Severe Angioproliferative Pulmonary Hypertension: The Lung Circulation Between Vasoconstriction and Cancer

Which Vascular Lesions? Which Cells?

Controversies still exist regarding the importance of the complex vascular lesions, which include the so-called plexiform (or glomeruloid) lesions, concentric intima fibrosis (or onion skin lesions in scleroderma), and angiomatoid lesions.11 Are these lesions hemodynamically important or just markers of severe PH? Some patients seem to have more of these lesions than others, yet the “pruning” of the pulmonary arteriolar tree, which can be documented radiographically and is seen in all patients with severe PH, can be explained as a drop out or loss of pre-capillary resistance vessels by an unknown mechanism or by angiogenic lumen obliteration. In the peripheral subpleural regions of the lungs the vascular pruning is most evident and complex, and lumen-obliterating lesions are likely detected here.

Muscularization of the arterioles alone is (in the opinion of these authors) not sufficient to explain severe and progressive PH. In the aggregate, a number of recent studies point to an angioproliferative process with a preference for particular sites of the vascular tree, namely bifurcations of precapillary arterioles, which makes severe PH a group of diseases characterized by structural alterations of microscopically small vessels. These alterations do not span a great length of an individual vessel; instead, three-dimensional reconstruction analysis shows there is a patent lumen proximal and distal to a “plug.”12 Careful examination of many serial sections of many subpleural lung tissue samples would likely result in the detection of many regionally obliterated vessels and lead to the conclusion that the occlusion or partial blockage of literally millions of these peripheral microvessels can explain why the pulmonary artery pressure is so high (usually 50 mm Hg), and why at the time of the first hemodynamic study only 20% to 25% of patients with severe PH display a significant acute vasodilator response.

Many of our earlier pathogenetic concepts were based on physiologic parameters, pressure, flow, and vasoconstriction causing an increase in precapillary vascular resistance. Understandably our thought models were those of 19th and 20th century physiology, and the still fascinating acute hypoxia-induced pulmonary vasoconstriction13 or chronic hypoxic pulmonary hypertension1415 animal experiments provided tools to study pulmonary vascular tone regulation and pulmonary vascular remodeling.16 Yet these models infringe on the human condition of severe angioproliferative PH (SAPH) only peripherally, and it is interesting that the development of the first endothelin receptor blocker for clinical use in “primary” PH was based to a large degree on the positive results of preclinical studies in hypoxia and monocrotaline rat models.1718 The assumption clearly was that these rodent models bore enough resemblance to human SAPH, and further, that endothelin was not only “bad” but also a central and very critical actor in a drama played out by a large score of characters. Because human SAPH occurs only in individuals with a still ill-defined genetic predisposition (or susceptibility) and because the pulmonary vascular biology and pathobiology are most certainly very complex, these assumptions are likely wrong or at least too simple.

New Concept of Severe Angioproliferative Pulmonary Hypertension

Histologically all the layers of the pulmonary arterioles—intima, media, and adventitia—and a great number of cell types (including lymphocytes, myofibroblasts, macrophages, mast cells, and bombesin-positive cells) are involved and present in SAPH. The vascular lesions in SAPH are truly complex and it is now clear that they contain not only normal but also very abnormal, phenotypically altered cells. Why is this important? We suggest that it is the nature of these phenotypically altered, apoptosis-resistant cells2619 that sets human SAPH apart from most of the rodent models and makes human angioproliferative PH so difficult to treat.

View Figure

• Download as Powerpoint
• Download Figure

A growing number of reports have provided evidence for clonal cell growth and somatic endothelial cell mutations as well as for loss of tumor suppressor genes and expression of proteins usually not found in endothelial cells, like 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP).19–21 Most likely a number of different trigger factors can induce programmed cell death/apoptosis of vascular endothelial cells. We hypothesize that “exuberant endothelial cell proliferation”2 may involve the participation of usually quiescent stem or precursor cells and/or perhaps bone marrow-derived hemeangioblasts. Circulating endothelial cells occur in greater numbers in severe PH;22 whether these cells have been sheared off in the lung circulation or originate from other sites is unclear. Regardless, in theory, precursor cells or phenotypically altered endothelial cells could—perhaps through shunts—gain access to the systemic circulation and also recirculate into the lung.

