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(Circulation. 1995;92:622-631.)
© 1995 American Heart Association, Inc.

Articles

Vulnerability of Pulmonary Capillaries in Heart Disease

John B. West, MD, PhD, DSc; Odile Mathieu-Costello, PhD

From the Department of Medicine, University of California San Diego (La Jolla).

Address correspondence to John B. West, MD, PhD, UCSD Department of Medicine 0623-A, 9500 Gilman Dr, La Jolla, CA 92093-0623.

	Abstract

Top Abstract Introduction Recent Work on Pulmonary... Wall Stress in Pulmonary... What Determines the Strength... Ultrastructural Changes in... Spectrum of `Cardiogenic' to... Role of Remodeling in... Clinical Conditions Involving... Dilemma of the Blood-Gas... References

 
Abstract The pulmonary blood-gas barrier presents a dilemma. It must be extremely thin for efficient gas exchange. However, it also needs to be immensely strong because the stresses in the pulmonary capillary wall become extremely high when the capillary pressure rises. Stress failure of the capillaries occurs in several pathological conditions. It causes high-permeability edema as in neurogenic pulmonary edema or high-altitude pulmonary edema; alveolar hemorrhage, which occurs in all galloping racehorses; or a combination of the two as in severe congestive heart failure. The vulnerability of the capillary wall to increased mechanical stress has not previously been sufficiently appreciated.

Key Words: edema • hemorrhage • heart failure • pulmonary heart disease • blood pressure

	Introduction

Top Abstract Introduction Recent Work on Pulmonary... Wall Stress in Pulmonary... What Determines the Strength... Ultrastructural Changes in... Spectrum of `Cardiogenic' to... Role of Remodeling in... Clinical Conditions Involving... Dilemma of the Blood-Gas... References

 
It is well known that the blood-gas barrier of the human lung is extremely thin. Over approximately half of its area, the thickness is only 0.2 to 0.4 µm.¹ This extraordinary thinness is necessary for efficient diffusion of oxygen and carbon dioxide through the barrier.

Despite the extreme thinness of the barrier, maintenance of its integrity is essential for efficient pulmonary function. Mechanical failure would result in alveolar edema or hemorrhage, which would be catastrophic for gas exchange. It is therefore remarkable that so little attention has been given to the strength of the blood-gas barrier, including the issues of what capillary pressures are required to damage it and from what its strength comes.

Recently, we have shown that raising the capillary pressure in animal lungs causes ultrastructural changes in the capillary wall, including disruption of the capillary endothelial layer, alveolar epithelial layer, or, sometimes, all layers of the wall.^{2 3} In the rabbit, occasional damage to the capillary wall is seen at a capillary pressure of 24 mm Hg, whereas raising the pressure to 39 mm Hg causes consistent ultrastructural changes. The result is high-permeability edema, alveolar hemorrhage, or a combination.

We briefly discuss the factors responsible for stress failure of pulmonary capillaries and show that this is a previously overlooked factor of importance in some types of heart disease.

	Recent Work on Pulmonary Capillary Pressure

Top Abstract Introduction Recent Work on Pulmonary... Wall Stress in Pulmonary... What Determines the Strength... Ultrastructural Changes in... Spectrum of `Cardiogenic' to... Role of Remodeling in... Clinical Conditions Involving... Dilemma of the Blood-Gas... References

 
There appears to be a perception among some physicians that vascular pressures in the normal pulmonary circulation remain low during exercise. Possibly this viewpoint originates in the early days of cardiac catheterization, when some studies apparently showed that mean pulmonary arterial pressure decreased as a result of exercise.^{4 5} More recent studies have shown that both pulmonary arterial and venous pressures increase substantially with exercise.

In a study by Wagner et al⁶ healthy volunteers exercised on a bicycle ergometer at an oxygen consumption of 3.7 L/min, that is 80% to 90% of their maximal oxygen consumption. Mean arterial pressure, as measured with an indwelling Swan-Ganz catheter, increased from 13.2 mm Hg at rest to 37.2 mm Hg, whereas the mean pulmonary arterial wedge pressure increased from 3.4 mm Hg at rest to 21.1 mm Hg (Fig 1). Other studies with human volunteers have provided similar results.^{7 8} Thus, it is clear that exercise causes large increases in both pulmonary arterial and pulmonary venous pressures in the normal lung.

View larger version (24K): [in this window] [in a new window]   Figure 1. Schematic showing pulmonary vascular pressures in healthy humans exercising at 80% to 90% of their maximal oxygen consumption. See text for details. Data from Wagner et al6 with permission. Part indicates arterial pressure; Pven, venous pressure; and Pcap, capillary pressure.

