Food, drug, insect sting allergy, and anaphylaxis
Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production

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Background

Clinical observations suggest that anaphylaxis is more common in adult women compared with adult men, although the mechanistic basis for this sex bias is not well understood.

Objectives

We sought to document sex-dependent differences in a mouse model of anaphylaxis and explore the role of female sex hormones and the mechanisms responsible.

Methods

Passive systemic anaphylaxis was induced in female and male mice by using histamine, as well as IgE or IgG receptor aggregation. Anaphylaxis was assessed by monitoring body temperature, release of mast cell mediators and/or hematocrit, and lung weight as a measure of vascular permeability. A combination of ovariectomy, estrogen receptor antagonism, and estrogen administration techniques were used to establish estrogen involvement.

Results

Anaphylactic responses were more pronounced in female than male mice. The enhanced severity of anaphylaxis in female mice was eliminated after pretreatment with an estrogen receptor antagonist or ovariectomy but restored after administration of estradiol in ovariectomized mice, demonstrating that the sex-specific differences are due to the female steroid estradiol. Estrogen did not affect mast cell responsiveness or anaphylaxis onset. Instead, it increased tissue expression of endothelial nitric oxide synthase (eNOS). Blockage of NOS activity with the inhibitor L-NG-nitroarginine methyl ester or genetic eNOS deficiency abolished the sex-related differences.

Conclusion

Our study defines a contribution of estrogen through its regulation of eNOS expression and nitric oxide production to vascular hyperpermeability and intensified anaphylactic responses in female mice, providing additional mechanistic insights into risk factors and possible implications for clinical management in the further exploration of human anaphylaxis.

Section snippets

Methods

Further details can be found in the Methods section in this article's Online Repository at www.jacionline.org.

Sex differences in systemic anaphylaxis are estrogen dependent

Resembling epidemiologic studies on systemic anaphylaxis, IgE-mediated PSA was more severe in female C57Bl/6 mice than in male mice (Fig 1, A), as determined by a decrease in core body temperature, which correlates with increases in plasma histamine and hematocrit values, hypotension, and visible behavioral changes.16 The differential severity between age-matched male and female mice was also observed in BALB/c mice (see Fig E1, A, left panel, in this article's Online Repository at //www.jacionline.org

Discussion

The increased incidence of anaphylaxis in women has been recognized in the clinic for years.34, 35, 36 Our study shows that sex-specific differences in systemic anaphylaxis are replicated in mice and, as in human subjects, are not restricted to IgE-mediated responses. The incidence, onset, and/or severity of many human diseases, including allergic diseases, such as asthma, show a sex bias that is likewise conserved across species.37, 38 Although in some instances these sex differences have been

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    Supported by the Division of Intramural Research Program within the National Institute of Allergy and Infectious Diseases/National Institutes of Health and by Research Foundation Flanders (F.W.O.). V.H. was a research fellow and the recipient of a Travel Grant from F.W.O. as well as a Gustave Boël–Sofina–Belgian American Educational Foundation (B.A.E.F.) fellow.

    Disclosure of potential conflict of interest: This work was supported by the Division of Intramural Research Program within the National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIH) and by Research Foundation Flanders (F.W.O.). V. Hox was a research fellow and the recipient of a Travel Grant from F.W.O. as well as a Gustave Boël–Sofina–Belgian American Educational Foundation (B.A.E.F.) fellow. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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