2-methoxyestradiol attenuates bleomycin-induced pulmonary hypertension and fibrosis in estrogen-deficient rats.
2-methoxyestradiol attenuates bleomycin-induced pulmonary hypertension and fibrosis in estrogen-deficient rats.
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DOI：
10.1016/j.vph.2009.06.002
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发表时间：
2009-08
影响因子：
4
通讯作者：
Petrusevska, Gordana
中科院分区：
文献类型：
--
作者：
Tofovic, Stevan P.;Zhang, Xinchen;Jackson, Edwin K.;Zhu, Hong;Petrusevska, Gordana
肺动脉高压（PH）是肺纤维化常见的危及生命的并发症。雌激素（E_2）对实验性PH具有保护作用，其非雌激素代谢产物2-甲氧基雌激素（2 ME）可阻止野百合碱诱导的雄性和雌性大鼠PH的发展和延缓PH的进展。然而，E2和2 ME对肺纤维化和相关PH的影响尚未研究。因此，我们比较了E2和2 ME对人肺成纤维细胞（hLF）和肺血管平滑肌细胞（hPASMCs）的生长抑制作用，并研究了雌激素缺乏和2 ME对博来霉素诱导的肺纤维化和PH的影响。完整和卵巢切除（OVX）的雌性Sprague道利大鼠气管内给予生理盐水或博来霉素（15 IU/kg），OVX博来霉素治疗的大鼠的一个子集接受2 ME（10 μg/kg/h）21天。在hPASMCs中，雌二醇对生长的抑制作用有限，在hLF中没有作用，而2 ME在两种细胞类型中均表现出强烈的浓度依赖性（1 - 10 μM）抗有丝分裂作用。博莱霉素引起肺损伤/PH（肺和右心室（RV）重量、RV峰值收缩压（RVPSP）和RV/左心室+间隔比（RV/LV+S）显著增加;引起肺动脉中膜肥大和外膜增宽;诱导显著局灶性/弥漫性纤维化伴炎性（ED 1+）细胞弥漫性浸润;并导致30%的死亡率）。OVX加重了疾病并增加了死亡率（至75%）;而2 ME倾向于降低死亡率（55.5%），并且在存活动物中降低了RVPSP和RV/LV+S比值，并减轻了血管重塑、肺部炎症和纤维化。这项研究表明，2 ME可能对博莱霉素诱导的PH和纤维化具有保护作用。需要进一步研究2 ME在肺纤维化和PH中的作用。
Pulmonary hypertension (PH) is a common and life-threatening complication of pulmonary fibrosis. Estradiol (E2) is protective in experimental PH, and its non-estrogenic metabolite 2-methoxyestradiol (2ME) prevents the development and retards the progression of monocrotaline-induced PH in male and female rats. However, the effects of E2 and 2ME on pulmonary fibrosis and associated PH have not been examined. Therefore, we compared the growth-inhibitory effects of E2 and 2ME in human lung fibroblasts (hLFs) and pulmonary vascular smooth muscle cells (hPASMCs), and we investigated the effects of estrogen deficiency and 2ME on bleomycin-induced pulmonary fibrosis and PH. Intact and ovariectomized (OVX) female Sprague Dawley rats were administered intratracheally either saline or bleomycin (15 IU/kg), and a subset of OVX bleomycin-treated rats received 2ME (10 μg/kg/h) for 21 days. Estradiol had only limited inhibitory effects on growth in hPASMCs and no effect in hLFs, whereas 2ME exhibited strong and concentration-dependent (1−10 μM) antimitogenic effects in both cell types. Bleomycin caused lung injury/PH (significantly increased lung and right ventricle (RV) weights, RV peak systolic pressure (RVPSP), and RV/left ventricle+septum ratio (RV/LV+S); caused medial hypertrophy and adventitial widening of pulmonary arteries; induced marked focal/diffuse fibrosis with diffuse infiltration of inflammatory (ED1+) cells; and resulted in 30% mortality). OVX exacerbated the disease and increased mortality (to 75%); whereas 2ME tended to reduce mortality (55.5%) and in surviving animals reduced RVPSP and RV/LV+S ratio, and attenuated vascular remodeling, pulmonary inflammation and fibrosis. This study suggests that 2ME may have protective effects in bleomycin-induced PH and fibrosis. Further investigation of 2ME in pulmonary fibrosis and PH is warranted.
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DOI：
10.1006/bbrc.1996.0535
发表时间：
1996-04-05
影响因子：
3.1
作者：
Espinosa, E;Oemar, BS;Luscher, TF
通讯作者：
Luscher, TF
影响因子：
9.6
作者：
Lettieri, CJ;Nathan, SD;Shorr, AF
通讯作者：
Shorr, AF
影响因子：
27.4
作者：
Artlett, CM;Rasheed, M;Jimenez, SA
通讯作者：
Jimenez, SA
影响因子：
5.5
作者：
Speyer, CL;Rancilio, NJ;Ward, PA
通讯作者：
Ward, PA
影响因子：
5.6
作者：
Issekutz, Andrew C.;Sapru, Kusum
通讯作者：
Sapru, Kusum