Why do the pressures rise so much? The simplest way of looking at this is that high pulmonary venous (or pulmonary arterial wedge) pressures are required for adequate filling of the left ventricle during the high cardiac outputs of intense exercise. The normal left atrium generates little pressure itself when the venous pressure is high.^{9 10} Note that there is no evidence of an increase in pulmonary vascular resistance; this resistance falls during exercise, because the increased capillary pressures cause recruitment and distention of capillaries. The pulmonary arterial pressure therefore simply passively rises in response to the increase in venous pressure. However, in extremely aerobic animals, such as the thoroughbred racehorse, the pulmonary vascular pressures are very much higher. For example, in these animals mean left atrial pressures have been as high as 70 mm Hg during galloping.

What is the relation of pulmonary capillary to pulmonary arterial and venous pressures? Again, there is a common perception that capillary pressure is close to venous pressure, as it generally is in the systemic circulation. However, experimental data indicate otherwise. Bhattacharya and colleagues^{11 12} measured the pressures in small pulmonary blood vessels in animals with the use of micropuncture and showed that mean capillary pressure was approximately halfway between arterial and venous pressures. Furthermore, they found that much of the pressure drop in the pulmonary circulation occurred in the capillary bed, so in upstream capillaries the pressure is close to arterial pressure. Their results probably underestimated mean capillary pressure when the pulmonary blood flow is high; under these conditions, Younes et al¹³ showed that mean capillary pressure was closer to arterial than venous pressure. Therefore, taking capillary pressure to be an average of arterial and venous pressures is likely to provide a conservative estimate during exercise.

If we apply these numbers to the upright human lung, as shown in Fig 1, the capillary pressure at midlung is 29 mm Hg. Because the bottom of the lung is 10 cm below midlung, adding the resulting hydrostatic gradient gives a capillary pressure here of >36 mm Hg. As we show, pressures of this magnitude cause ultrastructural damage to the walls of pulmonary capillaries in rabbit preparations. Of course, we cannot assume that the strength of capillaries in the rabbit lung is the same as that in the human lung. For example, we have shown that the strength of pulmonary capillaries is greater in the dog than in the rabbit and greater in the thoroughbred racehorse than in the dog.¹⁴ Nevertheless, we were very surprised to find that the safety factor in the human lung was apparently so small. However, we now understand why, as we will discuss.

Pulmonary arterial wedge pressures frequently rise to high levels in heart disease. For example, values as high as 40 mm Hg have been observed in patients with severe mitral stenosis,¹⁵ and similar high wedge pressures have been described in severe heart failure,¹⁶ particularly in catastrophic events such as rupture of chordae tendineae or papillary muscle of the mitral valve.

	Wall Stress in Pulmonary Capillaries When the Pressure Rises

Top Abstract Introduction Recent Work on Pulmonary... Wall Stress in Pulmonary... What Determines the Strength... Ultrastructural Changes in... Spectrum of `Cardiogenic' to... Role of Remodeling in... Clinical Conditions Involving... Dilemma of the Blood-Gas... References

 
We can regard the pulmonary capillary as a thin-walled tube. The wall stress (S) according to the Laplace relationship² is then given by

where P is the transmural pressure (difference between pressure inside and that outside of the capillary), r is the radius of curvature, and t is the wall thickness. In rabbit pulmonary capillaries, where stress failure is consistently seen at a transmural pressure of 39 mm Hg (52.5 cm H₂O),^{2 3} representative values for radius of curvature and wall thickness are 3.6 and 0.34 µm, respectively.¹⁴ This gives a calculated wall stress of 5.5x10⁵ dynes/cm², or 5.5x10⁴ N/m² (Fig 2).

View larger version (31K): [in this window] [in a new window]   Figure 2. Schematic showing calculation of wall stress in a rabbit pulmonary capillary at a transmural pressure of 52.5 cm H2O (39 mm Hg). See text for details.

This is an extremely high wall stress, and it approaches the ultimate tensile strength of collagen,² probably the strongest soft tissue in the body. The stresses in the capillary wall are close to those in the wall of the normal aorta, which is protected by large amounts of collagen and elastin. In contrast, the thin portion of the blood-gas barrier has approximately one half of its thickness made up of endothelial and epithelial cell layers, which presumably contribute little strength. The remarkable thing is not that the capillaries fail but that they do not do so more often.

This calculation of capillary wall stress is so simple that it is strange that these extremely high values have not previously been recognized. Presumably the reason is that people have been misled by the small radius of the capillary, which, other things being equal, reduces wall stress. In fact, the hoop or circumferential tension of the capillary wall is relatively small (25 dynes/cm [25 mN/m]), chiefly because of the small capillary radius.² What has been overlooked in the past is the extreme thinness of the wall, which follows directly from the gas exchange function of the blood-gas barrier.

