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Disruption of Calcium Signaling in Fibroblasts and Attenuation of Bleomycin-Induced Fibrosis by Nifedipine.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Mukherjee, Subhendu Ayaub, Ehab A. Murphy, John Stewart Lu, Chao Kolb, Martin Ask, Kjetil Janssen, Luke Jeffrey |
| Copyright Year | 2015 |
| Abstract | Fibrotic lung disease afflicts millions of people; the central problem is progressive lung destruction and remodeling. We have shown that external growth factors regulate fibroblast function not only through canonical signaling pathways but also through propagation of periodic oscillations in Ca(2+). In this study, we characterized the pharmacological sensitivity of the Ca(2+)oscillations and determined whether a blocker of those oscillations can prevent the progression of fibrosis in vivo. We found Ca(2+) oscillations evoked by exogenously applied transforming growth factor β in normal human fibroblasts were substantially reduced by 1 μM nifedipine or 1 μM verapamil (both L-type blockers), by 2.7 μM mibefradil (a mixed L-/T-type blocker), by 40 μM NiCl2 (selective at this concentration against T-type current), by 30 mM KCl (which partially depolarizes the membrane and thereby fully inactivates T-type current but leaves L-type current intact), or by 1 mM NiCl2 (blocks both L- and T-type currents). In our in vivo study in mice, nifedipine prevented bleomycin-induced fibrotic changes (increased lung stiffness, overexpression of smooth muscle actin, increased extracellular matrix deposition, and increased soluble collagen and hydroxyproline content). Nifedipine had little or no effect on lung inflammation, suggesting its protective effect on lung fibrosis was not due to an antiinflammatory effect but rather was due to altering the profibrotic response to bleomycin. Collectively, these data show that nifedipine disrupts Ca(2+) oscillations in fibroblasts and prevents the impairment of lung function in the bleomycin model of pulmonary fibrosis. Our results provide compelling proof-of-principle that interfering with Ca(2+) signaling may be beneficial against pulmonary fibrosis. |
| Starting Page | 97 |
| Ending Page | 97 |
| Page Count | 1 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://sclerodermaconference.ca/wp-content/uploads/2016/09/Dr.-Gerard-Cox.pdf |
| PubMed reference number | 25664495v1 |
| Alternate Webpage(s) | https://doi.org/10.1165/rcmb.2015-0009OC |
| DOI | 10.1165/rcmb.2015-0009oc |
| Journal | American journal of respiratory cell and molecular biology |
| Volume Number | 53 |
| Issue Number | 4 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Anti-Inflammatory Agents Bleomycin Calcium Signaling Extracellular Matrix Growth Factor Hippocampus (Brain) Hydroxyproline Inflammation Lung diseases Matrix Metalloproteinases, Membrane-Associated Mibefradil Nifedipine Pharmacology Pneumonia Potassium Chloride Pulmonary Fibrosis Respiratory physiology Smooth muscle (tissue) Structure of parenchyma of lung Tissue membrane Transforming Growth Factors Verapamil |
| Content Type | Text |
| Resource Type | Article |
