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Pressure-induced capillary stress failure: is it regulated?

Jahar Bhattacharya

Lung Biology Laboratory, College of Physicians and Surgeons, St. Luke's-Roosevelt Hospital Center, Columbia University, New York, New York 10019


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PRESSURE ELEVATION in the pulmonary circulation, a bed that physiologically downregulates pressure, has long been recognized as a cause of lung pathology. In the 1980s, the classic studies of N. C. Staub established a model in which high pressure induces fluid accumulation in the lung rather than causing direct injury to the vascular wall (2, 9). This benign, injury-sparing view of high vascular pressure has been challenged in recent studies. In several reports, West and colleagues have shown that if elevated sufficiently, pressure causes "stress failure" in lung capillaries and alveoli, as evident in the formation of breaks and discontinuities in endothelial and epithelial membranes of the blood-gas barrier (BGB) (10). These new findings center attention on high pressure as a direct agency for vascular injury and on stress failure as a critical mechanism underlying some forms of hydrostatic pulmonary edema.

The proneness of the lung to pressure-induced pathology is attributable to the fine BGB structure that comprises basolateral juxtapositions of alveolar epithelial and capillary endothelial cells. The BGB at its so-called "thick" part includes a sliver of extracellular matrix (ECM) between the basement membranes of these cells, although at the "thin" part, the basement membranes are directly apposed and fused. In a theoretical analysis, West and Mathieu-Costello (12) point out that the circumferential stress in the capillary wall (hoop stress) relates inversely to wall thickness and must, therefore, be greater in the thin than in the thick part. Consequently, the thin part is rendered more vulnerable to stress-induced disruption.

Estimates of the threshold pressure for inducing capillary breaks support the notion that a major determinant of stress failure in capillaries is BGB thickness. Thus threshold pressures vary among horse, dog, and rabbit because of differences in BGB thickness. In the adult dog lung, the breaks appear at an estimated capillary pressure of ~100 cmH2O and increase in number with further pressure increases (5). The threshold pressure is ~45 cmH2O higher in the horse, which has a thicker BGB (1), and ~45 cmH2O lower in the rabbit that has a thinner BGB (10). In a paper by Fu et al., the current article in focus (Ref 2a, see p. L703 in this issue), the group has further tested the hypothesis in the newborn rabbit, which has the least BGB thickness among species studied. Interestingly, the threshold pressure was also the least recorded, namely a mere 15 cmH2O. This low threshold pressure is particularly significant in the context of neonatal lung disease because it presages stress failure conditions in the range of clinically encountered pressures in newborns.

However, the question we may ask is: In addition to BGB thickness, what other factors should we take into account in trying to understand stress failure? Consider the following features of stress failure. The capillary breaks may occur with basement membranes intact (5), suggesting that disrupted segments of the cell membrane slide apart on the basement membrane. This was especially evident in the newborn study in which no capillary breaks associated with breaks in the basement membrane. An intriguing possibility is that increase in endothelial membrane fluidity, a feature characteristic of interstitial pulmonary edema (8) and one that may decrease tensile strength in the membrane, contributes to endothelial stress failure. The breaks spare endothelial junctions and appear to localize to the alveolus-facing plasma membrane of the capillary. In fact, electron micrographs of capillaries subjected to stress failure frequently depict red blood cells impacted at endothelial breaks (5, 10), possibly to block the leak sites. Staub considered this possibility to explain the beneficial effect of red blood cells in reducing abnormally high filtration rates in dog lungs (7). These features suggest that in addition to BGB thickness, specific responses of the endothelial cell may determine the biology of capillary stress failure.

In response to mechanical stress, cells develop focal adhesions at sites of cell-ECM contact. Although focal adhesions have not been reported in pressure-stressed capillaries, capillary stretch attributable to high tidal volume ventilation increases focal adhesion formation in lung endothelial cells (1a). Evidently, focal adhesions act as rivets that bind the endothelial plasma membrane to the ECM, thereby distributing the wall stress of the capillary to the ECM. Interestingly, the stress failure data indicate that despite the global application of high pressure, capillary breaks tend to occur at a relatively low rate along the capillary length. Thus for the dog, breaks occurred at a frequency of ~5/mm (5). Assuming that an endothelial cell in situ has a length of ~50 µm, a millimeter length of capillary may contain 20 cells. Hence, the reported break frequency indicates that only a few cells, 25% by this approximate calculation, are affected by stress failure. The question is, What makes the injury selective? Although the answers are unclear, the extent to which poor focal adhesion formation at break sites accounts for the data needs consideration.

The ability of capillary breaks to undergo repair is yet another fascinating aspect of the stress failure story. Thus no breaks are evident if pressure is first increased to stress failure levels and then returned to noninjurious levels (11). How are the breaks repaired? In disrupted cell membranes, membrane repair occurs by Ca2+-induced exocytosis of multiple vesicles that accumulate at the rupture site and that locally add membrane to the cell surface (5). Accordingly, inhibition of exocytosis inhibits membrane repair (11). Membrane wounding also induces the small GTPases Rho and Cdc42 that drive actin cable formation to secure the wound while filopodia close the gap (13). The extent to which these mechanisms operate in the recovery phase of stress failure is not known. Because pressure induces endothelial Ca2+ increases in lung capillaries (4), it is possible that vesicular exocytosis, a Ca2+-dependent process, is brought into play rapidly to repair stress-injured cell membranes.

