Alveolar edema fluid clearance and acute lung injury

https://doi.org/10.1016/j.resp.2007.05.010Get rights and content

Abstract

Although lung-protective ventilation strategies have substantially reduced mortality of acute lung injury patients there is still a need for new therapies that can further decrease mortality in patients with acute lung injury. Studies of epithelial ion and fluid transport across the distal pulmonary epithelia have provided important new concepts regarding potential new therapies for acute lung injury. Overall, there is convincing evidence that the alveolar epithelium is not only a tight epithelial barrier that resists the movement of edema fluid into the alveoli, but it is also actively involved in the transport of ions and solutes, a process that is essential for edema fluid clearance and the resolution of acute lung injury. The objective of this article is to consider some areas of recent progress in the field of alveolar fluid transport under normal and pathologic conditions. Vectorial ion transport across the alveolar and distal airway epithelia is the primary determinant of alveolar fluid clearance. The general paradigm is that active Na+ and Cl transport drives net alveolar fluid clearance, as demonstrated in several different species, including the human lung. Although these transport processes can be impaired in severe lung injury, multiple experimental studies suggest that upregulation of Na+ and Cl transport might be an effective therapy in acute lung injury. We will review mechanisms involved in pharmacological modulation of ion transport in lung injury with a special focus on the use of β-adrenergic agonists which has generated considerable interest and is a promising therapy for clinical acute lung injury.

Section snippets

Cellular mechanisms involved in edema clearance

The alveolar epithelium plays a primary role in the process of edema fluid clearance. In fact, the alveolar epithelium is not only a tight epithelial barrier that resists the movement of edema fluid into the alveoli, but it is also actively involved in the transport of ions and solutes, a process that is essential for edema fluid clearance (Berthiaume et al., 1999). Considerable experimental evidence indicates that active Na+ transport is the dominant ion transport mechanism involved in

Clinical relevance of alveolar liquid clearance

Although there is convincing experimental evidence demonstrating that Na+ transport is involved in this process, what is the clinical significance of alveolar liquid clearance? To explore this question the investigators had to identify a tool to estimate alveolar fluid clearance in the clinical environment. The method requires measurement of serial protein concentrations in pulmonary edema fluid. This approach is an adaptation of the experimental method used routinely to quantify alveolar fluid

Strategies to increase alveolar fluid clearance in the lung

Since patients with maximal alveolar fluid clearance have a lower mortality (Ware and Matthay, 2001), increasing alveolar liquid clearance could potentially enhance the evolution of lung injury. Multiple pharmacological or molecular tools could be used to stimulate alveolar fluid clearance (Fig. 2).

The best studied agents are cAMP agonists, i.e., β-adrenergic receptor agonists. β-Adrenergic agonist therapy enhances alveolar fluid clearance in multiple models of lung injury, including hyperoxic

Edema clearance in injured lungs

Although we have substantial evidence suggesting that Na+ transport is essential for edema clearance and that it can be modulated pharmacologically in vivo, can this process be altered in injured lungs and can it be upregulated by pharmacological tools?

Interestingly, the alveolar and distal airway epithelia are remarkably resistant to injury, particularly in comparison to the adjacent lung endothelium (Berthiaume et al., 1999) When lung endothelial injury occurs, the alveolar epithelial barrier

Conclusions

Collectively, these observations suggest that in human acute lung injury there could be either significant activation or inhibition of the Na+ and Cl transport mechanisms in lung injury. Since the alterations of alveolar liquid clearance are not the same in different models of lung injury, multiple mechanisms appear to lead to alveolar epithelial cell dysfunction (Fig. 5). Furthermore, based on the heterogeneous responses observed in the experimental studies, the variability of the systemic

Acknowledgements

This work was supported in part by the Canadian Institutes for Health Research Grant 10273 (YB) and by National Institute of Health Grants HL51856 (MAM) and HL51854 (MAM). Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5 were reproduced with permission from a chapter entitled: Epithelial function in Lung injury published in The Physiologic Basis of Respiratory disease. Ed. Q. Hamid, J.G. Martin and J. Shannon, Publ. B.C. Decker Inc., Hamilton, Ontario, 2005.

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