The Pulmonary Circulation
Snapshots of Progress

JOHN T. REEVES and LEWIS J. RUBIN

Department of Pediatrics, University of Colorado Health Services Center, Denver, Colorado; and Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland

	INTRODUCTION

TOP INTRODUCTION CONCLUSION REFERENCES

Although the entire cardiac output flows through the lung, the pulmonary circulation has long been a second-class citizen. It has been called the "lesser" circulation in comparison to the "greater" or systemic circulation. And so, the world's first conference dedicated solely to the pulmonary circulation was not held until March of 1958 (1). "Because of the urgency of the situation . . . the growing realization of its (the pulmonary circulation's) significance in many diseases of the heart and lungs. . . where pulmonary hypertension is the principal cause of death," the Chicago Heart Association organized the conference and published the proceedings simply as Pulmonary Circulation. In attendance were the world's leading scientists interested in the lung circulation. Here we use it as the benchmark of our basic and clinical knowledge in the field at that time. In the subsequent four decades there has been an explosion of research activity encouraged (in the United States) by the Division of Lung Diseases of the National Heart, Lung, and Blood Institute, the American Thoracic Society, and the American Heart Association. So, what have we learned since 1958? This article will consider advances in our basic understanding of the lung circulation and how these have been translated into clinical practice. As it is neither possible nor desirable to encompass everything in this brief review, interested readers are referred to the many symposia, books, and reviews on the lung circulation held and published since 1958, some of which are included among the references.

	BASIC SCIENCE ASPECTS

General

We have elected to consider here the advances in three interrelated basic aspects of the lung circulation: oxygen regulation of the lung circulation, endothelial contribution to the regulation, and control of composition of the pulmonary arterial wall. We chose to look at oxygen regulation because it is a fundamental mechanism in the lung circulation (2). When the oxygen level falls (hypoxia) in a lung alveolus, the blood flow to that alveolus also falls, thereby attempting to match perfusion to ventilation. Low levels of alveolar oxygen cause small pulmonary arteries to constrict. This mechanism for local control of blood flow within the lung works well until the oxygen level falls throughout the lung, thereby raising blood pressure to the entire lung (6). Thus, oxygen lack throughout the lung in newborn children, in persons living at high altitude, and in those with lung disease may cause serious, and even fatal, pulmonary hypertension. However, retarding and limiting the development of pulmonary hypertension is a series of checks and balances built into the lung circulation. One of the most important of these modulating mechanisms originates within the endothelial cell lining the lung blood vessel walls (7, 8). These lining cells liberate substances that can raise or lower pulmonary arterial pressure and usually act to moderate changes that might otherwise occur (8). Further, both the pressure within the lung blood vessels (11) and the function of the endothelial cells (9) determine, to a large extent, the thickness of the vascular wall. And it is the thickened wall of the pulmonary arteries themselves that causes most of the life-threatening pulmonary hypertension in man. Our focus here on oxygen regulation, endothelial function, and wall thickening are merely examples of the intricacy and complexity of the pulmonary circulation, and the reader is directed to more extensive reviews for other major advances in its control and function.

Oxygen Regulation of the Lung Circulation

A moralist might say that the air we breathe is as good as we deserve.

Joseph Priestly, ca. 1780

Foundations present in 1958. By 1958, it was acknowledged that hypoxia raised pulmonary arterial pressure, which likely served to match perfusion to ventilation in the adult and to maintain high vascular resistance in the fetus. But each of these two functions was initially considered to be of minor importance. In the adult, Fritts and Cournand, on finding definite but small hypoxic pulmonary pressor responses in humans, concluded, "the experimental evidence indicates that (the lung) vessels can constrict and dilate . . . but . . . only under extreme conditions" (1). Cournand had just received the Nobel Prize for cardiac catheterization, and he was the acknowledged authority of the day on the lung circulation. His group had shown that unilateral hypoxia redistributed flow away from the hypoxic lung, that general hypoxia raised pulmonary arterial pressure even in humans with denervated lungs, and that acetyl choline infusion (confined to the lung) reversed hypoxic pulmonary hypertension. Although the work strengthened the idea that hypoxia acted locally within the lung, in persons with normal pulmonary arterial pressure the changes were small.

