Clinical Modulation of Eicosanoids in Pulmonary Vascular Disease

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Attempts to treat PAH with pharmacological doses of epoprostenol (the synthetic salt of prostacyclin), 100 to 1,000 times that normally made endogenously, began in the early 1980s based on epoprostenol's vasodilatory properties. Because of the short half-life in vivo, epoprostenol must be continuously infused via a central venous catheter; acute clinical deterioration has been reported with acute interruption of the drug. Nevertheless, use of epoprostenol has been approved for the long-term treatment of PAH based on improvement in pulmonary hemodynamics, quality of life, and survival documented in a randomized, clinical trial [9]. Currently, epoprostenol is used to treat all forms of intrinsic PAH as well as other disorders that can affect the pulmonary microvasculature, such as distal chronic thromboembolic disease that is not amenable to operative treatment or sar-coidosis with diffuse vascular involvement.

Intravenous epoprostenol has dramatically improved the outcome of patients with PAH, most impressively in patients with PPH. Results in patients with the scleroderma spectrum of disease are not as impressive, perhaps because they have a systemic disease and are generally older than patients with PPH. Compared to historical controls or to survival predicted by the NIH PPH Registry survival equation, survival with epoprostenol is significantly improved [10]. However, not all patients respond to therapy, and one third of patients with PPH still die within three years of starting treatment. This may be explained by the fact that although most patients improve clinically, hemodynamics remain markedly abnormal. After one year of therapy, mean pulmonary artery pressure only decreases 10 to 15mmHg, and pulmonary vascular resistance remains five to six times normal. Rarely do patients demonstrate normalization of pulmonary hemodynamics. This indicates that while most patients improve clinically, the fundamental pathological remodeling process in the precapillary pulmonary vessels is not significantly affected.

Since the approval of epoprostenol, other prostacyclin analogues have been evaluated in the treatment of PAH. Beraprost, an oral analogue of prostacyclin, was originally used in uncontrolled studies in Japan that purported to show efficacy in PPH. More recently, two randomized, placebo-controlled studies have been performed. One was a three-month study that demonstrated improvement in six-minute walk distance. The other was a 12-month study that initially showed similar clinical improvement at 3 and 6 months. However, by 9 months of treatment, no clinical benefit was apparent, indicating that long-term benefit can not be maintained with the oral preparation. Iloprost is another longer-acting prostacyclin analogue, given intravenously and by inhalation, the latter of which requires 6 to 10 treatments per day. A recent multicenter, placebo-controlled three-month trial involving patients with PAH and inoperable chronic thromboembolic disease demonstrated improvement in a combined endpoint with inhaled iloprost. Although the treatment was effective in some patients, the frequency of the treatments makes this therapy difficult to use. Finally, treprostinil, a subcutaneously delivered analogue, has been studied in the largest randomized, placebo-controlled study in PAH. Modest improvement was found in six-minute walk distance with treprostinil. Local pain at the infusion site, related to binding of the prostacyclin analogue to pain receptors, limited the dose escalation in most patients in the study and has been an impediment to widespread use of treprostinil; however, those able to increase to greater doses experienced greater clinical improvement.

The mechanism of action of prostacyclin and its analogues remains uncertain. As noted previously, most patients continue to exhibit significant pulmonary hypertension despite treatment, indicating that vasodilation is unlikely to play a major role. Much of the benefit from epoprostenol may result from inotropic effects leading to improved right ventricular contractility. Increases in c-AMP, while important during acute use of epoprostenol, are unlikely to be sustained during long-term use. In cell culture studies of both proximal and distal pulmonary artery, smooth muscle growth was inhibited by a variety of prostacyclin analogues, which correlated with increases in c-AMP. However, levels peaked by 30 minutes and declined by 4 hours. We have measured c-AMP levels in plasma in patients receiving therapy with epoprostenol and found no increase compared to baseline values.

