Hypertensive Pulmonary Vascular Disease
Dawn of the Age of Prevention?

John H. Newman and Kirk B. Lane

Center for Lung Research, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee

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In this month's issue of AJRCCM (pp. 2252-2259), Faul and colleagues present data that a compound extracted from a traditional Chinese herb (Tripterygium wilfordii Hook. f.) attenuates neointimal reaction and pulmonary hypertension in rats that underwent pneumonectomy and were given monocrotaline to cause lung vascular injury (1). The compound, triplotide, has antiproliferative effects perhaps related to inhibition of NF-B activation and enhanced apoptosis. Models of hypertensive pulmonary vascular disease (HPVD) resulting in changes similar to those in the small pulmonary arteries seen in primary pulmonary hypertension have been difficult to develop, and monocrotaline is a well-known but poorly understood stimulus involving injury and repair of the resistance vessels. Pneumonectomy in the study by Faul and coworkers presumably enhanced the response by causing a doubling of flow and an increase in pressure in the remaining lung. The authors conclude that it is time to think of therapies for HPVD that are based on the pathogenic abnormalities that result in neointimal formation, and we, along with many others in the field, agree.

Major advances in the management of patients with HPVD have occurred in the last two decades (2). The first breakthrough was the observation that chronic vasodilator therapy could cause prolonged clinical remission in the 25% of patients with persistent pulmonary hypertension (PPH) who have a reversible vasoconstrictor component to the disease. The mid-1980s brought the landmark discovery that intravenous prostacyclin markedly improves functional status and survival in a high percentage of patients with PPH regardless of vasodilator effect. The mechanism of the beneficial effect of prostacyclin independent of vasodilation is not known, but speculation is that an antiproliferative, antiplatelet, or remodeling effect is responsible. A new wave of clinical trials is underway in a search for alternative methods of delivery of prostacyclin, including oral, inhaled, and subcutaneous. Inhaled nitric oxide and oral endothelin antagonists are under study as well. How these therapies may affect neointimal formation remains to be determined.

The second major area of progress has involved insights into the pathogenesis of HPVD. The era of subsetting PPH by pathological type was effectively brought to an end by the finding that all variations of vascular pathology could be found in the lungs of patients with familial PPH, and that other forms of HPVD including scleroderma, cirrhosis, and that associated with human immunodeficiency virus (HIV) shared these pathological subsets. Beginning in the 1990s a number of investigators have found that abnormalities of multiple endogenous mediators can be found in PPH and other forms of HPVD (2). These mediator abnormalities include excessively high levels of circulating thromboxanes, endothelin, and coagulation products, and low levels of NO and prostacyclin. What has remained unclear is whether these abnormalities represent responses of the vascular wall to injury, or whether one or more of these observed abnormalities promotes primary pathogenesis. All potentially are involved in the proliferative lesions of HPVD.

While these clinical observations have been accumulating, studies of the biology of the vascular wall have yielded insights into the abnormalities seen in HPVD. Surprisingly, the endothelium of the plexiform lesion becomes monoclonal in PPH (3). What this means mechanistically is tantalizingly unclear. Endothelial dysfunction with reduced prostacyclin synthase and transforming growth factor  (TGF-) receptor mRNA has been found. Clearly a variety of proliferative and fibroblastic genes must be active in HPVD, because the pathological condition of the vessels displays this phenotype. The initiating stimulus (or stimuli) for disease activation is unknown and the sequence of the cascade leading to the vasculopathy is unknown. When the mystery of this process is unraveled, attempts to intercede with drugs that inhibit neointimal proliferation will be easier to apply.

The gene that causes familial primary pulmonary hypertension has been discovered to be bone morphogenetic protein receptor 2 (BMPR2) (4, 5). This gene is part of the TGF- receptor superfamily. It was tested because of its potential as a vascular growth receptor and thus was considered an excellent positional candidate. Of further interest, we have found that at least 25% percent of patients tested with "sporadic" PPH also possess a mutation in BMPR2 (6). We do not yet know whether patients with HPVD from other associations such as liver disease, HIV, anorexigens, or scleroderma will have similar mutations, but the finding that this gene is a common feature in PPH should propel investigations into pathogenesis to the next phase. Mutations in BMPR2 have been found in intra- and extracellular domains and we suspect may all result in altered and reduced signal transduction. Work is underway to define the functional abnormalities of BMPR2 in transfected cells and transgenic species. It seems likely that a second hit, either as an environmental event or activation of a second gene, may be necessary for abnormalities in BMPR2 to initiate HPVD. Studies of BMPR2 in monocrotaline-treated rats, in other models of HPVD, and in affected vessels of patients with PPH should yield insights into the pathologic changes and pave the way for treatment and, more powerfully, preventive therapies. This is an exciting time to be involved in the problem of pulmonary vascular disease.

	References

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1. Faul JL, Nishimura T, Berry GJ, Benson GV, Pearl RG, Kao PN. Triptolide attenuates pulmonary arterial hypertension and neointimal formation in rats. Am J Respir Crit Care Med 2000; 162: 2252-2259 [Abstract/Free Full Text].

2. Rich S, editor. Primary pulmonary hypertension: executive summary from the world symposium. Geneva, Switzerland: World Health Organization; 1998. Available via the Internet (http://www.who.int/ncd/cvd/pph.html).

3. Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998; 101: 927-934 [Medline].

4. The International PPH Consortium, Lane KB, Machado VC, Pauciulo MW, Thomson JR, Phillips JA III, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 2000;26:81-84.

5. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Ficsher SG, Barst RJ, Hodge SE, Knowles JA. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000; 67: 737-744 [Medline].

6. Thomson JR, Machado RD, Pauciulo MW, Yang X, Morgan NV, Elliott G, Humbert M, Loyd JE, Yacoub M, Morrell N, Trembath RC, Nichols WC. J Hum Genet (In press)