In the fetus, Dawes reported on the fall in pulmonary arterial pressure following ventilation of the lamb, and emphasized the importance of lung inflation with the first breath. "Ventilation of the lungs of foetal lambs . . . caused a large and immediate fall in pulmonary vascular resistance. . . . A single sudden inflation even with nitrogen has on occasion caused a sudden four fold increase in flow" (1). He commented, however, that should there be continued lung hypoxia after birth of the newborn, "pulmonary vascular resistance increases and blood (flows) once more in the foetal direction." Here, at least, was a clue that during the critical period after birth, hypoxia could cause severe pulmonary hypertension. These were exciting findings from the world's leading laboratory in fetal and neonatal physiology.

Thus, in 1958 investigators were seeking the role of hypoxic pulmonary vasoconstriction. Inquiry into the mechanisms had hardly begun. Now, four decades later it is important to put the early findings with hypoxia into perspective and to summarize where we currently stand.

What is hypoxia? With the widespread application of cardiac catheterization, we know that for normal adults at sea level (ambient PO₂ ~ 160 mm Hg), pulmonary arterial pressure is only about 15 mm Hg or about one-sixth that in the systemic arteries, but that pressure becomes higher during residence at high altitude or when there is chronic oxygen toxicity (2, 12). Pulmonary circulatory health exists within the relatively narrow range of ambient oxygen pressures (PO₂) between approximately 125 to 350 mm Hg. Hypoxia is probably a continuum of PO₂ values downward from sea level normoxia, while hyperoxia extends to values upward. From the view of the lung circulation, perhaps Joseph Priestly, the Unitarian minister who discovered oxygen, had it about right.

Vascular sites of action by hypoxia. To be settled first of all was the question of whether alveolar hypoxia caused pulmonary vessels to constrict. The evidence as it accrued was positive, because with hypoxia the rise in pulmonary arterial pressure was greater than could be explained by an increased flow, the pressure rise occurred in isolated perfused lungs where flow was constant, the pressure rise was not accompanied by changes in airway resistance or lung compliance, and both in vivo and in vitro the rise could be prevented and reversed by vasodilators (2, 6). In isolated lungs, pressure rose to a peak during several minutes of hypoxia, consistent with development of increased smooth muscle tone. Neural activity was not required for the response, and hypoxia isolated even to a lung lobule could elicit localized vasoconstriction in that lobule (6). There is now consensus that hypoxia can constrict pulmonary vessels and that the response resides within the lung itself. Remarkably, systemic arteries, including the ductus arteriosus, behave in the opposite manner by relaxing with hypoxia and constricting with hyperoxia.

If there is hypoxic pulmonary vasoconstriction, which vessels are involved? Certainly, the pulmonary arterioles constrict with hypoxia, as was shown by high resolution arteriography in vivo, by quickly freezing the hypoxic lung, and by micropuncture in vitro to measure pressures in artery, arteriole, venule, and vein (13). Further, isolated lung arterioles constrict when made hypoxic in an aqueous bath, and hypoxic constriction can even be shown in fetal lung arterioles transplanted to the hamster cheek pouch (6, 13). But because blood flows from artery to vein, was it reasonable to ask how low oxygen in the alveolus could be sensed upstream on the arterial side of the capillaries? The answer appeared to lie in the anatomy of an arterial wall so thin and so close to the alveoli that a gas breathed by human subjects could promptly be sensed within the lumens of rather large pulmonary arteries. And oxygenation of venous blood in pulmonary arteries was found to begin well before the blood reached the capillaries. Apparently, the thin-walled pulmonary arteries are virtually suspended in the alveolar air and are promptly affected by compositional changes in that air (13). Pulmonary venules also apparently constrict with hypoxia, but less effectively, possibly because they are less muscular. Capillary constriction with hypoxia has been claimed but not conclusively shown. In any event, hypoxic vasoconstriction resides primarily distal to lobar arteries and proximal to the capillaries, and occurs in resistance arterioles 30 to 300 µm in diameter. And even isolated smooth muscle cells from pulmonary arterioles contract when made hypoxic.

