Vol. 84, Issue 4, 1111-1112, April 1998

INVITED EDITORIAL
Invited Editorial on "Gadolinium prevents high airway pressure-induced permeability increases in isolated rat lungs"

Department of Human Physiology, University of California, Davis, School of Medicine, Davis, California 95615

	ARTICLE

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THE STRUCTURE OF THE PULMONARY BLOOD to alveolar gas barrier represents a compromise between conflicting functional requirements: thin enough for adequate oxygen exchange, yet strong enough to resist the mechanical stress imposed as vascular volume and/or alveolar volume is expanded. The thinness of the barrier is determined by the endothelial and epithelial cells; the strength is determined by the very thin (~50 nm) layer of extracellular matrix, especially type IV collagen, formed from the fusion of basement membranes of the two cell layers. Several physiological and pathophysiological conditions, including increased vascular pressure and ventilation of the lung at high airway pressure, result in failure of the barrier, leading to high-permeability pulmonary edema. Investigations by West and Mathieu-Costello and colleagues (2, 9) conform to the hypothesis that the primary stress-induced failure occurs in the basement membrane. These investigators have concluded that disruption of the epithelial and endothelial layers results as the cells attached to the basement membrane are stretched and torn. However, it is noted that breaks in the epithelial layer are transcellular and that the basement membrane is intact in the region of many of the breaks. In contrast to a passive role for the endothelium, a paper in this issue (8) and two recently published papers (5, 7) indicate that the endothelial cells may be an active component of the response.

Parker et al. (8) report that gadolinium chloride, a putative blocking agent of stretch-activated nonselective cation channels in a number of different cell types, while not blocking all the increase in fluid uptake, abolished the increase in the filtration coefficient of the rat lung microvasculature measured when the lungs were exposed to peak inflation pressures of 30 cmH₂O or greater. To account for the attenuation of permeability increase, the authors suggest that the endothelial cells in the lung microcirculation respond to large imposed strains via a stretch-activated channel coupled to calcium influx. Increased intracellular calcium is known to cause endothelial cell contraction and/or retraction, leading to a high-permeability state. The report does not provide direct evidence to support a role of the endothelial cells. However, the two recent publications address this question and provide some support for the interpretation. These are reviewed briefly below.

An earlier paper from Parker's laboratory (7), published in this Journal in 1997, demonstrated that treatment of the lung endothelium with isoproterenol attenuated the increase in filtration coefficient when venous pressure was increased to 30 cmH₂O. However, cAMP did not significantly prevent fluid accumulation at a pressure of 40 cmH₂O. One interpretation of these results is that, at pressures close to 30 cmH₂O, cAMP acts in its classic role as a second messenger for anti-inflammatory agents, attenuating an injury response in the endothelial cells. Thus Parker and Ivey (7) concluded that, in response to stress, there is a calcium-dependent increase in endothelial barrier permeability, which is attenuated by cAMP-dependent mechanisms. These are presumed to decrease tension development by actin-myosin in the pulmonary endothelial cells. Because cAMP does not attenuate all the increase in fluid uptake at pressure >40 cmH₂O, the proposed endothelial component modulating the barrier may be overwhelmed by passive damage at higher pressure. Also at lower pressure some hydrostatic edema will form.

Parker et al. have extended the above argument in the present paper (8) by assuming that a stretch-activated channel in the pulmonary microvascular endothelial cells is coupled to influx of calcium ions into the endothelial cells and that this influx initiates a cascade of calcium-dependent processes, leading to the high-permeability state described above. Blocking of the stretch-activated channel by gadolinium chloride protects the endothelium by preventing a rise in endothelial cell calcium. Although no direct evidence for the involvement of calcium ions or the formation of gaps in the endothelium is described, the interpretation is consistent with one of the well-accepted models of calcium-endothelial cell response to injury and its modification by cAMP.

