Research
From Pahwiki
There is hope for those who suffer from PAH. Many researches and clinicians are investigating new and potentially breakthrough therapies. These therapies are summarized below:
[edit] Endothelial Progenitor Cells
Perhaps some of the more exciting research being performed right now is by Dr. Duncan Stewart in Toronto. His team has shown in laboratory rats that Hypoxia (lack of Oxygen) induced PAH treated with endothelial progenitor cells have demonstrated reversal of the artery damage associated with PAH.
Endothelial Progenitor Cell Overview
[edit] Relevant Papers
- Endothelial progenitor cell therapy for the treatment of coronary disease, acute MI, and pulmonary arterial hypertension: Current perspectives, Michael R Ward, Duncan J Stewart, Michael J B Kutryk
- Transplantation of Endothelial Progenitor Cells into the Lung to Alleviate Pulmonary Hypertension in Dogs Mitsuru Takahashi, Tatsuo Nakamura, Toshinari Toba, Naohiro Kajiwara, Harubumi Kato, Yasuhiko Shimizu. Tissue Engineering. May 1, 2004, 10(5-6): 771-779. doi:10.1089/1076327041348563.
[edit] Rho-kinase inhibitors
[edit] Tyrosine kinase inhibitors
[edit] Vasoactive Intestinal Peptide
[edit] Cicletanine
[edit] Combinational Therapy
[edit] PDGF signaling in pumonary arterial hypertension
The pathobiology of pulmonary arterial hypertension (PAH) includes endothelial cell dysfunction and proliferation and migration of VSMCs. As PDGF has been implicated in these processes, Schermuly et al. hypothesized that altered PDGF signaling may be involved in the vascular remodeling observed in PAH. To explore this notion further, the authors evaluated the effects of the PDGF receptor inhibitor STI571 in 2 different animal models of pulmonary hypertension. In both models, after development of pulmonary vascular disease, administration of STI571 reversed pulmonary vascular changes. These studies provide preclinical proof of concept for the clinical development of a PDGF inhibitor as a targeted therapy for PAH patients.
Barst, R., (2005), PDGF signaling in pulmonary arterial hypertension, The Journal of Clinical Investigation, 2691-2694, Retrieved Jan 29, 2008, from http://www.jci.org/115/10/2691?content_type=full#F2.
[edit] Reversal of experimental pulmonary hypertension by PDGF inhibition
Progression of pulmonary hypertension is associated with increased proliferation and migration of pulmonary vascular smooth muscle cells. PDGF is a potent mitogen and involved in this process. We now report that the PDGF receptor antagonist STI571 (imatinib) reversed advanced pulmonary vascular disease in 2 animal models of pulmonary hypertension. In rats with monocrotaline-induced pulmonary hypertension, therapy with daily administration of STI571 was started 28 days after induction of the disease. A 2-week treatment resulted in 100% survival, compared with only 50% in sham-treated rats. The changes in RV pressure, measured continuously by telemetry, and right heart hypertrophy were reversed to near-normal levels. STI571 prevented phosphorylation of the PDGF receptor and suppressed activation of downstream signaling pathways. Similar results were obtained in chronically hypoxic mice, which were treated with STI571 after full establishment of pulmonary hypertension. Moreover, expression of the PDGF receptor was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients compared with healthy donor lung tissue. We conclude that STI571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus. This regimen offers a unique novel approach for antiremodeling therapy in progressed pulmonary hypertension.
Schermuly, R. (2005), Reversal of Experimental Pumonary Hypertension By PDGF Inhibition, The Journal of Clinical Investigation, 2811-2821, Retrieved Jan 31, 2008, from http://www.jci.org/115/10/2811?content_type=abstract.
[edit] Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the rapamcyin-atorvastatin-simvastatin study
Pulmonary arterial hypertension (PAH) is characterized by excessive pulmonary artery smooth muscle cell proliferation and impaired apoptosis leading to obstruction of resistance pulmonary arteries. We hypothesized that antiproliferative (rapamycin) and proapoptotic (statins) agents, already used clinically for other indications, would decrease experimental PAH, facilitating translation to human therapies. Prior studies in the rat monocrotaline-PAH model have indicated that simvastatin regresses and rapamycin prevents, but cannot reverse, PAH. Two PAH regression strategies (rapamycin monotherapy vs. rapamycin + atorvastatin) and one prevention strategy (simvastatin) were tested in a rat monocrotaline-PAH model. Adult male Sprague-Dawley rats were randomized to saline (n = 6) or monocrotaline (60 mg/kg ip, n = 36) treatment groups. Monocrotaline rats were randomized to gavage with vehicle, rapamycin (2.5 mg·kg–1·day–1), or rapamycin + atorvastatin (10 mg·kg–1·day–1) treatment groups, beginning 12 days post-monocrotaline. Echocardiographic and hemodynamic end points were assessed 2 wk later. Additional monocrotaline-PAH rats (n = 20) were randomized to vehicle or simvastatin (2 mg·kg–1·day–1) treatment groups and followed echocardiographically for 4 wk. Monocrotaline-PAH increased lung p70 S6 kinase phosphorylation, and this was reversed by rapamycin, confirming the biological activity of rapamycin. Despite the use of high doses, neither rapamcyin nor rapamycin + atorvastatin improved survival nor reduced PAH, vascular remodeling, and right ventricular hypertrophy. Although prophylactic simvastatin slowed PAH progression, by 4 wk PAH severity and mortality were not different from placebo. Apart from the new finding of p70 S6 kinase phosphorylation in monocrotaline-PAH, this is a negative therapeutic trial (none of these promising therapies improved monocrotaline-PAH). These negative results should be considered as human trials with these agents are underway (simvastatin) or proposed (rapamycin).
McMurtry, M. Sean, Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the rapamcyin-atorvastatin-simvastatin study, AJP - Lung Cellular and Moecuar Physiology, L933-L940, Retrieved Feb 1, 2008, http://ajplung.physiology.org/cgi/content/abstract/293/4/L933.
[edit] Therapy of Pulmonary Hypertension The Evolution from Vasodilators to Antiproliferative Agents
Rubin,L., Therapy of Pulmonary Hypertension The Evolution from Vasodilators to Antiproliferative Agents, American Journal of Respiratory and Critica Care Medicine, Vol 166, pp. 1308-1309, Retrieved Feb 5, 2008, http://ajrccm.atsjournals.org/cgi/content/full/166/10/1308.