Provision of pharmacologic doses of prostacyclin has effects on other mediator systems. Investigators have shown that chronic infusion of epoprostenol decreases circulating levels of endothelin-1, which may account for some of the beneficial action of prostaglandins. Others have shown improvement in platelet aggregation and markers of endothe-lial injury, such as circulating levels of von Willebrand factor with long-term epoprostenol treatment. Interestingly, in preliminary studies, despite epoprostenol's potent effects on platelet aggregation, the drug does not appear to decrease excretion of thromboxane metabolites in patients with PPH. This suggests that much of the increase in thromboxane generation in patients with PPH may derive from cells other than platelets. More recently, epoprostenol has been reported to decrease markers of oxidative damage in lung tissue samples from patients with PPH.

Use of thromboxane receptor antagonists or synthase inhibitors have been unsuccessful, perhaps because TxA2 is not a pivotal mediator in the maintenance of the microvas-cular remodeling in PAH. Inhibition of thromboxane syn-thase with an oral agent was initially studied in the late 1980s and showed very modest improvement in resting hemodynamics. More recently, use of a combined thromboxane synthase inhibitor/receptor antagonist, terbogrel, was evaluated in a randomized, placebo-controlled study. Unfortunately, the study was stopped prematurely because of an unexpected adverse event, severe leg pain, that developed in approximately 25 percent of patients. In addition, there was no clinical or hemodynamic improvement in patients who completed the study, although TxA2 metabolite levels in serum (reflecting platelet capacity) and in urine (reflecting total body thromboxane production) decreased significantly with drug treatment. Furthermore, urinary prostacyclin metabolites increased, supporting the concept of endoperoxide shunt from platelet to endothelium at the vascular interface. Inhibition of PGD2 or modulation of leukotriene synthesis (or receptor blockade) or treatment with antioxidants (e.g., vitamins C and E) has not been studied in PAH.

A combination of empiric clinical trials of modulation of prostaglandin balance, translational research in patients with pulmonary vascular disease, and ongoing basic investigations of endothelial and smooth muscle biology have yielded clinically useful results over the last decade. Epoprostenol, and perhaps stable analogues of prostacyclin, have a beneficial effect in patients with PAH, particularly those with PPH. However, despite improvement in both quality of life and survival with pharmacological doses of prostacyclin, it is clear that the fundamental abnormalities of growth and disordered angiogenesis are not substantially altered by this therapy. Future studies spanning the spectrum from basic to clinic research are needed to determine more precisely the role of eicosanoids in pulmonary vascular disease.

Glossary

Cyclo-oxygenase: An enzyme protein complex present in most tissues that catalyses two steps in prostaglandin biosynthesis and produces prostaglandins and thromboxanes from arachidonic acid.

Eicosanoid: A class of oxygenated, endogenous, unsaturated 20-carbon fatty acids derived from arachidonic acid after it is cleaved from membrane phospholipids. They include prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acid (HETE) compounds. They exert their actions by binding to specific cellular receptors.

Epoprostenol: A prostaglandin that is biosynthesized enzymatically from prostaglandin endoperoxides generated by the action of cyclo-oxygenase in human vascular tissue. It is a vasodilator and a potent inhibitor of platelet aggregation. The sodium salt has also been used as a pharmaceutical (Flolan), to treat primary pulmonary hypertension.

Pulmonary arterial hypertension: A disorder primarily affecting the small precapillary pulmonary arteries and occurring either as an idiopathic illness [primary pulmonary hypertension (PPH)], or in association with other disorders including congenital heart disease, connective tissue diseases (especially scleroderma), liver disease, human immunodeficiency virus infections, and use of appetite suppressants. Characteristic pathologi-cial changes include smooth muscle medial hypertrophy, intimal proliferation, in situ thrombosis, and the development of plexiform lesions.

References

1. Claesson, H. E., and Haeggstrom, J. (1987). Metabolism of leukotriene A4 by human endothelial cells: Evidence for leukotriene C4 and D4 formation by leukocyte-endothelial cell interaction. In Samuelsson, B., Paoletti, R., and Ramwell, P. W. (eds.), Advances in Prostaglandin, Thromboxane, and Leukotriene Research. New York: Raven Press; 17: 115-119. One of the earliest articles documenting transcellular biosynthesis ofeicosanoids during cellular apposition. This paper documents donation of leukotriene A4, formed in neutrophils, to endothe-lial cells with subsequent metabolism to cysteinyl leukotrienes.