Mechanism of hypoxic pulmonary vasoconstriction. The foundation studies of mechanism were at the organ level, using the isolated perfused lung. The initial key finding was that calcium entry from perfusate to lung tissue was necessary for hypoxic vasoconstriction (4, 6). Maneuvers that increased calcium entry increased constriction and conversely, those that decreased entry, decreased constriction. Because the findings pointed to an essential role of the membrane of the smooth muscle cell, further steps must be at the cellular level. And progress came from study of the isolated smooth muscle cell (14). An essential role for the membrane was strengthened by finding that hypoxia depolarized smooth muscle cells from lung arteries, but hyperpolarized cells from systemic arteries. Accordingly, the response to hypoxia differs. In the lung, hypoxic-induced depolarization leads to calcium entry into arterial smooth muscle and vasoconstriction; in contrast, hypoxic-induced hyperpolarization of systemic arteries leads to vasorelaxation of these vessels. But what were the mechanisms within the membrane itself? Clues came from study of the glomus type I cell of the carotid body, where hypoxia was found to close voltage-gated potassium channels in the cell membrane, thereby inhibiting potassium ion efflux, increasing the positivity within the cell, promoting membrane depolarization, and initiating neural discharge of the cell. Findings in the pulmonary arterial smooth muscle cell were that a similar mechanism caused membrane depolarization and contraction of the cell (Figure 1) (15). What still remains a mystery is precisely how the hypoxia is sensed. The early idea that decreased intracellular ATP constitutes the hypoxic signal seems unlikely because intracellular energy stores are well maintained at PO₂ values far below those that depolarize the cells. Current research focus is on the diverse family of potassium channels, how they differ with age, location, and function, how they are controlled, and the intracellular consequences of their activation.

View larger version (19K): [in this window] [in a new window]   Figure 1.   The effect of redox state on membrane potassium channel activity. Normoxia is associated with open channels, whereas hypoxia results in closing of the potassium channels, leading to membrane depolarization, opening of voltage-gated calcium channels, influx of calcium into the cytosol, and vasoconstriction. Oxidizing compounds mimic normoxia, while reducing agents mimic the effects of hypoxia.

Modulation of hypoxic vasoconstriction. For the lung circulation during the last four decades, possibly the greatest amount of printer's ink has been spilled over the roles of chemical mediators in hypoxic pulmonary vasoconstriction. As that ink dries, it has become clear that known chemical substances liberated by the lung, including, for example, the catecholamines, histamine, angiotension II, 5-hydroxytriptamine, prostaglandins, thromboxane, the leukotrienes, nitric oxide, and the endothelins are not THE responsible mechanism for hypoxic pulmonary vasoconstriction although at some time, each has been in the news (6, 16). What has been learned is that each of these chemical substances is to some extent metabolized by the lung circulation, and each has a role to play in circulatory control. Thus, nitric oxide and prostacyclin support oxygenation and lung inflation in dilating the lung vasculature after birth (17, 18). The eicosanoids, prostacyclin, thromboxane, and leukotrienes are key determinants of pulmonary circulatory tone during various inflammatory stresses (6, 16). To a large extent these chemical mediators are responsible for the variable nature of hypoxic pulmonary vasoconstriction from person to person, and under varying conditions of age, gender, inflammation, altitude of residence, pregnancy, adrenergic tone, metabolic inhibition, redox state, ionic balance, temperature, alcohol intake, and exercise, just to name a few (16). In addition, the various mediators not only modulate the effects of hypoxia on the lung circulation, but each is an important regulator of tone in its own right.

Endothelial Contribution to Vascular Tone

An increase in flow rate increases drag and appears to induce the endothelium to generate a signal that triggers relaxation of the subadjacent medial smooth muscle.