	What Determines the Strength of the Capillary Wall?

Top Abstract Introduction Recent Work on Pulmonary... Wall Stress in Pulmonary... What Determines the Strength... Ultrastructural Changes in... Spectrum of `Cardiogenic' to... Role of Remodeling in... Clinical Conditions Involving... Dilemma of the Blood-Gas... References

 
Because of the vulnerability of the blood-gas barrier to stress failure when the capillary pressure rises, it is important to know what is responsible for the strength of the capillary wall. The thin side of the blood-gas barrier consists of the capillary endothelial layer, alveolar epithelial layer, and the extracellular matrix (ECM), which is made up of the fused basement membranes of the two cellular layers. There is strong evidence that most of the strength comes from the ECM, particularly the type IV collagen in the basement membranes.

One piece of evidence is the ultrastructural pattern of stress failure, which is often seen. Frequently, the capillary endothelial layer, the alveolar epithelial layer, or both are disrupted, but the basement membrane remains continuous.³ This suggests that the ECM is the strongest layer. Other evidence comes from studies of the mechanical properties of isolated rabbit renal tubules. It has been shown that the distensibility of these tubules is the same regardless of whether there is an epithelial layer around the basement membrane.¹⁷ This suggests that a single cell layer contributes little support. It has also been shown that the distensibility of frog mesenteric capillaries is consistent with the Young's modulus of basement membrane.¹⁸

The thickness of capillary basement membranes is frequently related to the transmural pressure. For example, patients with mitral stenosis who have an increased pulmonary capillary pressure over several years have thickened basement membranes^{19 20 21} ; an example is given in Fig 3. Glomerular capillaries, which normally have a hydrostatic pressure gradient across them of 40 mm Hg, have considerably thicker basement membranes than do pulmonary capillaries. Finally, the thickness of the basement membranes of systemic capillaries increases down the human body from the abdomen to the calf.²² All these observations taken together strongly suggest that the ECM of pulmonary capillaries is responsible for most of their strength.

View larger version (148K): [in this window] [in a new window]   Figure 3. Representative photomicrograph of marked thickening of the basement membrane of a pulmonary capillary in a patient with chronic increase in pulmonary capillary pressure caused by heart failure. Reproduced with permission.20

Alveolar wall basement membrane consists of four main molecules: type IV collagen, which is enormously strong; laminin, which links basement membrane to overlying cells; heparan sulfate proteoglycans, which form a charge shield and presumably regulate permeability; and entactin (or nidogen), which binds laminin to type IV collagen. The type IV collagen molecules are 400 nm long; two join at the C-terminal end, and four come together at the N-terminal end to give a matrix configuration similar to that of chicken wire.^{23 24 25} The resulting mesh structure apparently combines great strength with porosity, and the few studies that have been made of the ultimate tensile strength of basement membranes suggest that it approaches that of type I collagen.^{2 17 26}

The type IV collagen is not uniformly distributed throughout the ECM of the thin side of the blood-gas barrier. In electron micrographs, the ECM has a central lamina densa with a lamina rara on either side,²⁷ and antibodies to type IV collagen are strongly associated with the lamina densa.²⁸ Thus, the great strength of the thin part of the blood-gas barrier apparently comes from an extremely thin layer of type IV collagen (50 nm thick), which is sandwiched in the middle of the ECM (Fig 4).

View larger version (31K): [in this window] [in a new window]   Figure 4. Diagram of the structure of the thin part of the blood-gas barrier. Lamina densa (center of the extracellular matrix) contains much of the type IV collagen that apparently is responsible for the great strength of the barrier. Reproduced with permission.72

	Ultrastructural Changes in Pulmonary Capillaries When They Are Exposed to High Pressures

Top Abstract Introduction Recent Work on Pulmonary... Wall Stress in Pulmonary... What Determines the Strength... Ultrastructural Changes in... Spectrum of `Cardiogenic' to... Role of Remodeling in... Clinical Conditions Involving... Dilemma of the Blood-Gas... References

 
The ultrastructural changes have been studied in anesthetized rabbit preparations.^{2 3 29} Briefly, the chest was opened, cannulas were inserted into the pulmonary artery and left atrium, and the lung was perfused with each rabbit's own blood. After a short time, the blood was washed out with a saline/dextran mixture, and the lungs were fixed for electron microscopy with buffered glutaraldehyde, all at the same pressure. Preparations were made at capillary transmural pressures of 12.5, 32.5, 52.5, and 72.5±2.5 cm H₂O.^{2 3} These correspond to pressures of 9, 24, 39, and 53 mm Hg.

