Strategies to Increase Alveolar Epithelial Fluid Removal in the Injured Lung

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The morbidity and mortality of patients with acute hypoxemic respiratory failure with pulmonary edema remains high. Damage to the alveolocapillary barrier causes the accumulation of pulmonary edema, resulting in acute hypoxemic respiratory failure (AHRF). Recently it has been estimated that the mortality of patients with AHRF exceeds 50,000 in the United States annually. Thus, the search for therapeutic modalities to impact the high mortality of these patients remains a significant challenge for researchers and clinicians. Recent studies have suggested that the outcome of patients with AHRF appears to improve when the lung epithelial function is restored and pulmonary edema resolves, allowing for the extubation and liberation of the patient from mechanical ventilation (1).

In the current issue of the Journal, two articles report on two different animal models of lung injury induced by airspace instillation of hydrochloric acid, which resembles aspiration pneumonitis, and cold smoke inhalation from burning cotton cloth. Both models cause damage to the alveolocapillary barrier and thus accumulation of pulmonary edema (2, 3). Interestingly, these articles also report that in both of these models of lung injury there is not only increased permeability to solutes, and thus edemagenesis, but also a decrease in the lung's ability to clear edema. The two studies demonstrate that the changes in permeability and lung edema clearance can be prevented if the animals are pretreated with IL-8 monoclonal antibodies 5 minutes prior to cotton cloth smoke-induced or hydrochloric acid-induced lung injury. Interestingly, the deleterious effects of acid aspiration on the lung's ability to remove edema fluid were due to disruption of the alveolar epithelial function, without much contribution of the pulmonary endothelium. Although the alveolocapillary barrier probably involves different mechanisms in these two models, the fact that pretreatment with IL-8 antibodies prevents the lung edema in both models effects raises at least two questions. First, what are the common mechanisms that pretreatment with IL-8 antibodies preserve and/or upregulate. Second, since patients are usually admitted to the intensive care unit with an already established lung injury, could IL-8 antibodies or other agents be effective in ameliorating the alveolocapillary damage and restoring the lung's ability to clear edema fluid if administered in patients after lung injury has occurred.

Because of the short time needed for the IL-8 antibodies to have such a beneficial effect, it is plausible that the protective effects are due to the blockage of the receptors in the IL-8 pathway, thus preventing a cascade of inflammation causing lung injury. This reasoning is supported by the significant amount of data suggesting that IL-8 can initiate inflammatory cascades that increase pulmonary permeability and decrease the lung's ability to clear edema. Yet other possibilities to consider include that IL-8 antibodies upregulate protective mechanisms to enhance active Na+ transport, or a more general effect that reduces lung injury and thus does not inhibit the mechanisms responsible for vectorial Na+ flux and lung edema clearance.

Resolution of pulmonary edema occurs predominantly by vectorial Na⁺ transport. Na⁺ is transported across the alveolar epithelium mostly via apical amiloride-sensitive sodium channels (4) and basolaterally located Na,K-ATPases (5). There is experimental evidence from alveolar epithelial cell monolayers and animal models that upregulating alveolar epithelial Na⁺ channels and Na,K-ATPases increases active Na⁺ transport across the alveolar epithelium, resulting in increased capacity to clear edema. For example, recent studies have shown that dopamine and -adrenergic agonists, such as dobutamine, terbutaline and isoproterenol, increase lung edema clearance by stimulating apical Na⁺ channels and Na,K-ATPase function in the alveolar epithelium of normal rats.

Catecholamines elicit changes in active Na⁺ transport and lung edema clearance within one hour of treatment. These rapid effects are probably not due to further functional increase of the same Na⁺ channels and Na⁺ pumps present in the cell plasma membrane nor to de novo transcription-translation of new protein pumps, but rather are the result of Na,K-ATPase protein recruitment from intracellular endosomal compartments and inserted into the basolateral membrane of alveolar epithelial type 2 cells (AT2), upon stimulation of the dopaminergic receptor D1 or the -adrenergic agonist isoproterenol (5, 6). These effects are dependent on the dynamic interaction of protein transporting vesicles with microtubulae and the actin cytoskeleton, as pretreatment with colchicine, brefeldin A, or phallacidin prevented the insertion of functional Na⁺ pumps into the cell plasma membrane (5). Interestingly the short term regulation of Na,K-ATPase in AT2 cells by dopamine was the result of D1, but not the D2, receptor stimulation and via the novel protein kinase C pathway.

