title: Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: valeriehox@gmail.com.
authors.forename: Valerie
authors.initials: V
authors.lastname: Hox
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Avanti
authors.initials: A
authors.lastname: Desai
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Geethani
authors.initials: G
authors.lastname: Bandara
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Gilfillan
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Ana
authors.initials: A
authors.lastname: Olivera
mesh_terms: D000707:Anaphylaxis / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*; D000818:Animals; D001831:Body Temperature; D002199:Capillary Permeability; D004195:Disease Models, Animal; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006632:Histamine / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D010052:Ovariectomy; D066329:Protein Aggregates; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology; D017455:Receptors, IgE / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D065171:Estrogen Receptor Antagonists; D066329:Protein Aggregates; D011960:Receptors, Estrogen; D017455:Receptors, IgE; D017452:Receptors, IgG; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D004958:Estradiol; D006632:Histamine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
keywords: Anaphylaxis; estrogen; mast cells; nitric oxide synthase; vascular permeability