Simon Rodbard, 1975

Foundations present in 1958. In the conference proceedings of the Pulmonary Circulation, the word intima appeared several times, but the word endothelium did not appear. The presentation on "Functions of the Lung Circulation" by Dr. Julius H. Comroe, Jr., focused on gas exchange. "The primary function of the lung circulation is gas exchange. . . . Therefore, let me direct your attention first to the capillary bed" (1). He then considered the thinness of the barrier between the air and blood and its importance for oxygen transport. Although he did not detail any other function of the lung circulation, he did provide a litany of 22 questions of the "many things we do not know." It is likely that neither Comroe nor the other premier pulmonary scientists present imagined a great variety of roles for pulmonary endothelium, other than as a spectator in gas exchange or a policeman in water flux. In 1958 a whole field of pulmonary endothelial science awaited discovery. That the discovery proceeded so slowly is remarkable, given the lung endothelial cell's strategic locationone of receiving the entire cardiac output, linking the pulmonary and systemic circulations, while also regulating smooth muscle tone by continuously signaling the vascular wall.

Lung endothelium linking pulmonary with systemic circulations. Approximately one decade after the Chicago Pulmonary Circulation Conference, scientists began to realize that the lung endothelium metabolized circulating vasoactive substances. Those substances not particularly useful to the systemic circulation (i.e., bradykinin) might be removed by the lungs, while useful substances (i.e., angiotension II) might be produced by the lung endothelium. Endothelial receptors for these and other substances were then identified (19). Subsequently, hordes of substances were found to be metabolized by the lung endothelium, including kinins, other peptides, catecholamines, purines, insulin, lipoproteins, clotting and complement components, and many others.

Endothelium as a regulator of tone in the lung circulation. Another decade later, in the late 1970s, with the discovery and characterization of the vasodilator, prostacyclin, and the vasoconstrictor, thromboxane (16, 20), the concept arose that lung endothelium was more than a slave to the rest of the body, and that it had key roles to play in controlling the lung circulation itself. The endothelium was found to produce prostacyclin in response to vasoconstriction, as though to modulate shear stress within pulmonary vessels, and prostacyclin production appeared to be an important component for the crucial pulmonary vasodilation that normally occurs at birth (17). Next, the key role of the endothelium in lung circulatory control was strongly reinforced with the discovery in the 1980s of endothelial-derived relaxing factor (EDRF) (7) and the characterization of this factor as nitric oxide (NO) (21). What is remarkable is that a compound as simple as NO has been so recently discovered, even though nitroglycerin and other oxides of nitrogen, which probably metabolize to NO in the body, have been known to be powerful dilators of blood vessels for more than a century.

In the decade since the identification of NO as the EDRF, and as our understanding has increased, so do we marvel at the beauty of its contribution to system design. For example, among the fundamental design goals of vascular biology are the matching of lung vessel size to its blood flow and the restraining to within tolerable limits of shear stresses from the flowing blood. These design goals must be met: (1) continually; (2) for each vessel segment independently of other segments; and (3) during steady states as well as rapid change. The goals would be facilitated if lung endothelial cells could sense shear stress and could modulate it by prompt local action, as foreseen by Rodbard (22). Endothelial cells seem both to sense local shear and to initiate a response because of their inherent ability to synthesize NO (from the ubiquitous amino acid, L-arginine, and molecular O₂) in response to increased shear (Figure 2, top panel). Because the NO molecule is small and soluble, it diffuses quickly from the endothelial cell to the neighboring smooth muscle cells, resulting in prompt vasodilation, which in turn reduces shear stress in that vascular segment. And the effect is local, because NO has a brief half-life in tissue, and in blood it is bound to hemoglobin with an affinity even greater than that of carbon monoxide. Thus, in part through NO, the design goals for vascular regulation are met.

View larger version (29K): [in this window] [in a new window]   View larger version (30K): [in this window] [in a new window]   Figure 2.   Pathway of nitric oxide (NO) generation in the endothelial cell and mechanism of NO-induced relaxation in the smooth muscle cell (top panel ). Production of vasoconstrictors by the endothelium in response to a variety of stimuli contributes to the control of pulmonary vasomotor tone (bottom panel ).