In conclusion, the studies by West and colleagues (10, 12) have established pressure-induced stress failure as a quantifiable phenomenon in the lung. Clearly, the challenge for future research is to understand the cell biology underlying stress failure, both in terms of cellular signaling responses as well as of constituent cell proteins that might contribute to membrane integrity (3).


    FOOTNOTES

Address for reprint requests and other correspondence: J. Bhattacharya, College of Physicians and Surgeons, Columbia Univ., New York, NY (E-mail: jb39{at}columbia.edu).

10.1152/ajplung.00425.2002

Received 12 December 2002; accepted in final form 17 December 2002.


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REFERENCES

1a.   Bhattacharya, S, Sen N, Yiming MT, Patel R, Parthasarathi K, Quadri S, Issekutz AC, and Bhattacharya J. High tidal volume ventilation induces proinflammatory signaling in rat lung endothelium. Am J Respir Cell Mol Biol 28: 218-224, 2003[Abstract/Free Full Text].

1.   Birks, EK, Mathieu-Costello O, Fu Z, Tyler WS, and West JB. Very high pressures are required to cause stress failure of pulmonary capillaries in thoroughbred racehorses. J Appl Physiol 82: 1584-1592, 1997[Abstract/Free Full Text].

2.   Erdmann, AJ, III, Vaughan TR, Jr, Brigham KL, Woolverton WC, and Staub NC. Effect of increased vascular pressure on lung fluid balance in unanesthetized sheep. Circ Res 37: 271-284, 1975[Abstract].

2a.   Fu, Z, Heldt GP, and West JB. Increased fragility of pulmonary capillaries in newborn rabbit. Am J Physiol Lung Cell Mol Physiol 284: L703-L709, 2003.

3.   Kim, K, Drummond I, Ibraghimov-Beskrovnaya O, Klinger K, and Arnaout MA. Polycystin 1 is required for the structural integrity of blood vessels. Proc Natl Acad Sci USA 97: 1731-1736, 2000[Abstract/Free Full Text].

4.   Kuebler, WM, Ying X, Singh B, Issekutz AC, and Bhattacharya J. Pressure is pro-inflammatory in lung venular capillaries. J Clin Invest 104: 495-502, 1999[Abstract/Free Full Text].

5.   Mathieu-Costello, O, Willford DC, Fu Z, Garden RM, and West JB. Pulmonary capillaries are more resistant to stress failure in dogs than in rabbits. J Appl Physiol 79: 908-917, 1995[Abstract/Free Full Text].

6.   Miyake, K, and McNeil PL. Vesicle accumulation and exocytosis at sites of plasma membrane disruption. J Cell Biol 131: 1737-1745, 1995[Abstract].

7.   Onizuka, M, Tanita T, and Staub NC. Erythrocytes reduce liquid filtration in injured dog lungs. Am J Physiol Heart Circ Physiol 256: H515-H519, 1989[Abstract/Free Full Text].

8.   Palestini, P, Calvi C, Conforti E, Botto L, Fenoglio C, and Miserocchi G. Composition, biophysical properties, and morphometry of plasma membranes in pulmonary interstitial edema. Am J Physiol Lung Cell Mol Physiol 282: L1382-L1390, 2002[Abstract/Free Full Text].

9.   Staub, NC, Nagano H, and Pearce ML. Pulmonary edema in dogs, especially the sequence of fluid accumulation in lungs. J Appl Physiol 22: 227-240, 1967[Free Full Text].

10.   Tsukimoto, K, Mathieu-Costello O, Prediletto R, Elliott AR, and West JB. Ultrastructural appearances of pulmonary capillaries at high transmural pressures. J Appl Physiol 71: 573-582, 1991[Abstract/Free Full Text].

11.   Vlahakis, NE, Schroeder MA, Pagano RE, and Hubmayr RD. Role of deformation-induced lipid trafficking in the prevention of plasma membrane stress failure. Am J Respir Crit Care Med 166: 1282-1289, 2002[Abstract/Free Full Text].

12.   West, JB, and Mathieu-Costello O. Structure, strength, failure, and remodeling of the pulmonary blood-gas barrier. Annu Rev Physiol 61: 543-572, 1999[ISI][Medline].

13.   Wood, W, Jacinto A, Grose R, Woolner S, Gale J, Wilson C, and Martin P. Wound healing recapitulates morphogenesis in Drosophila embryos. Nat Cell Biol 4: 907-912, 2002[ISI][Medline].


Am J Physiol Lung Cell Mol Physiol 284(5):L701-L702
1040-0605/03 $5.00 Copyright © 2003 the American Physiological Society




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