10779/rcsi.10785614.v1 Christina Draijer Christina Draijer Machteld N. Hylkema Machteld N. Hylkema Carian E. Boorsma Carian E. Boorsma Pieter A. Klok Pieter A. Klok Patricia Robbe Patricia Robbe Wim Timens Wim Timens Dirkje S. Postma Dirkje S. Postma Catherine M. Greene Catherine M. Greene Barbro N. Melgert Barbro N. Melgert Sexual maturation protects against development of lung inflammation through estrogen. Royal College of Surgeons in Ireland 2019 Allergic lung disease Sex differences. Medicine 2019-11-22 16:35:39 Journal contribution https://repository.rcsi.com/articles/journal_contribution/Sexual_maturation_protects_against_development_of_lung_inflammation_through_estrogen_/10785614 <p>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.</p>