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This Article Abstract Full Text (PDF) All Versions of this Article: 544/2/335    most recent 2002.029595v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chinet, T. Search for Related Content PubMed PubMed Citation Articles by Chinet, T. Related Collections Perspectives

Journal of Physiology (2002), 544.2, p. 335
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.2002.029595

At the heart of pulmonary oedema

Thierry Chinet

Email : thierry.chinet{at}apr.ap-hop-paris.fr

During the past 30 years, numerous studies have investigated the mechanisms of oedema clearance in animal models, in isolated animal and human lungs and in preparations of epithelial cells from the distal lung (mainly type II cells). These studies have shown that the primary mechanism of fluid clearance is the vectorial transport of Na⁺ across the alveolar epithelium with water following the Na⁺ movement (for review see Matthay et al. 2002). Na⁺ enters the alveolar epithelial cells through apically located Na⁺-permeable channels and is extruded actively through basolaterally located Na⁺-K⁺-ATPases. Pharmacological inhibitors of Na⁺ channels, such as amiloride, and also ouabain, an inhibitor of Na⁺ -K⁺ -ATPase, reduce the rate of fluid clearance. Amiloride inhibits 30-70 % of basal fluid clearance and Na⁺ absorption in most animal species and human lungs. The amiloride-sensitive Na⁺ absorption has been thoroughly investigated and is attributed to the presence of amiloride-sensitive epithelial Na⁺ channels (ENaC) and amiloride-sensitive non-selective cation channels in alveolar epithelial cells. A substantial but less well understood fraction of alveolar fluid clearance and Na⁺ absorption is not inhibited by amiloride. There is some evidence from animal studies that it may be mediated in part through apically located cyclic nucleotide-gated cation channels (CNGC). The CNGC are expressed in alveolar epithelial cells in rats and inhibitors of CNGC, such as diltiazem, can inhibit a significant fraction of lung fluid absorption in animal models (Norlin et al. 2001). However, the amiloride-insensitive fraction of alveolar fluid clearance is not completely abolished by these drugs. The remaining fraction of alveolar fluid clearance could be mediated by yet unidentified amiloride-insensitive Na⁺-permeable channels and/or cotransporters such as the Na⁺-glucose cotransporter. Agents that increase levels of intracellular cAMP, such as ₂-adrenergic agonists, stimulate Na⁺ absorption and alveolar fluid clearance. The mechanisms by which intracellular cAMP stimulates alveolar fluid clearance have not been fully determined, but cAMP could act in multiple ways, e.g. by recruiting Na⁺-K⁺-ATPases and/or Na⁺ channels to the cell membrane, and/or by increasing the open probability of Na⁺-permeable channels (Chen et al. 2002). Salt and water absorption can also be stimulated by dopamine, hormones such as glucocorticoids and growth factors, such as epidermal growth factor (Matthay et al. 2002).

Pulmonary oedema is a common pathological state that results from increased transvascular pressure gradients, as in cardiogenic oedema, or increases in the microvascular permeability to solutes, as in acute lung injuries (Flick 1994). The most frequent form of pulmonary oedema encountered clinically is cardiogenic oedema, which is caused by ischaemic, valvular or congenital heart disease and other dilated myocardiopathies. Two important features of cardiogenic pulmonary oedema are that the fluid that fills the alveolar spaces is considered to be a low-protein filtrate of plasma and the epithelial barrier appears to be functionally intact. New observations reported in this issue of The Journal of Physiology suggest that in cardiogenic pulmonary oedema, the alveolar fluid contains one or several compound(s) that activate(s) an amiloride-insensitive Na⁺ absorptive process which in turn accelerates fluid resorption. Rafii et al. (2002) provoked acute heart failure in rats and collected the resultant pulmonary oedema fluid. They examined the effects of this liquid on the ion transport properties of epithelial preparations of rat fetal distal lung and of murine fetal tracheal cysts, on the size of distal lung explants from wild-type and -ENaC deficient fetal mice and on the expression of ENaC and Na⁺-K⁺-ATPase in rat distal lung epithelial cells. The numerous experimental data converge to indicate that pulmonary oedema fluid increases an amiloride-insensitive apical Na⁺ conductance and upregulate Na⁺-K⁺-ATPases. The nature of the active compound(s) remains undefined but when submitted to trypsin exposure or heat treatment, its effect disappears suggesting dependence upon protein integrity.