Peripheral Blood Cell Analysis in Diagnosis of Severe Pulmonary Hypertension

Patients with severe PH have elevated plasma levels of norepinephrine, vascular endothelial growth factor (VEGF), IL-1, IL-6, and endothelin;23–25 elevated levels of serotonin have also been described.26 This altered cytokine and growth factor milieu of the peripheral blood cells is bound to affect the gene expression pattern and behavior of these cells.

Bull et al27 recently acted on this concept and performed microarray gene expression analysis of peripheral blood monocytes (PBMC) in patients with severe PH and found that the patients' PBMC gene expression was clearly different from that of normal PBMCs. In addition, they identified a small number of genes that were differently expressed when patients with so-called primary PH and patients with secondary forms of severe PH were compared. It is likely that analysis of PBMCs will allow subgroup identification and possibly prediction of treatment response. We have entered only the first phase of this exploration.

Severe Angioproliferative Pulmonary Hypertension and Viral Infection

The first recognized association of viral infection and severe PH, a disease histologically indistinguishable from so-called primary PH, was the association with human immunodeficiency virus (HIV) infection.28 This association and the recently recognized second association with human herpes virus 8 (HHV-8, or Kaposi's sarcoma virus) infection,29 raise many new questions. These questions when answered will lead to a more complete understanding of the pathobiology of SAPH.

The first question is whether there is only an association with certain viral infections—based on an altered immune system—or whether the virus causes severe PH because of death of some endothelial cells and “transformation” of surviving cells as in Kaposi's sarcoma. Next, are there other viruses that need to be discovered? What is the mode of infection in HHV-8-associated severe PH? Does severe PH also occur in virally infected primates? Is the occurrence of severe PH in splenectomized patients30 also associated with viral infections, etc?

Infection, Inflammation, Phenotypically Altered Pulmonary Vascular Cells, and Vasodilator Therapy

As we31 and hopefully others, perhaps with a measure of reluctance, accept this new pulmonary vascular pathobiology, our patients expect and deserve new treatment strategies. These will likely not result in “complete molecular repair” of all of the lung lesions or a molecular remission, but in a partial desobliteration of precapillary arterioles because of removal of lumen obliterating cells (perhaps by induction of apoptosis in apoptosis-resistant cells). There is enough collective experience to say that the drugs currently in use—all vasodilators—do not reopen occluded vessels.32 It is not clear whether antiangioproliferative agents will be able to do the job. They may prevent further progression because of inhibition of further angioproliferation, but they may not remove already established lesions.

A rodent model of severe PH (mean pulmonary artery pressure >50 mm Hg) due to lumen obliteration of precapillary arterioles has been established.33 Inhibition of apoptosis with a broad-spectrum caspase inhibitor prevents the development of severe PH in these animals, but reversal of established SVP in this model is as difficult as in the human SAPH group.34 Patients with SAPH have millions of obliterating lesions and may not benefit from antiviral drugs. Instead, proteins expressed only in abnormal apoptosis-resistant vascular cells, not in normal endothelial and smooth muscle cells, are drug targets and cell-specific homing strategies can be developed.

Outlook

The continuous infusion of prostacyclin was the first real breakthrough in the treatment of severe PH,32;35;36 and this treatment has improved the survival of many patients afflicted with this rare and deadly disease. To accept that angioproliferative obliteration in severe PH is both pathobiologically and hemodynamically important is the first step. We hope that many investigators will be able to take this step. The next step is to take the fact seriously that the lumen-obliterating cells in SAPH are abnormal cells and actually cancerlike.1929 Primary PH was once called “the cardiologists' cancer” (Greg Eliot). The removal of these quasimalignant cells from established vascular lesions is our new treatment goal.34 If successful, such treatment would shorten the transplantation list.