As a result of its prompt local powerful actions, NO may be the lung's primary normal vasodilator with many key regulatory roles. It is considered to help maintain the normal low pulmonary vascular tone, to oppose increases in tone caused by acute or chronic hypoxia or other vasoconstrictors, to help regulate tone in fetal life, to be a major factor in the vasodilation that occurs at birth, and to mediate the reduced maternal pulmonary vascular tone associated with pregnancy. In diseases that damage lung endothelium, for example, primary pulmonary hypertension (see below), loss of NO production contributes to high smooth muscle tone and further vascular damage. And because it is a gas with local action, inhaled NO is a nearly ideal candidate for therapy of some forms of pulmonary hypertension (18).

We now know that endothelial metabolism is not a one-way street directed only at vasodilation. Rather, the endothelium can produce vasconstrictors and thus is well situated to help maintain the balance of vascular tone. These substances are summarized in Figure 2 (bottom panel). Of interest, these constrictors have also been implicated in causing smooth muscle hypertrophy and hyperplasia, as indicated below.

Endothelium in lung vessel remodeling. The early idea that vascular smooth muscle, like the blacksmith's arm, thickens simply from the work of contracting, has become too simple. The endothelium is adjacent to smooth muscle fibers and influences not only contraction but also hypertrophy and hyperplasia (9, 23). Vasodilators produced by the endothelium, such as prostacyclin and NO, appear generally to inhibit smooth muscle growth, whereas constrictors generated by endothelium, such as angiotensin II and endothelin, usually promote growth. Thus, there are links between endothelial function and the thickness of smooth muscle in the vascular media, and these links complement other regulators of the wall thickness (see below). We are just coming to realize the magnitude of communications between the different cell types in the pulmonary vascular wall, and that these communications involve both function and structure. For the lung circulation, one of the major advances in the last four decades is the realization that pulmonary endothelial cells are not simply inert vascular paving stones; rather, they are remarkably active with bewildering arrays of actions and interactions that medical scientists are only beginning to understand.

Control of Composition of the Pulmonary Arterial Wall

The basis for elevation of pulmonary blood pressure frequently, and perhaps always, depends on morphologic alterations. . . . [In left to right shunts] the high flows . . . are irritating to the lining and cause [it] to respond by development of proliferative lesions.

Jesse E. Edwards, 1958

Foundations present in 1958. In the 1958 Pulmonary Circulation Conference, the participants knew well that certain diseases, including primary pulmonary hypertension, congenital heart disease with left-to-right shunts, mitral stenosis, and pulmonary emphysema were associated with thickening of the arteriolar wall (1). They knew about the normal regression of pulmonary arteriolar medial hypertrophy following birth, and the recent classification of arterial lesions in pulmonary hypertensive diseases, where the media, adventitia, and sometimes the intima were abnormal. These were exciting times because nearly all of these findings were new. However, the relative roles of vasoconstriction, of a chronic and poorly reversible contracture, and of obstruction due to structural changes were hotly debated. Thus, in 1958 the arterial wall structural changes with pulmonary hypertension were known in broad outline, but their significance was not well understood, the descriptions were preliminary, and the mechanisms were waiting to be examined.

