ATS 2009 · San Diego
|
|
| Abstract Number: 2723 |
|
| Contact/Presenting Author: Gautam Damera | |
| Department/Institution: Medicine, University of Pennsylvania | |
| Address: 125 South 31st Street, TRL Suite 1200 | |
| City/State/Zip/Country: Philadelphia, PA, 19104 | |
| Phone: 215-746-2893 Fax: 215-746-1224 E-mail: DAMERA@MAIL.MED.UPENN.EDU | |
| ATS member: No Student or in training: Yes | |
| Funding Source: HL080676, HL081824, ES013508. | |
Abstract Category: 03.15 - Smooth Muscle: Airway |
|
| Presentation format: Either Poster or Oral | |
| Preview Disclosure | |
| Travel Award: Yes | |
|
Publication of email address:
No I confirm that all authors listed on this abstract have knowledge of the abstract submission: Yes |
|
|
Title: Vitamin D Attenuates Growth Factor-Induced Human Airway Smooth Muscle Cell Proliferation G. Damera, PhD1, H. Fogle, BSc1, E. A. Goncharova, PhD1, H. Zhao, MD, PhD1, V. P. Krymskaya, PhD1 and R. A. Panettieri, Jr, MD1. 1University of Pennsylvania, Philadelphia, PA. Airway remodeling in asthma manifests by increased airway smooth muscle (ASM) mass that in part is due to myocyte proliferation. Currently, no therapeutic agents abrogate human ASM (HASM) proliferation. We hypothesize that calcitriol, a non-secosteroidal vitamin D receptor modulator, inhibits growth factor-induced myocyte proliferation. Calcitriol, but not dexmethasone, markedly inhibited PDGF-induced HASM DNA synthesis in a dose-dependent manner, with a maximum inhibitory effect of 60% + 3% (n = 12) at 100 nM calcitriol. Calcitriol also equally inhibited HASM cell growth derived from normals or subjects with asthma. In parallel experiments, calcitriol increased expression of CYP24A1, an inducible protein dependent on vitamin D receptor activation. To determine the precise mechanism by which calcitriol inhibited growth, the effects of calcitriol on PDGF-induced p42/44 MAPK, PI3-kinase, S6kinase activation as well as cyclin D and E2F-1 expression were examined. Despite calcitriol inhibiting PDGF-induced cell growth, calcitriol had little effect on PDGF-induced activation of the aforementioned signaling pathways. In separate experiments, calcitriol treatment showed no substantial effects on HASM apoptosis as determined by caspase 3 expression and flow cytometry. Interestingly, calcitriol markedly inhibited retinoblastoma phosphorylation as well as increased CHK-1 expression. These data suggest that calcitriol uniquely inhibits PDGF-induced HASM cell growth by inhibiting signaling pathways downstream from cyclin D expression but upstream from retinoblastoma phosphorylation. Taken together, calcitriol may offer a unique therapeutic approach in the management of diseases characterized by increased ASM mass that include asthma and COPD. |
|