2-METHOXYESTRADIOL ATTENUATES BLEOMYCIN-INDUCED PULMONARY HYPERTENSION AND FIBROSIS IN ESTROGEN-DEFICIENT RATS（2ME减弱博来霉素在雌激素缺乏大鼠中所导致的肺动脉高压和肺纤维化）Tofovic S P, Zhang X, Jackson E K, et al.J. Vascular pharmacology, 2009, 51(2-3): 190.Abstract（摘要）Pulmonary hypertension (PH) is a common and life-threatening complication of pulmonary fibrosis.（肺动脉高压（PH）是一种常见和威胁生命的肺纤维化的并发症。） 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.（雌激素能在试验性肺动脉高压中提供保护并且它的非雌激素代谢物2 -甲氧基雌二醇能在野百合碱诱导的雌性和雄性大鼠肺动脉高压模型中阻止疾病进程的发展。） However, the effects of E2 and 2ME on pulmonary fibrosis and associated PH have not been examined. （然而，雌二醇和2 -甲氧基雌二醇对肺纤维化和涉及肺动脉高压的作用还没有研究出来。）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.（因此，我们对雌二醇和2 -甲氧基雌二醇在人肺成纤维细胞（hlfs）和人肺血管平滑肌细胞（hpasmcs）中的生长抑制作用进行了对比，我们还调查了雌激素不足和对博莱霉素诱导的肺纤维化和肺动脉高压的作用。） 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 g/kg/h) for 21 days.（在完整和切除卵巢的雌性SD大鼠的气管内给予生理盐水或者博莱霉素（15国际单位/千克），并且对切除卵巢并用博来霉素处理的部分雌性大鼠用治疗21天。） Estradiol had only limited inhibitory effects on growth in hPASMCs and no effect in hLFs, whereas 2ME exhibited strong and concentration-dependent (110 M) antimitogenic effects in both cell types.（雌激素对人肺血管平滑肌细胞只有有限的生长抑制作用，而对人肺成纤维细胞没有作用，然而，2 -甲氧基雌二醇对两种类型细胞都能表现出很强的浓度依赖性 (110 微米)抑制有丝分裂作用。） 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 2 / 26fibrosis with diffuse infiltration of inflammatory (ED1+) cells; and resulted in 30% mortality). （博莱霉素致肺损伤值（肺和右心室（RV）重量显著增加，右心室收缩压峰值（RVPSP），右心室/左心室+隔比率(RV/LV+S)；引起肺动脉内侧肥厚和外膜扩大；诱导明显的病灶性或弥漫性纤维化并伴有弥漫性浸润的炎症（ED 1 +）细胞；并导致30%的死亡率）。）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. （卵巢切除能使疾病加重并且死亡率上升（到75%）；然而2 -甲氧基雌二醇倾向于降低死亡率（55.5%）并且能降低幸存下来的动物的右心室收缩压峰值和右心室/左心室+隔比率，减弱血管重塑、肺部炎症和肺纤维化）This study suggests that 2ME may have protective effects in bleomycin-induced PH and fibrosis. （这项研究表明2 -甲氧基雌二醇，可能对博来霉素诱导的肺动脉高压和纤维化有保护作用。）Further investigation of 2ME in pulmonary fibrosis and PH is warranted.（对2 -甲氧基雌二醇在肺动脉高压和肺纤维化中作用的研究是把要的。）Keywords:Pulmonary fibrosis, pulmonary hypertension, estradiol, estradiol metabolitesINTRODUCTIONPulmonary fibrosis is a penultimate consequence of chronic interstitial lung disease from various etiologies and it is characterized by a limited response to available therapies and poor prognosis. Pulmonary hypertension is common in patients with pulmonary fibrosis and its presence has a significant adverse impact on survival (Lettieri et al., 2006). Mortality rates for pulmonary fibrosis are increasing (34% in the last 15 years), and importantly the rate of increase is twice as high in women than men (Olson et al., 2007). However, little is known regarding the effects of gender and estrogens in development of lung fibrosis and associated pulmonary hypertension.Among patients with systemic sclerosis (SSc, scleroderma), pulmonary hypertension is a serious complication and frequent cause of death (Proudman et al. 2007).（在患有系统性硬化症 (SSc, scleroderma)的患者中，肺动脉高压是一种严重的并发症和并且经常导致死亡） Notably, in women with SSc menopause significantly increases the risk for development of disease (Scorza et al. 2002), whereas hormone replacement therapy prevents the development of PH (Beretta et al.,2006).（值得注意的是，患有系统性硬化症妇女绝经后会增加疾病发展的风险，然而激素替代疗法能防止肺动脉高压的发展。） It seems also that pregnancy and estrogens may influence the development of disease and never-pregnant women with SSc are at higher risk for developing PH (Arlett et al. 2002).（看来怀孕和雌激素可能会影响疾病的发展并且从未怀过孕患有系统性硬化症的女性有更高患肺动脉高压的风险） Importantly, both estradiol and its non-estrogenic metabolite 2-methoxyestradiol (2ME) are present in high concentrations in women during the last trimester of pregnancy (Ball and Knuppen 1990; Tofovic et al., 2007), suggesting the notion that estrogens may attenuate the development and retard the progression of PH in patients with pulmonary fibrosis.（重要的是，雌激素和它非雌激素代谢雌激素产物2 -甲氧基雌二醇能高浓度的存在于妇女在怀孕后的最后三个月，表明了雌激素可以减轻和延缓患有系统性硬化症患者肺动脉高压的发展这一概念。）2ME is a major E2 metabolite which is the product of the sequential hydroxylation and methylation of E2 by the enzymes cytochrome P450 and catechol-O-methyltransferase. (2 -甲氧基雌二醇是雌二醇的一个主要代谢产物，它是雌二醇在细胞色素P450