An example of the ultrastructural changes in the capillary wall that occurred when the transmural pressure was raised to 39 mm Hg is shown in Fig 5a. Note that there is disruption of the capillary endothelium, but its basement membrane is continuous, as is the basement membrane of the alveolar epithelial layer and the epithelial layer itself. Fig 5b shows another example at the same transmural pressure. On the right side, the alveolar epithelial layer is disrupted, whereas on the left, the endothelium is broken and a platelet is closely applied to the exposed endothelial basement membrane. Fig 5c shows disruption of all layers of the blood-gas barrier at a capillary pressure of 53 mm Hg, with a red cell apparently passing through the opening. Fig 5d is a scanning electron micrograph showing disruptions of alveolar epithelial cells when the capillary pressure was 39 mm Hg.

View larger version (111K): [in this window] [in a new window]   Figure 5. Electron micrographs showing stress failure in pulmonary capillaries. a, Capillary endothelium is disrupted (arrow), but the alveolar epithelium and the two basement membranes are continuous. b, Alveolar epithelial layer (right) and capillary endothelial layer (left) are disrupted. Note the platelet closely applied to the exposed endothelial basement membrane (left). c, Disruption of all layers of the capillary wall, with a red cell apparently passing through the opening. d, Scanning electron micrograph showing breaks in the alveolar epithelium. a and b are from West et al61 ; c is from Tsukimoto et al3 ; and d is from Costello et al.29

Fig 6 shows that in this rabbit preparation, stress failure of the pulmonary capillaries was consistently seen at a capillary transmural pressure of 39 mm Hg. No breaks occurred in preparations where the capillary transmural pressure was 9 mm Hg (these were the normal controls), but a few examples occurred at a pressure of 24 mm Hg. The number of breaks further increased when the pressure was raised to 53 mm Hg.³

View larger version (15K): [in this window] [in a new window]   Figure 6. Plot showing frequency of breaks in the endothelium and epithelium as the capillary pressure was raised. Note that there were a few breaks at a pressure of 32.5 cm H2O (24 mm Hg), but the number of breaks increased at higher pressures. Reproduced with permission.3

	Spectrum of `Cardiogenic' to `High-Permeability' Edema as Capillary Pressure Is Raised

Top Abstract Introduction Recent Work on Pulmonary... Wall Stress in Pulmonary... What Determines the Strength... Ultrastructural Changes in... Spectrum of `Cardiogenic' to... Role of Remodeling in... Clinical Conditions Involving... Dilemma of the Blood-Gas... References

 
Pulmonary edema is traditionally classified as caused by either an increased capillary pressure ("hydrostatic" or "cardiogenic" edema) or an increased permeability of the capillary wall ("high-permeability" edema). The distinction between the two has usually been made on the basis of the protein concentration of the edema fluid.³⁰ The protein concentration is usually less than one half that of blood in hydrostatic or cardiogenic pulmonary edema, whereas the ratio is typically >0.7 in high-permeability edema.^{30 31} The differences arise because the pulmonary blood-gas barrier tends to retain its low-permeability characteristics in hydrostatic edema, with the result that the sieving of protein remains effective. By contrast, damage to the wall of the pulmonary capillary increases its permeability, resulting in a greater protein loss from the capillary.

In practice, this traditional classification does not always match expectations. For example, Fein et al³⁰ pointed out that there is a substantial overlap between the two groups, even in conditions where a pure form of hydrostatic or cardiogenic edema would be expected. Sprung et al³² showed that there is a continuous fall in the ratio of protein in edema fluid to serum when plotted against pulmonary artery wedge pressure for a large group of patients. They referred to an "intermediate type of pulmonary edema" on the basis of the protein concentration of the alveolar fluid and suggested that a combination of increased permeability and high hydrostatic pressure may account for this intermediate form.

We studied the characteristics of the alveolar edema fluid in our rabbit preparation described above by analyzing the bronchoalveolar lavage fluid (BALF).³³ At low capillary transmural pressure where our morphometric studies show no ultrastructural changes in the blood-gas barrier, the volume of alveolar fluid was very small, and the concentrations of proteins, cells, and leukotriene B₄ (LTB₄) in the BALF were low. However, at high capillary transmural pressures at which the typical morphological features of stress failure were seen (Fig 5), the volume of alveolar fluid and the concentrations of total protein and cells in the BALF were greatly increased. The amount of LTB₄ was also raised substantially from 6.0 to 49.5 µg (P<.001). Intermediate changes were seen at intermediate values of capillary transmural pressure.

