Redressing the balance – Understanding the disproportionate impact of Cystic Fibrosis on Women



Cystic fibrosis is a hereditary recessive disease which is the result of mutations in the Cystic Fibrosis Transmembrane Conductance (CFTR) gene. Mutation of the CFTR leads to decreased chloride transport across the surface epithelia and consequent dehydration of the airway surface liquid (ASL) which lines the airway. This dehydration causes the formation of a thick viscous mucus which traps pathogens and cannot be cleared by ciliary transport.

Improving therapies have increased the mean life expectancy of patients with CF from less than 5 years of age in the 1950s to almost 40 years of age today1. However, even with the advent of more advanced and specific therapies, CF continues to impact women to a greater degree than men. A study carried out by Raksha Jain et al in 2014 demonstrated that women with CF have a decreased median life expectancy (36.0 years), compared to men (38.7 years). They showed that female gender was a significant risk factor for death (hazard ratio 2.22, 95% CI 1.79-2.77), despite taking in to account many variables which a known to influence CF mortality2.

Given these gender differences, several groups have looked at the possible influence of sex hormones on the mucociliary apparatus, which is composed of mucus, cilia and the ASL. These studies showed that sex hormones were able to influence the airway epithelial cell apical sodium and chloride transport3,4, ASL volume5 and the beat frequency of cilia6 as well as affecting the inflammatory mediators predisposing women to increased infection and colonisation7.

Van Horn et al published a study in Science Advances in September 2016 which integrated NMR, molecular dynamics, homology modeling and protein structure predictive modeling to investigate the role of oestrogen in CF at a molecular level. Specifically, they studied the KCNE3 protein which modulates the voltage-gated potassium channel KCNQ1, removing voltage-dependant gating producing a constitutively open leak channel. In this way KCNE3 regulates the recycling of potassium ions (K+) which in turn impacts the flow of chloride ions (Cl) across epithelial tissues.

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Van Horn et al showed that oestrogen induces the phosphorylation of KCNE3 Ser82 residue resulting in the disruption of its complex with KCNQ1, thereby decreasing K+ ion recycling and subsequent Cl secretion leading to a further reduction in ASL volume and increased mucus viscosity. This in turn results in decreased mucociliary clearance, higher rates of infection and colonisation and increased morbidity in female CF patients.

It is hoped that the advent of new techniques in the imaging and structural analysis of membrane-protein interactions will not only help to redress the balance of prognosis between the sexes but ultimately make CF more treatable in the future.

References

  1. Marshall BC. Cystic Fibrosis Foundation Patient Registry: 2013. Annual Data Report. Available at http://cff.org
  2. Harnness-Brumlley CL., Elliot, AC., Rosenbluth DB., Raghavan D., Jain R. Gender Differences in Outcomes of Patients with Cystic Fibrosis. Journal of Women’s Health 2014;Dec 1;23(12) 1012-1020
  3. Sweezey NB., Ghibu F. Gagnon S. Sex hormones regulate CFTR in developing fetal rat lung epithelial cells. Am J Physiol 1997;272:L844–851
  4. Singh AK., Schultz BD., Katzenellenbogen JA, et al. Estrogen inhibition of cystic fibrosis transmembrane conductance regulator-mediated chloride secretion. J Pharmacol Exp Ther 2000;295:195–204
  5. Coakley RD., Sun H., Clunes LA, et al. 17beta-Estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid volume in human cystic fibrosis airway epithelia. J Clin Invest 2008;118:4025–4035
  6. Jain R., Ray JM., Pan JH. Brody SL. Sex hormone-dependent regulation of cilia beat frequency in airway epithelium. Am J Respir Cell Mol Biol 2012;46:446–453
  7. Chotirmall SH., Smith SG., Gunaratnam C, et al. Effect of estrogen on pseudomonas mucoidy and exacerbations in cystic fibrosis. N Engl J Med 2012;366:1978–1986

Blog written by Holly Charlton

 

 

 

 

 

 

 

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