Although the results need to be confirmed in other experimental models, this study has several merits: first, it reaffirms the importance of amiloride-insensitive Na⁺ transport as a significant mechanism of alveolar fluid clearance. The authors point out that the modest inhibition provided by diltiazem and the lack of effect of cGMP in preparations similar to theirs suggest that channels/ transporters other than the CNGC may be involved. This underlines the need to identify the molecular basis of amiloride-insensitive Na⁺ absorption in the alveolar epithelium. Second, the present observations are relevant to previous work investigating epithelial ion transport processes as a potential target for pharmacological interventions in pulmonary oedema. There is evidence that pharmacological treatment with -adrenergic agonists may accelerate the rate of alveolar liquid clearance in cardiogenic pulmonary oedema (Matthay et al. 2002). In addition, a recent study reported that salmeterol, a long-acting -adrenergic agonist, could prevent high-altitude oedema in at-risk patients brought to altitude (Sartori 2002). Interestingly, in the same study, the authors observed that the amiloride-sensitive fraction of the nasal transepithelial potential difference was significantly lower in subjects who were prone to high-altitude pulmonary oedema than in control subjects, suggesting that a defective amiloride-sensitive Na⁺ transport in respiratory epithelia could facilitate the development of pulmonary oedema in humans. Finally, the study by Rafii et al. (2002) suggests the existence of a new regulatory pathway that might be of clinical interest. The nature and the source of the compound(s) that activate amiloride-insensitive Na⁺ and fluid absorption in alveoli remain to be determined. Exposure to plasma did not yield the same results, suggesting that pulmonary oedema fluid contains factors released by cells in the lung that upregulate Na⁺ and fluid absorption. Thus the fluid that fills the alveoli in cardiogenic pulmonary oedema is not just a filtrate of the plasma. Alternatively, one could conceive that the plasma contains both the active factor(s) and a physiological inhibitor that did not pass through the alveolar barrier. In any case, identification of physiological compounds that accelerate resolution of pulmonary oedema, if they exist, would be exciting and could be of great benefit to patients.

Chen, X. J., Eaton, D. C. & Jain, L. (2002). American Journal of Physiology Ð Lung Cellular and Molecular Physiology 282, L609-620.	[Abstract/Full Text]
Flick, M. R. (1994).In Textbook of Respiratory Medicine, ed. Murray, J. F. & Nadel, J. A., pp. 1725-1777, W. B. Saunders Company, Philadelphia.
Matthay, M. A., Folkesson, H. G. & Clerici, C. (2002). Physiological Reviews 82, 569-600.	[Abstract/Full Text]
Norlin, A., Lu, L. N., Guggino, S. E., Matthay, M. A. & Folkesson, H. G. (2001). Journal of Applied Physiology 90, 1489-1496.	[Abstract/Full Text]
Rafii, B., Gillie, D. J., Sulowski, C., Hannam, V., Cheung, T., Otulakowski, G., Barker, P. M. & OÕBrodovich, H. (2002). Journal of Physiology 544, 537-548.	[Abstract/Full Text]
Sartori, C., Allemann, Y., Duplain, H., Lepori, M., Egli, M., Lipp, E., Hutter, D., Turini, P., Hugli, O., Cook, S., Nicod, P. & Scherrer, U. (2002). New England Journal of Medicine 346, 1631-1636.	[Abstract/Full Text]

This Article Abstract Full Text (PDF) All Versions of this Article: 544/2/335    most recent 2002.029595v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chinet, T. Search for Related Content PubMed PubMed Citation Articles by Chinet, T. Related Collections Perspectives