Role of sex hormones in allergic inflammation in mice

BACKGROUND: A number of clinical studies have documented both a pro- and anti-inflammatory role for sex hormones in the context of lung inflammation and worsening of asthma. OBJECTIVE: To determine the role of sex hormones in a murine model of allergic inflammation and airway hyper-responsiveness (AHR) induced by ovalbumin (OVA). METHODS: Female BALB/c were sensitized to OVA on days 0 and 7 and subsequently challenged on day 14 over a 3-day period. Mice had their ovaries removed either 7 days before or 8 days after the first OVA injection on day 0. Pulmonary eosinophilia and AHR were measured 24 h following the last antigen challenge. In other experiments, ovariectomized mice (Ovx) were pre-treated with oestradiol benzoate. In further studies, the effect of the oestradiol antagonist tamoxifen on allergic inflammation in intact mice was evaluated. Spleens from all groups were collected for proliferation assays and measurement of cytokine release. RESULTS: Removal of the ovaries 7 days before sensitization to OVA significantly inhibited lung eosinophilia and IL-5 levels in lung lavage. Furthermore, airway reactivity (maximum response) but not sensitivity (PC100) to methacholine were significantly reduced in these mice. Proliferation of spleen cells and release of IL-5 collected from Ovx mice was significantly attenuated compared with spleen cells obtained from non-Ovx mice. Ovx mice treated with oestradiol benzoate presented partially restored levels of eosinophils and IL-5 in sensitized mice. Moreover, pharmacological antagonism of the effect of endogenous oestrogen with tamoxifen significantly reduced the number of eosinophils in the lung of intact sensitized mice, reproducing the effect of ovariectomy, and suggested a role for oestrogen in the process of antigen sensitization in female mice. In contrast, removal of ovaries 8 days after the first OVA injection failed to alter significantly pulmonary eosinophilia or AHR to methacholine in comparison with non-Ovx mice. Moreover, removal of the ovaries 8 days after the sensitization period induced a significant increase in levels of IL-5 in lung fluid. Spleen cells collected from these mice also had a significantly higher proliferation index and production of IL-5 in response to OVA than non-Ovx mice. Treatment with oestradiol benzoate partially reduced levels of eosinophils present in the lung of Ovx mice, supporting an anti-inflammatory role of sex hormones during the effector phase of the response to inhaled antigen. CONCLUSION: Sex hormones play a dual role in regulating allergic lung inflammation in mice.