Other studies have shown that active Na+ transport, and thus lung edema clearance, can be increased by activating transcription and translation of ion-transporting proteins such as Na+ channels and Na,K-ATPase. The corticosteroids, dexamethasone and aldosterone, as well as the growth factors KGF and EGF, have been shown to increase Na⁺ transport and clearance in alveolar epithelial cell monolayers and normal mammalian lungs. It has been recently demonstrated that, in addition to steroids and growth factors, dopamine (via D2 receptors) and -adrenergic agonists, drugs routinely used in clinical practice, can transcriptionally activate Na,K-ATPase genes in alveolar epithelial cells. In the case of dopaminergic D2 receptor stimulation of Na,K-ATPase mRNA and new protein translation appears to occur via mitogen-activated kinases (MAPK) and the Ras-Raf-MEK pathway.

Studies using recombinant gene technology have demonstrated that utilizing adenoviral vectors to overexpress Na,K-ATPase subunits genes results in increased Na,K-ATPase activity in alveolar epithelial cells. The increase in Na,K-APTase function in these cells was due to effective transduction of the foreign gene (Na,K-ATPase) producing new functional Na⁺ pump proteins within 18 hours (7). Furthermore, the introduction of the adenoviral vectors for the expression of Na,K-ATPase to healthy rats resulted in increased ability of these rat lungs to clear edema, suggesting that gene therapy could be used to accelerate lung edema clearance in mammals.

The studies described above have reported upregulation of lung edema clearance in normal lungs, but more recent studies demonstrated that lung edema clearance can be stimulated both prior to inducing injury and also in animal models with established lung injury (2, 3, 8). The studies in the current issue of the Journal show that injury decreased lung edema clearance, which was prevented by the pretreatment of IL-8 antibodies. However, the same group of investigators and other recent studies have shown that the ability of the lung to clear edema can be increased to almost preinjury levels after hyperoxic lung injury when lungs are treated with terbutaline, isoproterenol, or dopamine within one hour of treatment (8- 10). Also, in a model of sepsis, it has been shown that the ability of rat lungs to clear edema may be increased by the release of endogenous catecholamines. The fact that catecholamines can increase lung edema clearance by defined short term mechanisms of Na,K-ATPase activated is interesting and of possible clinical relevance.

An additional important issue to be further explored is what would be the route for the delivery of the different compounds. In the case of dopamine and -adrenergic agonists the intravenous route can certainly be used, as well as aerosolization of these and other compounds, with the caveat that the aerosolized particles must be ~ 2 µm in size in order to reach the alveolar epithelial surface.

In summary, there is increasing evidence demonstrating that clearance of pulmonary edema in mammals can be increased in normal lungs and in various models of lung injury. In most models of lung injury, the same mechanisms that produce changes in permeability and cause alveolar flooding can also decrease the ability of the alveolar epithelium to remove edema fluid. The studies described above with IL-8 antibodies suggest that mechanisms that affect vectorial Na⁺ transport and thus lung edema clearance can be upregulated, which may be of benefit in the treatment of acute lung injury. Conceivably, the short-term regulation of Na⁺ channels and Na,K- ATPase by adrenergic or dopaminergic agonists can be implemented in the intensive care unit, as the alveolar epithelial cells express dopaminergic as well as adrenergic receptors, and thus, if not too injured, they may respond to cathecolamines such as dopamine, dobutamine, isoproterenol, and terbutaline.

JACOB IASHA SZNAJDER

Pulmonary and Critical Care Medicine

Northwestern University

Chicago, Illinois

	Footnotes

	References

TOP ARTICLE REFERENCES

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