A different line of evidence for an active role of endothelial cells in response to high intravascular pressure was also described by Neal and Michel in 1996 (5). They demonstrated breaks in endothelial barrier in midcapillaries and venular microvessels of frog mesentery exposed to high pressure in which the hydraulic permeability was increased. The most surprising finding was that 80% of the breaks were across the thinnest regions of the endothelium (average thickness 60 nm) when the pressure was increased to >70 cmH₂O. Whereas the higher pressure at which breaks were detected was consistent with a higher mechanical yield stress in the basement membranes of frog mesenteric microvessels, two observations support the idea that the properties of the endothelial cells, rather than the basement membrane, determine the fragility of the endothelial barrier. One was that the pressure-induced breaks lay on apparently intact basement membrane. The second observation was the rapid reversal of the permeability increase when pressure was lowered. Thus, although the basement membrane may carry most of the circumferential stress as pressure is raised, the critical factor determining fragility may be the extent to which the endothelial cells can follow the strain on the basement membrane. Instead of a model invoking a calcium-dependent contractile mechanism, Neal and Michel suggest that transcellular openings may have formed from vesicles or groups of vesicles that were not evaginated rapidly into the plasmalemma membrane to supply some of the predicted 11% increase in cell surface as the cells were stretched. In a preliminary report, Neal and Michel found that cooling the microvessels increases the pressure at which there is a sudden increase in the hydraulic conductivity of the microvessel wall, a measure of wall fragility (6). They conclude that openings in the endothelium develop more easily at higher temperatures. Furthermore, Adamson et al. (1) have recently demonstrated that, in unstimulated endothelial barriers of frog mesenteric capillaries, conditions that increased cAMP concentrations in endothelial cells significantly increased the number of junctional strands, forming the barrier between adjacent endothelial cells, and reduced permeability. Thus an alternative interpretation of results by Parker et al. (8) is that a stretch-activated channel is coupled more directly to a mechanism leading to depletion of endothelial cAMP, without the involvement of increased calcium. Increased cAMP may enhance the ability of the cells to undergo mechanical deformation, whereas decreased endothelial intracellular cAMP in the endothelial cells may lower the threshold for fragility.

Mechanisms that modify the mechanical responses of endothelial cells to applied stress, and mechanisms that modify tension development within endothelial cells, are not necessarily independent. Transcellular breaks similar to those reported after exposure to high pressures have been seen in frog and mammalian vessels exposed to inflammatory mediators (3, 4). Both mechanisms may be evidence for the role of endothelial cells as integrators of mechanical forces, whether applied to the endothelial cell surface, focal adhesion sites, sites of cell-to-cell adhesion, or developed within the cells by actin-myosin interactions. Whatever the mechanisms, the hypothesis that the endothelial cells play a role in modulating the fragility of the pulmonary endothelial cells caused by increased vascular pressures or high airway pressure clearly warrants more attention. Understanding these mechanisms may provide a strategy to intervene in the associated high-permeability states leading to pulmonary edema.

	REFERENCES

Top Article References

1.  Adamson, R. H., B. Liu, G. Nilson-Fry, L. L. Rubin, and F. E. Curry. Microvascular permeability and number of tight junctions are modulated by cyclic AMP. Am. J. Physiol. 274 (Heart Circ. Physiol. 43). In press.

2.   Costello, M. L., O. Mathieu-Costello, and J. B. West. Stress failure of alveolar epithelial cells studied by scanning electron microscopy. Am. Rev. Respir. Dis. 145: 1446-1455, 1992[Medline].

3.   Feng, D., J. A. Nagy, J. Hipp, K. Pyne, H. F. Dvorak, and A. M. Dvorak. Reinterpretation of endothelial cell gaps induced by vasoactive mediators in guinea-pig, mouse and rat: many are transcellular pores. J. Physiol. (Lond.) 504: 747-761, 1997[Abstract/Free Full Text].

4.   Neal, C. R., and C. C. Michel. Transcellular gaps in microvascular walls of frog and rat when permeability is increased by perfusion with the ionophore A-23187. J. Physiol. (Lond.) 488: 427-437, 1995[Abstract/Free Full Text].

5.   Neal, C. R., and C. C. Michel. Openings in frog microvascular endothelium induced by high intravascular pressures. J. Physiol. (Lond.) 492: 39-52, 1996[Abstract/Free Full Text].

6.   Neal, C. R., and C. C. Michel. Effects of temperature on the fragility of frog mesenteric microvessels (Abstract). J. Physiol. (Lond.) 491: 26P, 1996.

7.   Parker, J. C., and C. L. I. Ivey. Isoproterenol attenuates high vascular pressure-induced permeability increases in isolated rat lungs. J. Appl. Physiol. 83: 1962-1967, 1997[Abstract/Free Full Text].

8.   Parker, J. C., C. I. Ivey, and J. A. Tucker. Gadolinium prevents high airway pressure-induced permeability increases in isolated rat lungs. J. Appl. Physiol. 84: 1113-1118, 1998[Abstract/Free Full Text].

9.   West, J. B., O. Mathieu-Costello, J. H. Jones, E. K. Birks, R. B. Logemann, J. R. Pascoe, and W. S. Tyler. Stress failure of pulmonary capillaries in racehorses with exercise-induced pulmonary hemorrhage. J. Appl. Physiol. 75: 1097-1109, 1993[Abstract/Free Full Text].