Effect of Estrogen on Pseudomonas Mucoidy and Exacerbations in Cystic Fibrosis

Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
New England Journal of Medicine (Impact Factor: 55.87). 05/2012; 366(21):1978-86. DOI: 10.1056/NEJMoa1106126
Source: PubMed


Women with cystic fibrosis are at increased risk for mucoid conversion of Pseudomonas aeruginosa, which contributes to a sexual dichotomy in disease severity.
We evaluated the effects of estradiol and its metabolite estriol on P. aeruginosa in vitro and in vivo and determined the effect of estradiol on disease exacerbations in women with cystic fibrosis.
Estradiol and estriol induced alginate production in P. aeruginosa strain 01 and in clinical isolates obtained from patients with and those without cystic fibrosis. After prolonged exposure to estradiol, P. aeruginosa adopted early mucoid morphology, whereas short-term exposure inhibited bacterial catalase activity and increased levels of hydrogen peroxide, which is potentially damaging to DNA. Consequently, a frameshift mutation was identified in mucA, a key regulator of alginate biosynthesis in P. aeruginosa. In vivo levels of estradiol correlated with infective exacerbations in women with cystic fibrosis, with the majority occurring during the follicular phase (P<0.05). A review of the Cystic Fibrosis Registry of Ireland revealed that the use of oral contraceptives was associated with a decreased need for antibiotics. Predominantly nonmucoid P. aeruginosa was isolated from sputum during exacerbations in the luteal phase (low estradiol). Increased proportions of mucoid bacteria were isolated during exacerbations occurring in the follicular phase (high estradiol), with a variable P. aeruginosa phenotype evident in vivo during the course of the menstrual cycle corresponding to fluctuating estradiol levels.
Estradiol and estriol induced mucoid conversion of P. aeruginosa in women with cystic fibrosis through a mutation of mucA in vitro and were associated with selectivity for mucoid isolation, increased exacerbations, and mucoid conversion in vivo. (Funded by the Molecular Medicine Ireland Clinician-Scientist Fellowship Programme.).

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Available from: Shane J O'Neill, Dec 19, 2013
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    • "Pulmonary exacerbations occur, possibly due to changes in the metabolism or phenotype of Pa[3,4], and contribute to deterioration of the patient’s respiratory status. Of note, the effect of gender and the menstrual cycle has been shown to affect Pa phenotypes [5]. Thus chronic colonization of the lungs with Pa is considered to be the leading cause of respiratory morbidity and mortality in CF patients [6,7]. "
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    ABSTRACT: Background The aim was to measure flagellin concentrations in the expectorations of CF patients and to examine whether there are correlations with the level of respiratory insufficiency and inflammation. Methods Sputum samples from 31 adult patients chronically colonized with P. aeruginosa were collected and analysed for their content of flagellin and IL-8. Clinical data were extracted from patient files. Results Regardless of whether patients are colonized with mucoid strains or not, they carry clones of P. aeruginosa that express flagellin. While flagellin was present in airways of all of our CF patients, it is difficult to ascertain its contribution to inflammation (IL-8) and lung function deterioration. Conclusions This is the first demonstration that flagellin is present in the sputum of patients. Thus, attempts to down regulate inflammation by the use of TLR5 (flagellin receptor) antagonists remain a possibility. However, this result needs to be extended to a larger number of patients to validate it for future research on this subject.
    BMC Pulmonary Medicine 06/2014; 14(1):100. DOI:10.1186/1471-2466-14-100 · 2.40 Impact Factor
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    • "Furthermore, sex may be associated with more intractable pulmonary infection. Oestrogen induces the mucoid form of Pseudomonas aeruginosa (a phenotype associated with poor prognosis [22]), and more mucoid P. aeruginosa is isolated from women who experience more pulmonary exacerbations [23]. This study has used 'current survival' to describe trends in estimated survival over time. "
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    Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 01/2014; 13(4). DOI:10.1016/j.jcf.2013.12.002 · 3.48 Impact Factor
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    • "Recently, a strain of P. aeruginosa isolated from the lung of a woman with cystic fibrosis showed an increased production of alginate (an extracellular polymer involved in biofilm development) in the presence of estradiol, which correlates with the exacerbation of cystic fibrosis occurring at the end of the follicular phase when levels of estradiol are high [65]. "
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