These studies therefore show that there is a spectrum of types of pulmonary edema as the capillary pressure is raised from low to high values. Initially, as the Starling equilibrium is disturbed, fluid moves from the capillary lumen into the alveolar wall interstitium and possibly into the alveolar spaces. Nothing that we have observed did not follow the Starling hypothesis. The result is interstitial and perhaps alveolar edema with a relatively low protein concentration, so-called hydrostatic or cardiogenic edema.

As the capillary pressure is raised to higher levels, we may see the phenomenon known as "pore stretching" (Fig 7). This is somewhat controversial, but Pietra et al³⁴ showed that when the pulmonary capillary pressure was increased, large tracer molecules such as hemoglobin solution moved between capillary endothelial cells into the interstitium of the alveolar wall.

View larger version (27K): [in this window] [in a new window]   Figure 7. Diagram showing changes in the capillary wall as the pressure is raised. A, Normal morphology, which is associated with low-protein hydrostatic or cardiogenic edema when the pressure is raised. B, Pore stretching with leakage of proteins into the alveolar wall interstitium. C, Endothelial and epithelial disruption caused by stress failure with movement of protein into the alveolar spaces, causing a high-permeability type of edema. Reproduced with permission.2

Finally, at even higher pressures, stress failure of the blood-gas barrier occurs with disruption of the capillary endothelial layer, alveolar epithelial layer, or sometimes all layers of the blood-gas barrier (Fig 7). The result is a high-permeability type of edema. Thus, in summary, as the capillary pressure is gradually raised from normal to high levels, the first stage is a low-permeability, hydrostatic or cardiogenic form of pulmonary edema, but this is followed by a high-permeability type of edema.

It could be argued that whenever alveolar edema occurs, there is some damage to the alveolar epithelium. It is known that the normal epithelium is very impermeable to water, ions, and proteins and that it normally actively pumps water from the alveolar to the interstitial space, probably with an Na⁺-K⁺,ATPase pump.^{35 36} Whenever the fluid of alveolar edema is carefully analyzed, it always contains some red blood cells, which is strong evidence of damage to both the capillary endothelium and the alveolar epithelium. Thus, it may be that isolated, small areas of stress failure of pulmonary capillaries occur at the relatively low capillary transmural pressures associated with alveolar edema. This would be consistent with the data on the frequency of the stress failure referred to previously (Fig 6) in which it was found that occasional morphological damage was seen in rabbit lung at capillary transmural pressures as low as 24 mm Hg.³

	Role of Remodeling in Pulmonary Circulation

Top Abstract Introduction Recent Work on Pulmonary... Wall Stress in Pulmonary... What Determines the Strength... Ultrastructural Changes in... Spectrum of `Cardiogenic' to... Role of Remodeling in... Clinical Conditions Involving... Dilemma of the Blood-Gas... References

 
When experimental animals such as rats are exposed to a hypoxic environment, for example in a low-pressure chamber, hypoxic pulmonary vasoconstriction occurs, and this is followed by morphological changes in the pulmonary arteries. These include increases in the amount of vascular smooth muscle and extracellular matrix.^{37 38} This remodeling persists if the hypoxic exposure continues, and humans who permanently reside at high altitude have increased vascular smooth muscle and extracellular matrix in their pulmonary arteries.

In experimental animals exposed to hypoxia, the remodeling is rapid, and histological changes in smooth muscle appear within 2 days.^{37 38} If excised rings of pulmonary artery in Krebs-Ringer solution are stretched, changes occur within 4 hours, including an increase in mRNA for pro--1 (I) collagen and increased collagen and elastin synthesis as determined from incorporation of ¹⁴C proline and valine.³⁹ The response is endothelial dependent because it is not seen whether the endothelium is removed from the lumen of the pulmonary artery.

A result of the pulmonary arterial remodeling is to return the lung to a condition similar to that in fetal life, where the pulmonary arterial pressure is high because of the anatomic connection with the aorta through the ductus arteriosus but the capillaries are protected by large amounts of vascular smooth muscle and hypoxic pulmonary vasoconstriction. Thus, it is arguable that the role of pulmonary arterial remodeling is to protect the very vulnerable capillaries when the pulmonary arterial pressure rises.

In this context, clinical observations of high-altitude pulmonary edema (HAPE) may provide a useful clue. There is evidence that this condition is caused by stress failure of pulmonary capillaries (see later) because when the pulmonary arterial pressure rises, the vasoconstriction is uneven, and those capillaries not protected from the increased pressure develop ultrastructural changes in their walls. The clinical observation is that if a person goes to a high altitude, the HAPE will develop within 1 week or not at all. A reasonable explanation is that during the first few days of hypoxic exposure, remodeling rapidly occurs in the pulmonary arteries, and the capillaries are then protected from the increased pulmonary arterial pressure.

