EDITORIAL
Lung edema clearance: 20 years of progress

Journal of Applied Physiology, October 2002, Volume 93

	ARTICLE

TOP ARTICLE REFERENCES

This year marks the 20th anniversary of the publication of a landmark paper by Dr. Michael Matthay and colleagues in the Journal of Applied Physiology that proved to be pivotal in the study of lung edema clearance. To honor this achievement, I am pleased to introduce the newest Highlighted Topics series entitled, "Lung Edema Clearance: 20 Years of Progress." In addition to featuring original research articles in this important area of investigation, we have invited several related review articles. The paper by Matthay and colleagues is an example of the high-quality research that is published in the Journal of Applied Physiology having substantial enduring impact. For example, there have been ~20 citations to this article in the past 2 years alone.

The 1982 Matthay et al. article (1) provided the first in vivo evidence that active transport mechanisms were likely to be responsible for removal of edema fluid from the distal air spaces of the lung across the tight alveolar epithelium. Dr. Matthay studied anesthetized, ventilated sheep that were surgically prepared to measure pulmonary and systemic hemodynamics, as well as lung lymph flow. To simulate the clinical problem of alveolar edema, an isosmolar solution of autologous serum was instilled with a fiberoptic bronchoscope into the distal air spaces of one lung. At the end of 4 h, the water volume of the instilled fluid was reduced by approximately 25-30%, as measured by standard gravimetric methods. Most importantly, the protein concentration of the serum instilled into the distal air spaces of the lung increased by approximately 30% above the concentration of the instilled serum (from 6.2 g/100 ml to 8.4 g/100 ml). The protein concentration in the distal air spaces of the lung was higher than circulating plasma protein concentration. Dr. Matthay used a flexible catheter inserted into the distal airways of the fluid-instilled sheep lung to obtain the sample of the residual alveolar fluid at the end of the experiment, a method that he later adapted for clinical studies of the resolution of alveolar edema in patients (2, 3).

The higher alveolar protein concentration after 4 h in the fluid-instilled sheep lung indicated that active transport mechanisms must be responsible for the removal of salt and water across the tight alveolar epithelium, a novel observation of substantial physiological and clinical importance. This result suggested that active ion transport was responsible for the removal of edema fluid from the distal air spaces of the lung. The results of this study stimulated both in vivo and in vitro studies to pursue the basic mechanisms responsible for the resolution of alveolar edema across the distal air spaces of the lung. The forces that are responsible for the formation and removal of edema from the lung play a critical role in the development of respiratory failure from hydrostatic or increased permeability pulmonary edema. Hydrostatic or cardiogenic pulmonary edema as well as increased permeability or acute lung injury edema are major causes of acute respiratory failure in critically ill patients. Therefore, understanding the mechanisms responsible for the resolution and clearance of pulmonary edema has fundamental importance to understanding how to treat patients with respiratory failure from pulmonary edema. The magnitude of pulmonary edema in patients with either cardiogenic or noncardiogenic edema represents the balance of physiological forces responsible for the formation and the resolution of lung edema.

Pulmonary edema results in flooding of the distal air space of the lung, so-called alveolar edema, causing oxygenation to be severely impaired and leading to respiratory failure. As Dr. Matthay's clinical studies have shown, the capacity to reabsorb edema fluid from the distal air spaces of the lung in critically ill patients is a major prognostic factor in patients with acute respiratory failure (2, 3). Thus the mechanisms that regulate the resolution of alveolar edema have a fundamental importance to understanding and potentially treating acute respiratory failure from clinical pulmonary edema.

