title: Sexual maturation protects against development of lung inflammation through estrogen.
abstract: Increasing levels of estrogen and progesterone are suggested to play a role in the gender switch in asthma prevalence during puberty. We investigated whether the process of sexual maturation in mice affects the development of lung inflammation in adulthood and the contributing roles of estrogen and progesterone during this process. By inducing ovalbumin-induced lung inflammation in sexually mature and immature (ovariectomized before sexual maturation) adult mice, we showed that sexually immature adult mice developed more eosinophilic lung inflammation. This protective effect of "puberty" appears to be dependent on estrogen, as estrogen supplementation at the time of ovariectomy protected against development of lung inflammation in adulthood whereas progesterone supplementation did not. Investigating the underlying mechanism of estrogen-mediated protection, we found that estrogen-treated mice had higher expression of the anti-inflammatory mediator secretory leukoprotease inhibitor (SLPI) and lower expression of the proasthmatic cytokine IL-33 in parenchymal lung tissue and that their expressions colocalized with type II alveolar epithelial cells (AECII). Treating AECII directly with SLPI significantly inhibited IL-33 production upon stimulation with ATP. Our data suggest that estrogen during puberty has a protective effect on asthma development, which is accompanied by induction of anti-inflammatory SLPI production and inhibition of proinflammatory IL-33 production by AECII.
authors.affiliation: University of Groningen, Department of Pharmacokinetics, Toxicology, and Targeting, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands; c.draijer@rug.nl.
authors.forename: Christina
authors.identifier: http://orcid.org/0000-0002-7466-0437
authors.initials: C
authors.lastname: Draijer
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands;
authors.forename: Machteld N
authors.initials: MN
authors.lastname: Hylkema
authors.affiliation: University of Groningen, Department of Pharmacokinetics, Toxicology, and Targeting, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands;
authors.forename: Carian E
authors.initials: CE
authors.lastname: Boorsma
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands;
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Klok
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands;
authors.forename: Patricia
authors.identifier: http://orcid.org/0000-0001-9654-9775
authors.initials: P
authors.lastname: Robbe
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands;
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland; and.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Greene
authors.affiliation: University of Groningen, Department of Pharmacokinetics, Toxicology, and Targeting, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands;
authors.forename: Barbro N
authors.initials: BN
authors.lastname: Melgert
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000378:metabolism*; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000096:biosynthesis; D012741:Sexual Maturation / Q000502:physiology*
chemical_list: D016207:Cytokines; D004967:Estrogens; D053481:Secretory Leukocyte Peptidase Inhibitor
keywords: allergic lung disease; sex differences