2. Nomura, T., Lu, R., Pucci, M. L., and Schuster, V. L. (2004). The two-step model of prostaglandin signal termination: In vitro reconstitution with the prostaglandin transporter and prostaglandin 15 dehydroge-nase. Mol. Pharmacol. 65, 973-978.

3. Imig, J. D., Breyer, M. D., and Breyer, R. M. (2002). Contribution of prostaglandin EP(2) receptors to renal microvascular reactivity in mice. Am. J. Renal Physiol. 283, F415-F422.

4. Smyth, E. M., and Fitzgerald, G. A. (2002). Human prostacyclin receptor. Vit. Horm. 65, 149-165.

5. Cheng, Y., Austin, S. C., Rocca, B., Koller, B. H., Coffman, T. M., Grosser, T., Lawson, J. A., and Fitzgerald, G. A. (2002). Role of prostacyclin in the cardiovascular response to thromboxane A2. Sci ence 296, 539-541. Important study used transgenic murine models of acute lung injury to examine the relative importance of activation of prostacyclin (IP) and thromboxane (TP) receptors during inflammation. Animals lacking the IP receptor had more injury-induced platelet activation and vascular proliferation. Both were decreased in animals genetically deficient in the TP receptor or pretreated with a TP receptor antagonist.

6. Wright, L., Tuder, R. M., Wang, J., Cool, C. D., Lepley, R. A., and Voelkel, N. F. (1998). 5-lipoxygenase and 5-lipoxygenase activating protein (FLAP) immunoreactivity in lungs from patients with primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 157, 219-229.

7. Robbins, I. M., Newman, J. H., and Brigham, K. L. (1998). Sepsis induced pulmonary edema: Cellular and physiological mechanisms. In Matthay, M. A., and Ingbar, D. H. (eds.), Pulmonary Edema, 116: 203-245 in Lung Biology in Health and Disease series. New York: Marcel Dekker.

8. Christman, B. W., McPherson, C. D., Newman, J. H., King, G. A., Bernard, G. R., Broves, B. M., and Loyd, J. E. (1992). An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N. Engl. J. Med. 327, 70-75.

9. Barst, R. J., Rubin, L. J., Long, W. A., McGoon, M. D., Rich, S., Badesch, D. B., Groves, B. M., et al. for the Primary Pulmonary Hypertension Study Group. (1996). A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N. Engl. J. Med. 334, 296-301. This was the pivotal randomized clinical trial that established the efficacy of intravenous epoprostenol in PPH. Patient received either conventional therapy (oxygen, diuretics, inotropes, etc.) or conventional therapy plus continuous infusion of epoprostenol via an indwelling catheter. Both exercise tolerance and short-term mortality were significantly improved in the group receiving prostaglandin therapy. 10. Galie, N., Manes, A., and Branzi, A. (2003). Prostanoids for pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2, 123-137.

Capsule Biographies

Dr. Robbins has directed the Adult Pulmonary Hypertension Center at Vanderbilt University since 2001. His research has focused on the mechanism of action of epoprostenol in the treatment of pulmonary hypertension, and he has been the lead investigator at Vanderbilt in numerous clinical trials evaluating new medications for the treatment of pulmonary hypertension. His work is supported by grants from the NIH.

Dr. Christman trained in internal medicine and pulmonary/critical care medicine at Vanderbilt University, where he is currently Vice-Chair of Medicine at Vanderbilt University and Chief of the Medical Service for the VA Tennessee Valley Health System. His laboratory uses both basic and clinic research approaches to decipher contribution of the urea/nitric oxide cycle and eicosanoid pathways in modulating both liver/lung injury after endotoxemia and pulmonary hypertension. His work is supported by an NIH Program Project Grant from the NIH National Heart Lung and Blood Institute and by a grant from the NIH National Cancer Institute.

Section B

Vascular Development: Vasculogenesis and Angiogenesis

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