The term "remodeling" in the context of the pulmonary circulation usually refers to the changes in the pulmonary arteries described previously. However, there is another type of remodeling—the increase in extracellular matrix that occurs in pulmonary capillaries when capillary pressure rises, as in mitral stenosis.^{19 20 21} An example is shown in Fig 3. This is the type of remodeling that occurs if there is a rise in pulmonary venous pressure. Clearly, no changes in the pulmonary arteries can protect the capillaries under these conditions. Remodeling of pulmonary capillaries has been little studied, and the mechanism is unknown.

	Clinical Conditions Involving Stress Failure of Pulmonary Capillaries

Top Abstract Introduction Recent Work on Pulmonary... Wall Stress in Pulmonary... What Determines the Strength... Ultrastructural Changes in... Spectrum of `Cardiogenic' to... Role of Remodeling in... Clinical Conditions Involving... Dilemma of the Blood-Gas... References

 
Group 1
This group includes disease in which an increased capillary pressure causes a high-permeability type of pulmonary edema (Table).

View this table: [in this window] [in a new window]   Table 1. Clinical Conditions Involving Stress Failure of Pulmonary Capillaries

Neurogenic Pulmonary Edema
There is strong evidence that neurogenic pulmonary edema (NPE) is caused by stress failure of pulmonary capillaries. Studies in experimental models of this disease, and occasional clinical measurements, show that both pulmonary arterial and wedge pressures are very high.^{40 41} These high pressures are associated with greatly increased catecholamine concentrations in the blood. The mechanism by which this "sympathetic storm" raises pulmonary vascular pressures is disputed, but factors probably include intense peripheral vasoconstriction, which shifts blood to the thorax; acute left ventricular failure caused by overwhelming systemic hypertension; and reduced compliance of the left ventricle, necessitating very high filling pressures. The alveolar edema has been shown to be of the high-permeability type with large concentrations of high-molecular-weight proteins and cells.⁴² Finally, Minnear and colleagues^{43 44} have demonstrated ultrastructural changes in the walls of the pulmonary capillaries that essentially are identical to those seen in the rabbit lungs with stress failure. Thus, the evidence that this condition is caused by stress failure of pulmonary capillaries is very strong.

HAPE
HAPE is probably also caused by stress failure of pulmonary capillaries. There is a very strong association between the occurrence of HAPE and a high pulmonary arterial pressure caused by hypoxic pulmonary vasoconstriction.^{45 46 47} Therefore, the edema presumably has its basis in an increased capillary pressure. The explanation of how hypoxic vasoconstriction, which primarily affects small pulmonary arteries, can raise capillary pressure is presumably that given by Hultgren,⁴⁸ ie, that the vasoconstriction is uneven, with the result that those capillaries not protected by arterial constriction are exposed to a high pressure. This would not be surprising in view of the very patchy distribution of smooth muscle in small pulmonary arteries in the normal adult lung⁴⁹ and the great variability in the intensity of hypoxic pulmonary vasoconstriction between individuals.⁵⁰ The case can be made that hypoxic pulmonary vasoconstriction in the adult is vestigial, the evolutionary pressure for this mechanism being the changes that occur in the perinatal period in the transition from placental to air breathing. After birth, extensive involution of vascular smooth muscle occurs.⁴⁹

The edema fluid of HAPE is of the high-permeability type, with a large concentration of cells and high-molecular-weight proteins.^{51 52} The protein concentration in severe HAPE can, in many cases, exceed that of the adult respiratory distress syndrome (ARDS).⁵¹ Thus, the problem is how to reconcile this extreme high-permeability type of edema with its presumed hydrostatic basis, and it was this dilemma that led us to begin a study of the effects of high pressure on the ultrastructure of pulmonary capillaries.

A feature of HAPE is that the BALF contains LTB₄, other lipoxygenase products of arachidonic acid oxidation, and C5a complement fragments. In this context, it is interesting that, as described, BALF studies in the rabbit lung show increased levels of LTB₄ when the capillary transmural pressure is high. A possible source is activation of platelets and white blood cells as a result of contact with the exposed basement membranes caused by disruption of the capillary endothelial cell layer (Fig 5b).

