It is clear from the above that the blood-gas barrier has a bioengineering dilemma. On the one hand it needs to be extremely thin for adequate gas exchange, but on the other it must be immensely strong to withstand the high mechanical stresses that develop when the capillary pressure rises on exercise, or the lung is expanded to high volumes. We have seen that the human blood-gas barrier maintains its integrity under all but the most exceptional physiological conditions, that is, maximal exercise in elite athletes. However, pathological conditions associated with an unphysiologically high capillary pressure inevitably cause stress failure.
A central question in lung biology is how the structure of the blood-gas barrier is regulated to optimize these conflicting requirements. The most likely hypothesis is that the capillary wall senses wall stress in some way, and then the wall structure, presumably particularly the amount of type IV collagen in the extracellular matrix, is regulated accordingly. Much of our research over the past few years has been devoted to testing this hypothesis.
Remodeling of the walls of larger pulmonary blood vessels in response to increased stress is well known, and there is an extensive literature on the subject; see Stenmark and Mecham  for a review. As an example, Tozzi and colleagues stretched explanted rings of rat main pulmonary artery and showed increases in collagen synthesis, elastin synthesis, mRNA for pro-al(I) collagen, and mRNA for proto-oncogene V-sis within 4 hours. A feature of these changes is that they were endothelium dependent because they did not occur when the endothelium was removed.
However, it is remarkable that in contrast to the large literature on vascular remodeling in larger pulmonary blood vessels, remodeling of pulmonary capillaries has been almost completely neglected. There is certainly evidence that it occurs because marked thickening of the basement membranes of the capillary endothelial and alveolar epithelial cells is seen in the pulmonary capillaries of patients with mitral stenosis where the capillary pressure is raised over months or years. The same appearances have been described in patients with pulmonary veno-occlusive disease who also have an increased pulmonary capillary pressure.
To investigate mechanisms of pulmonary capillary remodeling, experiments have been designed in which the capillary wall stress is raised either by increasing the transmural pressure of the capillaries, or by inflating the lung to high volumes. One of the challenges in these experiments is to measure only the changes associated with increased wall stress of pulmonary capillaries, and not those associated with the larger pulmonary blood vessels. This is difficult to achieve because both experimental maneuvers have effects on all the pulmonary blood vessels. We have attempted to overcome this by analyzing tissue from only the outer few millimeters of lung, which is predominantly occupied by capillaries. There is not space to describe the results in detail here, and indeed no clear consensus has emerged as yet. Suffice it to say that experiments have shown increases in mRNA for procollagens al(I), a2(II), and a2(IV), fibronectin, laminin, basic fibroblast growth factor, transforming growth factor pi, and platelet-derived growth factor-B. The cell that senses the increased stress has not yet been identified, nor the cells in which the increased gene expression occurs. Much more work needs to be done on this central problem in lung biology.
Fragility: In this context, the tendency of pulmonary capillaries to develop breakages in part or all of their walls when exposed to increased stresses.
Laplace relationship: Expression relating the pressure across a curved surface such as the wall of a tube to the radius of curvature of the tube, the wall thickness, and the stress in its wall.
Remodeling: In this context, histological changes in the walls of blood vessels in response to some physiological stimulus, often increased pressure.
Stress: The force per unit area, in this case in the wall of the capillary, which tends to cause breakages.
Stress failure: Ultrastructural changes in the walls of capillaries as a result of their exposure to high mechanical stresses.
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4. Tsukimoto, K., et al. (1991). Ultrastructural appearances of pulmonary capillaries at high transmural pressures. J. Appl. Physiol. 71, 573-582.
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9. West, J. B., et al. (1993). Stress failure of pulmonary capillaries in racehorses with exercise-induced pulmonary hemorrhage. J. Appl. Physiol. 75, 1097-1109. This article presents the evidence that all thoroughbred racehorses in training break their pulmonary capillaries and discusses the cause.
10. Hopkins, S. R., et al. (1997). Intense exercise impairs the integrity of the pulmonary blood-gas barrier in elite athletes. Am. J. Respir. Crit. Care Med. 155, 1090-1094. This is a study showing that high levels of exercise in elite human athletes apparently alter the structure of the pulmonary blood—gas barrier.
11. Brower et al. (2000). Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N. Engl. J. Med. 342, 1301-1308.
12. Stenmark, K. R., and Mecham, R. P. (1997). Cellular and molecular mechanisms of pulmonary vascular remodeling. Ann. Rev. Physiol. 59, 89-144.
West, J. B. (2003). Thoughts on the pulmonary blood-gas barrier. Am. J.
Physiol. Lung Cell. Mol. Physiol. 285, L501-L513. This is an extensive review of the topic with many references.
Dr. West has been a Professor of Medicine and Physiology in the School of Medicine, University of California, San Diego, since 1969. He is a Member of the Institute of Medicine of the National Aademy of Sciences, a Fellow of the American Academy of Arts and Sciences and has received many other awards. His research covers many aspects of respiratory physiology, high-altitude physiology, space physiology, and the history of physiology. Most of his work is support by grants from the NIH and NASA.
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