No abstract

Extracts of Tripterygium wilfordii hook. f. (leigong teng, Thundergod vine) are effective in traditional Chinese medicine for treatment of immune inflammatory diseases including rheumatoid arthritis, systemic lupus erythematosus, nephritis and asthma. Characterisation of the terpenoids present in extracts of Tripterygium identified triptolide, a diterpenoid triepoxide, as responsible for most of the immunosuppressive, anti-inflammatory and antiproliferative effects observed in vitro. Triptolide inhibits lymphocyte activation and T-cell expression of interleukin-2 at the level of transcription. In all cell types examined, triptolide inhibits nuclear factor-kappaB transcriptional activation at a unique step in the nucleus after binding to DNA. Further characterisation of the molecular mechanisms of triptolide action will serve to elucidate pathways of immune system regulation.

Background-Pulmonary vascular injury by toxins can induce neointimal formation, pulmonary arterial hypertension (PAH), right ventricular failure, and death. We showed previously that simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized rats injected with the alkaloid toxin monocrotaline. The present study was undertaken to investigate the efficacy of simvastatin and its mechanism of reversing established neointimal vascular occlusion and pulmonary hypertension. Methods and Results-Pneumonectomized rats injected with monocrotaline at 4 weeks demonstrated severe PAH at 11 weeks (mean pulmonary artery pressure [mPAP]ϭ42 versus 17 mm Hg in normal rats) and death by 15 weeks. When rats with severe PAH received simvastatin (2 mg · kg Ϫ1 · d Ϫ1 by gavage) from week 11, there was 100% survival and reversal of PAH after 2 weeks (mPAPϭ36 mm Hg) and 6 weeks (mPAPϭ24 mm Hg) of therapy. Simvastatin treatment reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor-␣ and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type 1a. Conclusions-Simvastatin reverses pulmonary arterial neointimal formation and PAH after toxic injury. (Circulation.