期刊
BIOCHEMICAL PHARMACOLOGY
卷 80, 期 2, 页码 236-246出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2010.03.035
关键词
Calcium-sensing receptor; Airway epithelial wound repair; Migration; Proliferation
资金
- Ministry of Science and Innovation and Health Institute 'Carlos III' of Spanish Government [SAF2005-00669/SAF2008-03113, SAF2006-01002/SAF2009-08913, CIBERES (CB06/06/0027), CAIBER (CAI08/01/0039)]
- Regional Government [Prometeo/2008/045]
- Fondo de Investigaciones Sanitarias' (FIS) of Health Institute 'Carlos III' of Ministry of Health (Spain)
The airway epithelium routinely undergoes damage that requires repair to restore epithelial barrier integrity. Cell migration followed by proliferation are necessary steps to achieve epithelial repair. Calcium-sensing receptor (CaSR) is implicated in cell migration and proliferation processes. Thus we hypothesized that CaSR mediates lung epithelial wound repair. We detected CaSR expression in human lung and in well-differentiated human bronchial epithelial cells (HBEC). To test the CaSR functionality, HBEC loaded with fura-2 were stimulated with extracellular Ca2+ ([Ca2+](out)) which resulted in a concentration-dependent intracellular Ca2+ ([Ca2+](i) increase (potency similar to 5.6 mM [Ca2+](out)). Furthermore, increasing [Ca2+](out) induced phosphorylation of the extracellular signal-regulated kinase (ERK1/2) which was blocked by siRNA-CaSR and the specific inhibitor of CaSR, NPS2390. Epithelial repair after mechanical injury of differentiated HBEC was a process dependent of [Ca2+](out) since it accelerated wound repair and HBEC proliferation being highest at 5 mM [Ca2+](out). Furthermore, U73122 (an inhibitor of phospholipase C (PLC)) and PD 98059 (an inhibitor of ERK1/2) as well as siRNA-CaSR and NPS2390 partially inhibited wound repair and HBEC proliferation. On the other hand, mechanical injury produced an [Ca2+](i) wave propagation that was partially inhibited by siRNA-CaSR, NPS2390 and the extracellular Ca2+ chelator EGTA, which suggest a link of CaSR between cell-cell communication and wound repair in differentiated HBEC. Our data, for the first time, shows that CaSR plays an important role in airway epithelial repair, which may help to develop novel regenerative therapeutics allowing the rapid repair of lung damaged epithelium. (C) 2010 Elsevier Inc. All rights reserved.
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