Favre Shirley, Gambini Elisa, Nigro Patrizia, Scopece Alessandro, Bianciardi Paola, Caretti Anna, Pompilio Giulio, Corno Antonio F, Vassalli Giuseppe, von Segesser Ludwig K, Samaja Michele, Milano Giuseppina
Laboratory of Cardiovascular Research, Department of Surgery and Anesthesiology, University Hospital Lausanne, Lausanne, Switzerland.
Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
J Cell Mol Med. 2017 May;21(5):871-880. doi: 10.1111/jcmm.13026. Epub 2016 Nov 18.
The recruitment of bone marrow (BM)-derived progenitor cells to the lung is related to pulmonary remodelling and the pathogenesis of pulmonary hypertension (PH). Although sildenafil is a known target in PH treatment, the underlying molecular mechanism is still elusive. To test the hypothesis that the therapeutic effect of sildenafil is linked to the reduced recruitment of BM-derived progenitor cells, we induced pulmonary remodelling in rats by two-week exposure to chronic hypoxia (CH, 10% oxygen), a trigger of BM-derived progenitor cells. Rats were treated with either placebo (saline) or sildenafil (1.4 mg/kg/day ip) during CH. Control rats were kept in room air (21% oxygen) with no treatment. As expected, sildenafil attenuated the CH-induced increase in right ventricular systolic pressure and right ventricular hypertrophy. However, sildenafil suppressed the CH-induced increase in c-kit cells in the adventitia of pulmonary arteries. Moreover, sildenafil reduced the number of c-kit cells that colocalize with tyrosine kinase receptor 2 (VEGF-R2) and CD68 (a marker for macrophages), indicating a positive effect on moderating hypoxia-induced smooth muscle cell proliferation and inflammation without affecting the pulmonary levels of hypoxia-inducible factor (HIF)-1α. Furthermore, sildenafil depressed the number of CXCR4 cells. Collectively, these findings indicate that the improvement in pulmonary haemodynamic by sildenafil is linked to decreased recruitment of BM-derived c-kit cells in the pulmonary tissue. The attenuation of the recruitment of BM-derived c-kit cells by sildenafil may provide novel therapeutic insights into the control of pulmonary remodelling.
骨髓源性祖细胞向肺的募集与肺重塑及肺动脉高压（PH）的发病机制相关。尽管西地那非是PH治疗中的一个已知靶点，但其潜在分子机制仍不清楚。为了验证西地那非的治疗效果与骨髓源性祖细胞募集减少有关这一假设，我们通过让大鼠暴露于慢性低氧（CH，10%氧气）两周来诱导肺重塑，慢性低氧是骨髓源性祖细胞的一个触发因素。在CH期间，大鼠分别接受安慰剂（生理盐水）或西地那非（1.4 mg/kg/天，腹腔注射）治疗。对照大鼠置于常氧（21%氧气）环境中且不接受治疗。正如预期的那样，西地那非减轻了CH诱导的右心室收缩压升高和右心室肥大。然而，西地那非抑制了CH诱导的肺动脉外膜中c-kit细胞的增加。此外，西地那非减少了与酪氨酸激酶受体2（VEGF-R2）和CD68（巨噬细胞标志物）共定位的c-kit细胞数量，表明其对减轻缺氧诱导的平滑肌细胞增殖和炎症有积极作用，而不影响肺组织中缺氧诱导因子（HIF）-1α的水平。此外，西地那非降低了CXCR4细胞的数量。总的来说，这些发现表明西地那非对肺血流动力学的改善与肺组织中骨髓源性c-kit细胞募集减少有关。西地那非对骨髓源性c-kit细胞募集的抑制作用可能为控制肺重塑提供新的治疗思路。