We have obtained direct morphological evidence supporting the hypothesis that HAPE is caused by stress failure of pulmonary capillaries. We have shown that rats exposed to low barometric pressure in a chamber develop disruptions of both the capillary endothelial and alveolar epithelial layers, with red blood cells escaping into the interstitium and alveolar spaces.⁵³ Similar appearances were described by Mooi et al⁵⁴ and are consistent with the ultrastructural changes that we have seen in the rabbit lung with stress failure.³

ARDS
It is possible that the high-permeability edema of some patients with ARDS may be caused by stress failure of pulmonary capillaries. This is particularly likely when ARDS follows trauma, which causes a large release of catecholamines. The result would be a transient increase in pulmonary vascular pressures leading to stress failure of pulmonary capillaries. This scenario has features similar to those of NPE and HAPE. Ultrastructural studies of the pulmonary capillaries in patients with ARDS⁵⁵ show many of the features seen in rabbit lungs as a consequence of stress failure.³

Group 2
This group includes conditions in which an increased capillary pressure causes alveolar hemorrhage.

Exercise-Induced Pulmonary Hemorrhage
Exercise-induced pulmonary hemorrhage (EIPH) in racehorses is the most dramatic example of such a condition. There is good evidence that essentially all thoroughbreds in training develop alveolar bleeding.⁵⁶ The reason is that these animals have been selectively bred to develop enormously high maximal oxygen consumptions, which necessitates very high cardiac outputs and therefore extreme pulmonary vascular pressures. Direct measurements of mean pulmonary arterial and left atrial pressures in animals galloping on a treadmill are as high as 120 and 70 mm Hg, respectively⁵⁷ (Fig 8), and pulmonary arterial wedge pressures are consistent with these levels.^{58 59} Pulmonary capillary pressures must therefore approach 100 mm Hg. The very high left atrial pressures are apparently required to fill the left ventricle, which is pumping against a mean arterial pressure of 240 mm Hg at heart rates as high as 240 beats per minute. We have demonstrated the ultrastructural features of stress failure of pulmonary capillaries in thoroughbreds after they have galloped on a treadmill.⁶⁰

View larger version (15K): [in this window] [in a new window]   Figure 8. Schematic of mean pulmonary vascular pressures in galloping thoroughbred racehorses. The right atrial (RA), right ventricular (RV), and left atrial (LA) pressures were measured with indwelling catheters. LV indicates left ventricle. Data from Jones et al,57 Erickson et al,59 and Manohar58 with permission.

A possible objection to this explanation is that the lesions of EIPH are most marked in the dorsal-caudal region of the lung, where the hydrostatic pressures are lower than in the ventral regions. However, the important pressure is the capillary transmural pressure, and it may be that alveolar pressure transiently falls to very low values in this region because of the oblique inclination of the diaphragm or the high airway resistance. Another possibility is that these alveoli have a high volume because of distortion of the lung by its weight.⁶⁰ We show that overinflation of the lung causes stress failure of capillaries.

Catastrophic Increase in Pulmonary Venous Pressure
Occasionally, a catastrophic event such as rupture of the chordae tendineae or a papillary muscle of the mitral valve causes alveolar hemorrhage. Alveolar bleeding has also been described in patients with very high left atrial pressures who are awaiting cardiac transplantation.

Bleeding in Elite Human Athletes
There are anecdotal accounts of hemoptysis after extreme exercise, although no systematic studies have been made. One example is a 35-year-old rugby player who repeatedly developed hemoptysis during the extreme physical exertion of the games.⁶¹ Extensive investigations revealed no abnormalities except that blood could be seen coming from peripheral parts of the lung at bronchoscopy. It is possible that alveolar bleeding occurs more commonly in elite athletes but that it is unrecognized. Hemoptysis is a relatively late sign of alveolar bleeding; for example, patients with Goodpasture's syndrome frequently have radiological evidence of alveolar hemorrhage without hemoptysis. Further studies in this area are warranted.

Group 3
In group 3 conditions, the increase in pulmonary capillary pressure gives rise to a combination of edema and hemorrhage.

Chronic Venous Hypertension
Chronic venous hypertension is exemplified by mitral stenosis where hemoptysis occurs in approximately one half of patients¹⁵ and the lungs contain large amounts of hemosiderin at autopsy. Both interstitial and alveolar pulmonary edema occur, although sometimes patients with remarkably high pulmonary arterial wedge pressures do not develop alveolar edema.¹⁵ A possible explanation is that the extensive thickening of the extracellular matrix of the capillaries, as shown in Fig 3, reduces the permeability of the capillaries.^{19 20 21} Recent studies in animals support this hypothesis. Dogs with chronic left ventricular failure induced by heart pacing over 4 to 7 weeks show changes in the morphology of the capillary basement membrane and have lower capillary filtration coefficients when the capillary pressure is raised compared with control animals.⁶²