Regulation of cellular components. Keys to our subsequent understanding of the structure of the lung circulation were descriptions of the changes following birth, where from the original fetal pulmonary arteries, new arterioles sprouted. The offspring arterioles differed from the parent vessels by having less smooth muscle and thinner walls. As one proceeds distally along the "new" arterioles in maturing individuals, the smooth muscle thins, then becomes intermittent, and then disappears, giving rise to the low pressure, low resistance vascular bed in the normal adult (24). Just a few years after the Pulmonary Circulation Conference, chronic hypoxia was shown in humans and animals to cause chronic pulmonary hypertension with thickening of the pulmonary arteriolar walls, particularly the smooth muscle and the adventitia (5, 25). Using hypoxic animals, the mechanisms by which the normally poorly muscularized arteries increase their wall thickness could then be studied. There were several surprises. Replication of adventitial cells precedes and often exceeds that of the smooth muscle (24). The adventitia can increase its thickness enough to contribute to narrowing of the vascular lumen (26, 27). Neither smooth muscle nor adventitial fibroblasts are a single cell population, as was originally thought, but rather each is composed of diverse cells with diverse functions. Replication in the various cell populations responds to many stimuli, including mechanical forces (23), hypoxia per se, and mitogenic chemicals, and in each case the replication appears to be governed by some sort of biological clock that ticks from fetal life (27). Surprising also was the degree by which extracellular matrix controls cellular replication within the vascular wall (27, 28). Although the complexities of wall thickening and the intracellular pathways involved are just now beginning to be understood (Figure 3), the concept is established that many cells of diverse types in the vascular wall participate in response to injury, and that to understand the response requires integrating the communication among cells.

View larger version (41K): [in this window] [in a new window]   Figure 3.   Pathways by which increased wall stress leads to vessel growth and stiffening.

Regulation involving the vascular matrix. In 1958 the extracellular matrix of arteries was considered to be composed of collagen, which like the steel in a belted radial tire, provides strength, and elastin, which provides flexibility. While these concepts have stood the test of time (23, 29), we now know, in addition, that collagen, in particular, is a protein in flux. There are dozens of collagens of varying tensile strengths that come and go in the vascular wall, depending on location of the vascular segment, its age, and the stress within its wall. Elastin is primarily laid down in fetal and early postnatal life, when it is actively regulated. Further, elastin does not constitute an impervious sheet, but rather is a lattice through which regulating cells and substances pass. Both collagen and elastin, in addition to other matrix proteins such as fibronectin and proteoglycans, are important in controlling mitotic activity of cells in the vascular walls (23, 27, 29). We now know that matrix proteins are not just the product of the fibroblast but are also made by the other cell types in that vascular wall. Also, the extracellular matrix proteins are connected to receptors that regulate intracellular events and serve as transducers, which signal increased wall stress and thus promote matrix production and cell replication (Figure 4). And for balance to oppose wall thickening, the heparan families of proteins are recognized as important inhibitors of matrix synthesis and smooth muscle replication (28).

View larger version (29K): [in this window] [in a new window]   Figure 4.   Receptor-mediated events linking mechanical stress and extracellular mediators with intracellular signaling, ultimately resulting in cell proliferation.

Thus, the metabolic activity of the vascular cells is determined by influences within the cells, by communication among the cells, and also by the matrix proteins that surround the cells. All of these are under profound genetic control, which is the area of the most intense current investigation. Clearly, progress has been made since the 1958 conference on the Pulmonary Circulation. However, Edwards' statement above still stands: that pulmonary hypertension nearly always depends upon structural change in the vascular wall. The prevention and treatment of pulmonary hypertension will certainly require more complete understanding of that structural change.

	CLINICAL ASPECTS

General

In parallel with basic research advancements over the past 50 years, considerable progress has been achieved in understanding the pathogenesis and in developing improved methods for the diagnosis and treatment of pulmonary vascular diseases. Conditions that were previously diagnosed either at autopsy or, at best, late in their clinical course, and that could be treated only with supportive management, are now diagnosed sooner and treated with approaches that target basic pathophysiologic mechanisms. Success in this arena is a tribute to the collaborative efforts of basic and clinical investigators as well as the development of multicenter clinical trials supported by the National Heart, Lung and Blood Institute (NHLBI). This section will focus on three areas of clinical pulmonary vascular diseases: pulmonary hypertension, acute and chronic thromboembolic disease, and pulmonary vasculitis.

