Abstract
Chronic obstructive pulmonary disease (COPD) is due to structural changes and narrowing of small airways and parenchymal destruction (loss of the alveolar attachment as a result of pulmonary emphysema), which all lead to airflow limitation. Extracorporeal shock waves (ESW) increase cell proliferation and differentiation of connective tissue fibroblasts. To date no studies are available on ESW treatment of human bronchial fibroblasts and epithelial cells from COPD and control subjects. We obtained primary bronchial fibroblasts from bronchial biopsies of 3 patients with mild/moderate COPD and 3 control smokers with normal lung function. 16HBE cells were also studied. Cells were treated with a piezoelectric shock wave generator at low energy (0.3 mJ/mm2, 500 pulses). After treatment, viability was evaluated and cells were recultured and followed up for 4, 24, 48, and 72 h. Cell growth (WST-1 test) was assessed, and proliferation markers were analyzed by qRT-PCR in cell lysates and by ELISA tests in cell supernatants and cell lysates. After ESW treatment, we observed a significant increase of cell proliferation in all cell types. C-Kit (CD117) mRNA was significantly increased in 16HBE cells at 4 h. Protein levels were significantly increased for c-Kit (CD117) at 4 h in 16HBE (p < 0.0001) and at 24 h in COPD-fibroblasts (p = 0.037); for PCNA at 4 h in 16HBE (p = 0.046); for Thy1 (CD90) at 24 and 72 h in CS-fibroblasts (p = 0.031 and p = 0.041); for TGFβ1 at 72 h in CS-fibroblasts (p = 0.038); for procollagen-1 at 4 h in COPD-fibroblasts (p = 0.020); and for NF-κB-p65 at 4 and 24 h in 16HBE (p = 0.015 and p = 0.0002). In the peripheral lung tissue of a representative COPD patient, alveolar type II epithelial cells (TTF‐1+) coexpressing c-Kit (CD117) and PCNA were occasionally observed. These data show an increase of cell proliferation induced by a low dosage of extracorporeal shock waves in 16HBE cells and primary bronchial fibroblasts of COPD and control smoking subjects.
Highlights
After Extracorporeal shock waves (ESW) treatment, we observed a significant increase of cell proliferation in all cell types
The attempts to stimulate lung regeneration in chronic obstructive pulmonary disease (COPD) patients with emphysema with orally administered all-trans RA (ATRA) yielded no differences in computed tomography (CT), lung function, or quality of life scores between treatment groups [13, 14], and RAR-c selective agonist administration showed no differences in CT scores or lung function in treated vs. nontreated COPD patients [15, 16]
ESW combined with osteogenic medium increased the osteogenic differentiation of treated human adiposederived stem cells (hASCs) [22], while stem cell differentiation into myofibroblasts was partially reduced by ESW treatment [23]
Summary
Markers of cell proliferation include CD117 (c-Kit or SCFR), a receptor tyrosine kinase protein that binds to stem cell factor (SCF), expressed on hematopoietic stem cells It can be expressed by mast cells, melanocytes in the skin, interstitial cells of Cajal in the digestive and urogenital tract [24], cardiac pericytes [25], amniotic fluid stem cells [26], stem/progenitor cells in conducting airway epithelium of porcine lung [27], and dendritic cells in the lung [28]. We aimed in this study to analyze the proliferative effect of shock waves when applied as an external challenge to primary bronchial fibroblasts of COPD patients and control smokers, and to immortalized bronchial epithelial cells (16HBE) To this end, we investigated cell markers expression related to this proliferative stimulus
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