Ultrastructural studies of the pulmonary capillaries in patients with mitral stenosis have shown breaks in the capillary endothelium and red blood cells in the interstitium of the alveolar wall and in the alveolar spaces.¹⁹ Another finding is rows of type II alveolar cells lining parts of the alveolar wall.^{19 20} The explanation may be that alveolar type II cells replace type I cells that were damaged by stress failure (Fig 4b through 4d). All of these features are consistent with stress failure. Similar morphological appearances have been described in the less common condition of pulmonary veno-occlusive disease.^{63 64}

Hemorrhagic Pulmonary Edema in Elite Athletes
This condition has occasionally been described during prolonged intense exercise. An example was the study by McKechnie et al,⁶⁵ in which two athletes running the 90-km Comrade's Marathon in South Africa developed hemorrhagic pulmonary edema. The duration of the race was 8 to 10 hours, and both athletes had developed the condition previously during similar races. Follow-up studies showed no cardiopulmonary disease.

Group 4
Overinflation of the Lung
Overinflation of the lung is known to cause increased permeability of pulmonary capillaries⁶⁶ and is a serious problem in the intensive care unit, where patients with respiratory failure are treated with high levels of positive end-expiratory pressure. Experiments in animal preparations have shown that the increased permeability is due to the high lung volume rather than the increased alveolar pressure because chest banding prevents the increased permeability.⁶⁷ There is strong evidence that the increased permeability is caused by stress failure of pulmonary capillaries. If we increase lung volume in our anesthetized rabbit preparation while maintaining a constant capillary transmural pressure, the number of both endothelial and epithelial breaks is greatly increased.⁶⁸ For example, in a study in which the capillary transmural pressure was held constant at 24 mm Hg, the number of endothelial breaks per millimeter of cell lining was 7.1 at the high volume compared with only 0.7 at the low volume. The corresponding numbers for epithelial breaks were 8.5 versus 0.9. The explanation is that at high states of lung inflation, there is a large increase in tension in the alveolar wall, and some of this tension is transmitted to the capillary wall.

Group 5
Finally, stress failure of pulmonary capillaries occurs if the main structural element of the capillary wall—the extracellular matrix—is abnormal. In Goodpasture's syndrome, autoantibodies are produced that attack the NC1 globular domain of type IV collagen,⁶⁹ and bleeding occurs into both the alveolar and glomerular spaces. As pointed out, the glomerular capillaries are vulnerable because they are normally exposed to a high hydrostatic pressure of 40 mm Hg.

	Dilemma of the Blood-Gas Barrier

Top Abstract Introduction Recent Work on Pulmonary... Wall Stress in Pulmonary... What Determines the Strength... Ultrastructural Changes in... Spectrum of `Cardiogenic' to... Role of Remodeling in... Clinical Conditions Involving... Dilemma of the Blood-Gas... References

 
The vulnerability of pulmonary capillaries can be regarded as an inevitable result of the evolutionary forces responsible for the design of the lung. To allow efficient gas exchange, the blood-gas barrier must be extremely thin. We know that it cannot be any thicker because some elite human athletes show diffusion limitation of oxygen transfer in the lung during intense exercise.^{6 70} This is also true of thoroughbred racehorses.⁷¹ The extreme thinness of the barrier therefore confers a survival advantage.

On the other hand, the blood-gas barrier must be immensely strong because it forms the walls of the pulmonary capillaries, and the stresses become extremely high when the capillary pressure rises. In other words, the barrier has evolved to be as thin as possible for maximum efficiency of gas exchange but to have just enough strength to maintain its integrity under the most challenging normal physiological conditions. In fact, it is possible that the amount of type IV collagen in the capillary wall is continuously being regulated, possibly by the level of pressure within the capillary, and this explains why the extracellular matrix increases in disease such as mitral stenosis when the capillary pressure is raised. However, if the capillary transmural pressure rises to unphysiologically high levels, or wall stress is greatly increased by overinflation, or the wall is weakened by disease, alveolar edema, or hemorrhage, or both are inevitable.

	Acknowledgments

 
This work was supported by NHLBI Program Project grants HL-17731 and R01-46910. We acknowledge the collaboration of Eric Birks, Michael Costello, Ann Elliott, Zhenxing Fu, James Jones, Sadi Kurdak, Yasuo Namba, John Pascoe, Renato Prediletto, Koichi Tsukimoto, and Walter Tyler.

	References

Top Abstract Introduction Recent Work on Pulmonary... Wall Stress in Pulmonary... What Determines the Strength... Ultrastructural Changes in... Spectrum of `Cardiogenic' to... Role of Remodeling in... Clinical Conditions Involving... Dilemma of the Blood-Gas... References

 
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