Pulmonary Hypertension

The clinical description by Dresdale in 1951 of primary pulmonary hypertension (30) was followed by a series of case reports detailing successes and failures of attempts at treating this rare, fatal disorder. In the 1959 monograph (1), Wood reviewed his experience infusing acetylcholine into the pulmonary circulation of patients with pulmonary hypertensionan observation that, years later, would be explained as vasodilation produced by endothelial-derived nitric oxide (7). In the years that followed, a variety of vasodilator agents were tested in the hopes of reversing what Wood described as the "vasoconstrictive factor" in pulmonary hypertension (31), but the limited knowledge concerning pathogenesis and natural history hampered progress. In the 1980s the NHLBI undertook a coordinated collection of clinical data on primary pulmonary hypertension from over 65 centers in the United States. The objectives were to define the clinical and pathologic characteristics of the disease, as well as to determine its natural history and to survey then-available treatments. The registry provided the first prospective analysis of all aspects of this disease and established criteria for its diagnosis (32). Most importantly, it established a network of investigators and served as a framework for subsequent trials. Many of the original registry participants subsequently demonstrated the efficacy of vasodilator therapy in a subset of patients and the impact on survival of chronic anticoagulant therapy. Most recently, several multicenter trials, including the first randomized trial in this condition, demonstrated the beneficial effects of continuous intravenous epoprostenol (prostacyclin, PG₁₂) on hemodynamics, exercise tolerance, quality of life, and survival (36). These studies led to the approval of epoprostenol by the Food and Drug Administration for the treatment of primary pulmonary hypertension when it was refractory to other therapies. This was the first drug approved for the disease. Efforts are ongoing to develop new approaches to treatment based on enhanced understanding of the pathogenesis of pulmonary hypertension, such as when therapies should include chronic inhaled nitric oxide, endothelin and thromboxane receptor blockers, and oral, inhaled, and transdermal delivery of epoprostenol or its analogues.

It is clear that altered vasoreactivity alone is not responsible for the pathogenesis of primary pulmonary hypertension. Vascular remodeling, perhaps resulting from altered expression of growth factors, contributes to the vasculopathic process. However, remodeling is a two-way street, since regression of extensive hypertensive changes can occur, for example, after discontinuation of exogenous inducers of pulmonary hypertension (cocaine, anorexigens) or with epoprostenol (37). Clarification of the mechanisms for vascular growth and repair will lead to the development of newer treatments directed at these processes.

The registry also demonstrated that approximately 7% of the pulmonary hypertension cases are familial, prompting efforts to identify the gene responsible for its inheritance (32). Recently a group of investigators have localized the responsible gene to a region on chromosome 2 (38).

Acute and Chronic Pulmonary Thromboembolic Disease

Urokinase Pulmonary Embolism Trial. The background for this trial was the well-known fact that deep venous thrombosis in the lower extremities affects approximately 2 million Americans each year, and of these, nearly 600,000 will experience pulmonary embolism. The embolism is fatal in approximately 10% of patients, many of whom did not have a diagnosis prior to death (39, 40). As any clinician who has cared for patients with pulmonary embolism knows, the clinical presentation is often subtle and the diagnosis requires both a high index of suspicion and a reliance on diagnostic testing.

The Urokinase Pulmonary Embolism Trial provided the first large-scale study of the clinical presentation and course of patients with massive and submassive pulmonary embolism (41). this pioneering trial presented early data on the utility of ventilation/perfusion (/) scans, the effects of therapy on hemodynamics and resolution of perfusion defects, complications of anticoagulant and thrombolytic therapy, and survival. Subsequent studies, based on the findings of the trial, refined diagnostic and treatment approaches to both deep venous thrombosis and pulmonary embolism. Among these are included the development of duplex scanning of the lower extremities as a widely available, sensitive, and noninvasive test for the presence of venous thrombosis, low-molecular-weight heparin as a safe parenteral anticoagulant; and criteria for the use of thrombolytics and vena cava interruption devices (40).

Prospective investigation of pulmonary embolism diagnosis. This was a multicenter study that further enhanced our understanding of the demographics, diagnosis, and natural history of pulmonary embolism. The sensitivity and specificity of / scanning was quantified, risk factors for the development of pulmonary embolism explored and quantified, and guidelines for the approach to suspected embolism developed (40, 42, 43). Thus, pulmonary embolism has evolved from a clinical condition whose diagnosis was often elusive and convoluted to a condition that can often be prevented or, at the very least, effectively diagnosed and treated in a timely manner using established guidelines and often with noninvasive technologies.