This Highlighted Topics series will include contributions from Dr. Matthay and colleagues, as well as from other noted scientists in this field. In this issue, a Historical Perspectives article by Drs. Crandall and Effros, entitled "Historical perspectives on lung edema clearance," analyzes three different approaches used over the years to study transport and exchange between the vascular and air space compartments in intact lungs. In a mini-review entitled, "Active fluid clearance from the distal air spaces of the lung," Drs. Matthay, Clerici, and Saumon briefly summarize evidence indicating that active ion transport drives fluid removal across the alveolar epithelium of several species (including sheep, dog, rabbit, rat, and mouse lung) as well as evidence for active removal of edema fluid from the distal air spaces of the ex vivo human lung. In a second mini-review in this issue, entitled "Clearance of lung liquid during the perinatal period," Drs. Barker and Olver describe the developmental regulation of membrane transport proteins in the newborn lung and also discuss the major changes in lung function that occur at birth.

In November, a mini-review entitled "Biophysical properties of Na⁺ channels in lung alveolar epithelial cells" by Drs. Matalon, Lazrak, Jain, and Eaton examines a variety of amiloride-sensitive, sodium-permeable channels in alveolar type II cells. The diversity of these channels may play a significant role in both normal lung physiology and pathophysiological states. Also in November, a mini-review entitled "Lung edema clearance: role of Na-K-ATPase" by Drs. Sznajder, Factor, and Ingbar explores the mechanisms of Na-K-ATPase regulation in the alveolar epithelium during lung injury. Alveolar epithelial Na-K-ATPase impacts the ability of the lung to clear edema, when Na-K-ATPase is inhibited or increased. These authors also explore the importance of accelerating lung edema clearance by modulating Na-K-ATPase activity.

In December, a mini-review entitled "Role of aquaporin water channels in fluid transport in lung and airways" by Drs. Borok and Verkman explores aquaporin water channels that are expressed in the airway and lung, where they facilitate osmotically driven water movement between the air space and capillaries. These authors also raise many related questions about the role of aquaporins that beg future study. Also in December, a mini-review entitled "Alveolar edema fluid clearance in the injured lung" by Drs. Berthiaume, Folkesson, and Matthay summarizes how alveolar edema fluid clearance occurs in the injured lung. This mini-review provides a concise perspective of experimental and clinical studies, which demonstrate the importance of active ion transport mechanisms in the removal of edema fluid after clinically relevant acute lung injury.

Until Dr. Matthay's landmark article (1), the idea that salt and water flux from alveoli could be regulated by active transport was hardly considered. Indeed, investigators ignored evidence that should have raised this possibility. At the time, it was appreciated that "passive" Starling forces played an important role in fluid filtration. Therefore, it only seemed logical to conclude that fluid clearance also occurred by the same mechanism but in the reverse order. For this reason, it was troubling to learn that the alveolus seemed to be rather impermeant to the movement of water and solute. Restoration of "normal" Starling forces did not drive fluid back into the interstitium at a rate that would have been predicted based on fluid filtration coefficients. Dr Matthay's seminal observation that the lung "concentrates" protein labels in alveolar fluid clearly pointed out the reason for this phenomenon. Two decades later, we have learned quite a lot about alveolar edema clearance. We now know that alveolar water and salt transport is regulated by ion channels and pumps. Expression and activity of these membrane proteins are altered in disease and can be experimentally manipulated. Needless to say, compounds with actions on channel and pump proteins are attractive candidates for treating patients with pulmonary edema. Although the efficacy of clearance targeted interventions has yet to be established in clinical trials, several such trials are underway and will add a chapter to the bench to bedside story that was begun by Dr. Matthay some 20 years ago. This study epitomizes the translational physiology that has been the longstanding tradition of research published in the Journal of Applied Physiology. A major purpose of this and any Highlighted Topics series is to draw attention to the importance of such research and to encourage future submissions in translational physiology.

	FOOTNOTES

10.1152/japplphysiol.00629.2002

	REFERENCES

TOP ARTICLE REFERENCES

1.   Matthay, MA, Landolt CC, and Staub NC. Differential liquid, and protein clearance from the alveoli of anesthetized sheep. J Appl Physiol 53: 96-104, 1982.

2.   Matthay, MA, and Wiener-Kronish JP. Intact epithelial barrier function is critical for the resolution of alveolar edema in humans. Am Rev Respir Dis 142: 1250-1257, 1990.

3.   Ware, LB, and Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 163: 1376-1383, 2001.