratio of the lung tissue itself. Moreover histological examination showed clearly that these tissues had become oedematous. The interesting point, however, is that both of these manoeuvres had much larger effects upon the transgenic mice. Indeed, the measurements of wet/dry weight ratio showed that the lungs of these animals accumulated up to 6 times more water than normal whilst histological examination demonstrated much more pronounced oedema. Functional studies confirmed that these exaggerated responses were associated with reduced alveolar fluid clearance and, most importantly, showed the genetic manipulations had had no effect upon the passive permeability properties of the alveolar–capillary barrier. The increased susceptibility to pulmonary oedema must therefore be attributed to the abnormally low rate of Na+ transport.

These new data provide further evidence that active Na+ transport provides an important mechanism that normally protects lung function by preventing the accumulation of liquid in the alveolar region. This highlights the overriding importance of Na+ transport to the integrated functioning of the respiratory tract and stresses the importance of fully understanding the way in which this Na+ absorbing phenotype is initiated and maintained. Moreover, by showing clearly that loss of Na+ transport capacity renders lung tissues far more vulnerable to oedema, the work provides a very strong indication that, rather than being simply due to of altered pulmonary haemodynamics, pulmonary oedema involves defective Na+ transport (e.g. Sartori et al. 2000). Moreover, these new studies also establish a potentially important animal model of this condition and this may well allow further studies of the aetiology of pulmonary oedema and provide a means of testing potential therapies in vivo.