Estrogen reduces inflammation of asthmatic airways by inhibiting pathways leading to oxidant stress.

Abstract

We have previously reported that estrogen replacement therapy reduces inflammation in a murine model of allergic asthma. We now studied the mechanisms responsible for this protective effect. Female C57/Bl6 mice were ovariectomized, implanted with subcutaneous osmotic minipumps releasing either vehicle or estrogen and subjected to a 25‐day regimen of ovalbumin sensitization. On day 26, animals were sacrificed and lung tissue was analyzed as described below. Asthmatic, vehicle‐treated mice exhibited strong oxidant stress, as revealed by immunohistological staining of lung tissue for 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG), an indicator of oxidative DNA damage; 8‐OHdG staining was significantly reduced in asthmatic, estrogen‐treated mice and resembled that in non‐asthmatic controls. Furthermore, asthmatic, vehicle treated animals demonstrated increased Akt phosphorylation, and Rac‐1 activation, suggesting that NADPH oxidase may be an important contributor to the observed oxidant stress in asthmatic animals. Akt phosphorylation and Rac‐1 activation were profoundly inhibited in estrogen‐treated asthmatic mice, to levels resembling those on non‐asthmatic controls. These data suggest that the protective effects of estrogen replacement therapy may include inhibition of pathways leading to increased oxidant stress.