Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production

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Fig. 1. Timeline: Adult (6-month-old) and old (22-month-old) rats were ovariectomized. Half of the animals received immediate E2 replacement.

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Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production Valerie Hox, MD, PhD, Avanti Desai, MSc, Geethani Bandara, PhD, Alasdair M. Gilfillan, PhD, Dean D. Metcalfe, MD, Ana Olivera, PhD Journal of Allergy and Clinical Immunology Volume 135, Issue 3, Pages 729-736.e5 (March 2015) DOI: 10.1016/j.jaci.2014.11.003 Copyright © 2014 Terms and Conditions

Fig 1 Enhanced anaphylaxis in female mice is estrogen dependent. A, Temperature changes in female and male C57Bl/6 mice during anaphylaxis. Mice were sensitized with DNP-specific IgE and challenged 24 hours later with DNP-HSA. Data are from 3 independent experiments of 6 mice per group. B-D, Temperature changes during anaphylaxis in ovariectomized (OVX) or sham-operated female mice (Fig 1, B) after implantation in OVX mice of E2–releasing (OVX+E2) or placebo pellets (OVX; Fig 1, C) and in female mice after treatment with the ER antagonist ICI182,780 (ER-ant; Fig 1, D). In Fig 1, B-D, there were 6 mice per group. ***P < .001. Journal of Allergy and Clinical Immunology 2015 135, 729-736.e5DOI: (10.1016/j.jaci.2014.11.003) Copyright © 2014 Terms and Conditions

Fig 2 Estrogen does not affect mast cell responses. A, Histamine and MCPT-1 released into the circulation 90 seconds after challenging ovariectomized (OVX) or sham-operated female mice with antigen (n = 5 mice per group). B, β-Hexosaminidase release from BMMCs in the presence of different concentrations of E2. Results are the average of 4 independent cultures (3 female and 1 male donor). The inset shows ERα expression in BMMCs from male (M) and female (F) mice. C and D, Temperature changes during anaphylaxis induced by histamine (Fig 2, C) or anti-CD16/CD32 2.4G2 (Fig 2, D) in OVX and sham-operated mice. In Fig 2, C and D, there were 6 mice per group. ***P < .001. Journal of Allergy and Clinical Immunology 2015 135, 729-736.e5DOI: (10.1016/j.jaci.2014.11.003) Copyright © 2014 Terms and Conditions

Fig 3 The presence of female sex hormones leads to increased vascular permeability during anaphylaxis. A, Hematocrit values at baseline and after PSA in male (M), female (F), sham-operated, and ovariectomized (OVX) mice. B, Wet/dry lung weight ratios of male and female mice 2 hours after anaphylaxis. In Fig 3, A and B, there were 6 mice per group. C, Representative hematoxylin and eosin–stained lung slides from a male and female mouse 2 hours after IgE/antigen-induced PSA showing peribronchial edema (arrows) and red blood cells accumulated in the airspace (arrowheads). Scale bar = 100 μm. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2015 135, 729-736.e5DOI: (10.1016/j.jaci.2014.11.003) Copyright © 2014 Terms and Conditions

Fig 4 Estrogen regulates eNOS expression in vivo. Expression levels of eNOS and Ser1177-phosphorylated eNOS (p-eNOS) are shown in lung lysates from female (F), male (M), and ovariectomized (OVX) female mice at baseline and after IgE/antigen-induced PSA. A, Representative Western blots of lung lysates are shown. Numbers below indicate the fold increases in eNOS or p-eNOS band intensities (corrected to their respective β-actin loading control) compared with male mice. B, Band intensities in lung eNOS and p-eNOS (n = 5 mice per group) are shown. *P < .05, **P < .01, and ***P < .001. No statistical differences were found in levels of eNOS or p-eNOS between male and OVX female mice. Journal of Allergy and Clinical Immunology 2015 135, 729-736.e5DOI: (10.1016/j.jaci.2014.11.003) Copyright © 2014 Terms and Conditions

Fig 5 eNOS activity is crucial for determining female susceptibility to anaphylaxis. A and B, Temperature changes during anaphylaxis induced by IgE/antigen in female and male mice pretreated with the NOS inhibitor L-NAME or vehicle (Fig 5, A) or in NOS3−/− female and male mice (Fig 5, B). C and D, Effect of L-NAME on temperature (Fig 5, C) and hematocrit (Fig 5, D) changes during IgE/antigen-induced anaphylaxis in female mice pretreated with the ER antagonist ICI182,780 (upper panels) or vehicle (lower panels). In Fig 5, A-D, there were 5 to 8 mice per group. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2015 135, 729-736.e5DOI: (10.1016/j.jaci.2014.11.003) Copyright © 2014 Terms and Conditions

Fig E1 A, Core body temperature decrease induced by antigen challenge in IgE-sensitized BALB/c female and male mice (left panel) or ovariectomized (OVX) and sham-operated female mice (right panel; n = 6 mice per group). B, Changes in body temperature induced by IgE/antigen in weight-matched C57BL/6 female and male mice (n = 5 mice per group). Inset, Body weights of female (F) and male (M) mice at the time of the experiment. The ages of female and male mice were 15 and 7 weeks, respectively. C, Serum E2 levels in sham-operated female mice and OVX female mice 2 weeks after implantation of E2-releasing (OVX+E2) or placebo-releasing (OVX) pellets (n = 6 mice per group). D, Linear correlation between serum levels of estradiol in female mice 10 weeks of age and the temperature decrease measured 90 minutes after antigen challenge. **P < .01 and ***P < .001. Journal of Allergy and Clinical Immunology 2015 135, 729-736.e5DOI: (10.1016/j.jaci.2014.11.003) Copyright © 2014 Terms and Conditions

Fig E2 A and B, TNF-α released into the circulation 5 minutes (Fig E2, A) or 2 hours (Fig E2, B) after challenging ovariectomized (OVX) or sham-operated female mice with antigen (n = 6 mice per group). Mice were killed, and blood was collected by means of cardiac puncture. C, TNF-α release from BMMCs stimulated with antigen for 6 hours in the presence of different concentrations of E2, as indicated. Results are the average of 4 independent cultures. TNF-α production after E2 treatment in each experiment is represented as the fold change compared with IgE/antigen-stimulated cells (second bar). No antigen (no Ag) indicates cells treated with IgE and no antigen, and control (Co) indicates untreated cells. TNF-α levels in plasma or supernatants from BMMCs were assessed by using ELISA. Journal of Allergy and Clinical Immunology 2015 135, 729-736.e5DOI: (10.1016/j.jaci.2014.11.003) Copyright © 2014 Terms and Conditions

Fig E3 A, Expression levels of eNOS in aorta lysates from female (F), male (M), and ovariectomized (OVX) female. The graph represents expression levels of eNOS in aortas from 5 mice measured as the intensity of the eNOS bands relative to the corresponding loading control (β-actin). Blots represent 2 representative samples of aortas from male and female mice. B, Expression levels of eNOS in MLECs cultured for 48 hours in the presence of different concentrations of E2 (10 and 100 pg/mL, n = 2 per condition). Blots show a representative sample for each condition. C, Quantification of eNOS expression levels in cultures of human PAECs derived from 2 male (M) and 2 female (F) donors. Blots show a representative sample of each group. All graphs represent expression levels of eNOS measured as the intensity of the eNOS bands relative to the corresponding loading control (β-actin). *P < .05. Journal of Allergy and Clinical Immunology 2015 135, 729-736.e5DOI: (10.1016/j.jaci.2014.11.003) Copyright © 2014 Terms and Conditions