Pulmonary thromboendarterectomy. Although most patients who experience an acute embolism will recover without significant sequelae, a few will develop chronic thromboembolic pulmonary hypertension. This condition was often confused with primary pulmonary hypertensionindeed, it was once thought to be a form of this condition. The lifelong efforts of the late Kenneth M. Moser not only delineated the clinical aspects of this condition but also led to the development of pulmonary thromboendarterectomy as a highly successful treatment approach to this condition (44). Pulmonary thromboendarterectomy is now performed in specialized centers throughout the world, often with dramatic hemodynamic and clinical improvement in patients with severe pulmonary hypertension. Results with pulmonary thromboendarterectomy also first demonstrated the remarkable capacity of the right ventricle to improve its function with restoration of a reduced afterload, even in the setting of right ventricular failure. This observation was fundamental to the development of isolated lung transplantation for end-stage pulmonary vascular disease (45).

Pulmonary Vasculitis

Inflammatory disorders affecting the pulmonary vasculature have long been recognized as unusual but highly lethal conditions that were difficult to diagnose and refractory to treatment. Fauci and colleagues (46) at the National Institutes of Health first described the clinical manifestations of Wegener's granulomatosis based on a large series of patients followed at the clinical center, and demonstrated a significant improvement in survival with combined treatment using cyclophosphamide and prednisone. More recently, cotrimoxazole has been useful in reducing the incidence of relapse after remission is achieved with the above regimen (47). Patients with Goodpasture's syndrome, as well as other inflammatory conditions affecting the small intrapulmonary vessels, resulting in pulmonary hemorrhage, can often be successfully treated with plasmapheresis in combination with immune suppression therapy (48).

The demonstration that many patients with vasculitis have circulating autoantibodies to the cytoplasm of neutrophils and monocytes led to the development of a test for antineutrophil cytoplasmic antibodies (ANCA) for establishing a diagnosis of vasculitis (49). Between 67 and 96% of patients with Wegener's granulomatosis will have the circulating antibodies, usually in a cytoplasmic pattern (c-ANCA), depending on the disease activity, while patients with Churg-Strauss vasculitis often have perinuclear-staining antibodies (p-ANCA). Patients with pulmonary hemorrhage syndromes may have circulating antiglomerular basement antibodies or antinuclear cytoplasmic antibodies. These studies have helped aid not only the diagnosis of these conditions, but also in monitoring the effects of therapy as well (49, 50).

	SUMMARY

TOP INTRODUCTION CONCLUSION REFERENCES

The past 50 years have witnessed considerable progress in our understanding of the mechanisms responsible for controlling pulmonary vasomotor tone and vascular growth, which are now leading to new approaches for the prevention and treatment of disorders of the pulmonary circulation. Technologic and biologic advances are rapidly moving from the bench to the bedside, aiding both in diagnosis and treatment, due to collaborations between basic and clinical investigators. Pulmonary hypertension and pulmonary thromboembolism are two examples of life-threatening conditions whose management has been improved as a result of these advances.

The basic mechanisms responsible for inflammation of the pulmonary vessels remain, however, poorly understood. Perivascular inflammation is an early feature of allograft rejection after lung transplantation (51), a major complication impacting survival. Thus, future basic efforts directed at clarifying the immunologic basis for vascular inflammation will affect the course of increasing numbers of patients in the future.

	Footnotes

Correspondence and requests for reprints should be addressed to John T. Reeves, M.D., Department of Pediatrics, B-131, University of Colorado Medical Center, Denver, CO 80262.

Acknowledgments: Supported in part by a Vascular Disease Academic Award to Dr. Rubin from the National Heart, Lung, and Blood Institute, Bethesda, MD.

	References

TOP INTRODUCTION CONCLUSION REFERENCES

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