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.