2-methoxyestradiol attenuates bleomycin-induced pulmonary hypertension and fibrosis in estrogen-deficient rats.
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 (15IU/kg), and a subset of OVX bleomycin-treated rats received 2ME (10microg/kg/h) for 21days. Estradiol had only limited inhibitory effects on growth in hPASMCs and no effect in hLFs, whereas 2ME exhibited strong and concentration-dependent (1-10microM) 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.
Tofovic
Stevan P
SP
Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh School of Medicine, United States. tofovic@dom.pitt.edu
Zhang
Xinchen
X
Jackson
Edwin K
EK
Zhu
Hong
H
Petrusevska
Gordana
G
D000077584:2-Methoxyestradiol; D000704:Analysis of Variance; D000818:Animals; D050256:Antimitotic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects / Q000473:pathology; D001761:Bleomycin; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality; D008168:Lung / Q000098:blood supply / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011651:Pulmonary Artery / Q000166:cytology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D050256:Antimitotic Agents; D004967:Estrogens; D001761:Bleomycin; D004958:Estradiol; D000077584:2-Methoxyestradiol