Conference: 2010 International PHA Conference and Scientific Sessions
Release Date: 06.24.2010
Presentation Type: Abstracts
Ogawa A1,2, Nakamura K1, Kusano KF1, Ito H1, Yuan JX2.
1. Okayama Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
2. University of California, San Diego, CA, USA
BACKGROUND: Pulmonary vascular remodeling in patients with idiopathic pulmonary arterial hypertension (IPAH) is partially due to increased pulmonary artery smooth muscle cells (PASMC). Platelet-derived growth factor (PDGF) is a potent mitogen which plays a key role in the pathogenesis of IPAH. In this study, we tested the hypothesis that prednisolone, an immunosuppressant with anti-inflammatory effects, inhibits PDGF-induced proliferation of PASMC by regulating NF-kB, a transcription factor involved in inflammatory responses.
METHODS: PASMC were isolated from patients with IPAH who underwent lung transplantation and control cells were obtained from patients with bronchogenic carcinoma at lung lobectomy. Cells were incubated in the media containing PDGF (10 ng/ml) with or without prednisolone. Cell proliferation was assessed by 3H-thymidine incorporation and migration was assessed by Boyden chamber method. Intracellular calcium concentration was measured using Intracellular Imaging system. Cell cycle was analyzed using a microscope-based multiparameter laser scanning cytometer.
RESULTS: Prednisolone (2x10-4 mol/L) successfully inhibited PDGF-induced proliferation and migration of PASMC from patients with IPAH (P<0.05). Prednisolone inhibited PDGF-induced nuclear translocation of NF-kB and attenuated PDGF-induced store operated calcium entry. Upregulation of cyclin-dependent kinase inhibitor p27 and G1 arrest were caused by prednisolone. Inhibition of NF-kB activation successfully attenuated PDGF-induced proliferation of PASMC.
CONCLUSIONS: We demonstrated that PDGF caused activation of inflammatory process and prednisolone induced decrease of intracellular calcium concentration and cell cycle arrest via inactivation of NF-kB. This subsequently caused attenuation of PDGF-induced proliferation and migration of PASMC. Modulating inflammatory process by prednisolone can be a therapeutic option for treatment of IPAH.