3 years ago

17β-estradiol dysregulates innate immune responses to Pseudomonas aeruginosa respiratory infection and is modulated by estrogen receptor antagonism.

Katzenellenbogen JA, Terada LS, Jain R, Greenberg DE, Thomas PJ, Shaul PW, Kim SH, Brody SL, Abid S, Xie S, Bose M
Rationale: Females have a more severe clinical course than males in several inflammatory lung conditions. Notably, females with cystic fibrosis (CF) suffer worse outcomes, particularly in the setting of Pseudomonas aeruginosa infection. Sex hormones are implicated in experimental and clinical studies, however immune mechanisms responsible for this sex-based disparity are unknown and the specific sex hormone target for therapeutic manipulation has not been identified.Objectives: Assess mechanisms behind the impact of female sex hormones on host immune responses to P.aeruginosa.Methods: Wild type and CF mice, hormone manipulated and inoculated with P. aeruginosa, were examined for outcomes and inflammatory responses. Neutrophils isolated from mice and human subjects were tested for responses to P. aeruginosaResults: Female mice inoculated with P. aeruginosa died earlier and showed slower bacterial clearance than males (p < 0.0001). Ovariectomized females supplemented with 17β-estradiol succumbed to P. aeruginosa challenge earlier than progesterone- or vehicle-supplemented mice (p = 0.0003). 17β-estradiol-treated ovariectomized female mice demonstrated increased lung levels of inflammatory cytokines, and when rendered neutropenic, the mortality difference was abrogated. Neutrophils treated with 17β-estradiol demonstrated an enhanced oxidative burst, but decreased P. aeruginosa killing and earlier cell necrosis. The estrogen receptor (ER) antagonist, ICI 182,780, improved survival in female mice infected with P. aeruginosa and restored neutrophil function.Conclusions: ER antagonism rescues estrogen-mediated neutrophil dysfunction and improves survival in response to P. aeruginosa. ER-mediated processes may explain the sex-based mortality gap in CF and other inflammatory lung illnesses, and ER blockade represents a rationale therapeutic strategy.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28784925

DOI: PubMed:28784925

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