Pulmonary Arterial Hypertension

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A major disorder involving the pulmonary microvasculature and eicosanoids is pulmonary arterial hypertension (PAH). PAH primarily affects the small pulmonary arteries with a diameter of less than 100 microns. Pathological changes include medial hypertrophy, intimal proliferation, in situ thrombosis, and plexiform lesions, the latter likely a disordered attempt at neovascularization. PAH may occur without an associated disorder, primary pulmonary hypertension (PPH), or in association with connective tissue disease, congenital heart disease, portal hypertension, HIV infection, or use of appetite suppressants. Disruption of the endothelial lining of the microvasculature in PAH is associated with changes in the local milieu of protein and lipid mediators. Whether these changes are causative or secondary to the pathological changes is uncertain. It is noteworthy that similar pathological changes have been found in the microvasculature of patients undergoing thromboen-darterectomy for treatment of large-vessel thromboembolic pulmonary hypertension, suggesting that small-vessel vas-culopathy can result from multiple processes.

More specifically, alterations in the production of eicosanoid mediators have been demonstrated in animal models of pulmonary hypertension and in PAH. Although several eicosanoid products can affect the pulmonary microvasculature, PGI2 and TxA2 appear to play the largest role in vascular homeostasis. Both compounds are rapidly metabolized within seconds to minutes, and therefore, circulating levels of both prostacyclin and TxA2 are extremely low (< 4pg/mL). This implies that these eicosanoids are primarily synthesized locally in the pulmonary vasculature, and perturbations in the local environment are associated with changes in mediator production.

In an animal model of pulmonary hypertension using calves exposed to hypoxia at high altitude, investigators found decreased synthesis of PGI2 compared to control animals. More recently, studies using in situ hybridization and Western blots have demonstrated a decrease in prostacyclin synthase in both large and small pulmonary arteries from patients with PAH. Additional studies in mouse models support a pivotal role for prostacyclin in the development of pulmonary hypertension. In a prostacyclin receptor knockout model, mice exposed to hypoxia developed more severe pulmonary hypertension and vascular remodeling compared to control animals. Conversely, when exposed to hypobaric hypoxia, transgenic mice with overexpression of prostacy-clin synthase produced more prostacyclin and histologically exhibited nearly minimal medial hypertrophy in precapillary arteriole vessels compared to significant changes in control animals.

In patients with pulmonary vascular disease, with PPH or related to connective tissue disease, we found increased urinary metabolites of TxA2 when corresponding metabolites of prostacyclin were decreased, so the overall ratio of TxA2/PGI2 was significantly increased compared to control subjects [8]. These findings have subsequently been confirmed in patients with PAH related to congenital heart disease. Although TxA2 is usually synthesized by platelets (and to a lesser extent by other circulating cells), vascular synthesis of TxA2 has been demonstrated, at least in systemic arteries. This abnormal production of TxA2 may be even more marked in PAH where an abnormal vascular lining promotes platelet binding and activation. Combined, these studies, in humans and in animal models, suggest that the pathogenesis and/or maintenance of pulmonary hypertensive vascular disease may involve alterations in the production of PGI2 and TxA2.

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