© 2004 American Thoracic Society
Advancing Therapy for Pulmonary Arterial HypertensionCan Animal Models Help?Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville, Tennessee Pulmonary arterial hypertension (PAH) is a disorder predominantly affecting the small pulmonary arteries. It can occur without an identifiable cause, primary pulmonary hypertension, or in association with other disorders such as connective tissue diseases or congenital heart defects. Characteristic pathological changes include medial hypertrophy, intimal proliferation, in situ thrombosis, and plexiform lesions (1). A number of animal models have been used to study pulmonary hypertension, most commonly employing hypoxia or monocrotaline. Monocrotaline is a toxin that causes endothelial injury leading to medial hypertrophy in the pulmonary arterioles. More recently, pneumonectomized rats injected with monocrotaline have exhibited neointimal overgrowth in addition to medial hypertrophy (2). No animal model, however, reproduces the full spectrum of changes seen in lung specimens from patients. Despite the lack of a robust model to guide therapy, treatment of PAH has markedly improved over the last decade in large part because of the discovery that infusion of epoprostenol, the synthetic salt of prostacyclin, improves function and prolongs survival in patients with this disorder (3, 4). Although the full mechanism of action of epoprostenol is uncertain, it increases intracellular levels of cyclic adenosine monophosphate (cAMP), resulting in vasodilation and inhibition of platelet aggregation. Sildenafil, a highly specific phosphodiesterase 5 inhibitor, has recently been used to treat patients with PAH. Phosphodiesterase 5 is abundant in the lung and inactivates another vasodilator, cyclic guanosine monophosphate (cGMP). Inhibition of phosphodiesterase 5 increases levels of cGMP, which in turn, can also inhibit phosphodiesterases that are specific for cAMP, allowing accumulation of both cyclic nucleotides with the potential for synergistic benefit (5). In this issue of the Journal (pp. 34–38), Itoh and coworkers (6) have employed a monocrotaline model of pulmonary hypertension in rats to compare the effects of treatment with sildenafil, beraprost (an oral prostacyclin analog), and both drugs in combination. Animals were randomized to one of the three treatments at the time they were injected with monocrotaline, and continued to receive treatment for three weeks. Compared with a control group, all three treatments caused significant inhibition of pulmonary artery medial hypertrophy. The effect of combination therapy, however, was significantly greater than with either sildenafil or beraprost alone. Additionally, the increase in right-ventricular systolic pressure was significantly less with combination therapy. In concert with these effects, plasma levels of cAMP and cGMP increased substantially more, and remained elevated for a longer period of time, in animals treated with the combination of sildenafil and beraprost. Although therapy for PAH has improved with the use of epoprostenol, only two-thirds of patients with PAH are alive three years after starting therapy (3, 4). The study by Itoh and associates (6) provides further impetus for the use of combination therapy to treat PAH. In 14 patients with deterioration of their condition despite treatment with iloprost (an inhaled prostacyclin analog), the addition of sildenafil produced a sustained improvement in exercise capacity and hemodynamics (7). A larger study comparing epoprostenol to epoprostenol plus sildenafil is currently underway and should provide a more definitive answer about synergist effects between prostanoids and sildenafil. A recent study comparing epoprostenol alone with epoprostenol plus bosentan, an endothelin receptor antagonist, in patients with PAH showed only a trend toward greater improvement with combination therapy, which may reflect the small number of patients in the study (8). Although combination therapy may improve treatment, it seems likely that the benefit of vasodilator therapy alone will be limited, and indeed, the focus of treatment is shifting to the proliferative aspect of PAH. The growth-promoting properties of mediators, such as serotonin, and growth factors, such as transforming growth factor ß, have been implicated in the pathogenesis of PAH (9, 10). Germline mutations of bone morphogenic protein receptor 2, involved in the signaling pathway for transforming growth factor ß, have been identified in most patients with familial PAH (11, 12) and in a minority of patients with apparently sporadic primary pulmonary hypertension (13). How these mutations affect cell growth, vascular fibrosis, and apoptosis, leading to the end-stage pathological changes seen in patients, is still not known. Transgenic mice with a mutation in bone morphogenic protein receptor 2 are currently being developed and may provide insight into human disease. With regard to the future, animal models may provide guidance. Eddahibi and colleagues initially demonstrated the importance of the serotonin transporter in the development of pulmonary vascular changes after exposure to hypoxia in mice (14). Subsequently, allelic variants predisposing to serotonin transporter over-expression have been linked to pulmonary artery smooth muscle hyperplasia in patients with primary pulmonary hypertension and suggest the possibility of treatment with selective serotonin reuptake inhibitors (9). In an intriguing study published this year, eight patients with PAH were treated with vasoactive intestinal peptide based on beneficial findings in animal models of pulmonary hypertension (15). While the clinical improvement was impressive, there was no control group and the findings need to be confirmed in a larger cohort. Nearly complete regression of monocrotaline-induced changes in rats has been demonstrated with HMG-Co-A reductase inhibitors, suggesting another potential treatment for patients (2). In another model, overexpression of prostacyclin synthase in mice exposed to hypoxia prevented the development of medial hypertrophy (16). While not yet ready for human trials, aerosol administration of prostacyclin synthase or nitric oxide synthase genes to increase endogenous mediator production at the site of disease, should be considered in the future. In the study by Itoh and colleagues, therapy was initiated before the development of pulmonary hypertension, making it difficult to extrapolate their findings to patients with advanced disease (6). Their results, however, provide support for an early intervention study in patients diagnosed with mild PAH, as well as a preventative study in obligate carriers from families with a known mutation in bone morphogenic protein receptor 2. The molecular and genetic tools are at hand to improve the treatment of PAH. Animal models, even with their limitations, can be used to evaluate a variety of combination therapies and more novel treatments, perhaps sparing patients unnecessary or harmful therapy. FOOTNOTES Conflict of Interest Statement: I.M.R. serves on an advisory board for Actelion Pharmaceuticals, and has received financial reimbursement for speaking at conferences and meetings sponsored by Actelion Pharmaceuticals. REFERENCES
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