Researchers at RCSI and Beaumont Hospital have made a major breakthrough in understanding how female sufferers of cystic fibrosis (CF) fare worse compared to male sufferers, due to higher levels of the hormone oestrogen.

The new insights into the mechanisms at work in CF revealed from this research, may lead to new treatments for the disease.

Cystic fibrosis is a life threatening inherited disease which primarily affects the lungs and the digestive system. A build-up of mucus can make it difficult to clear bacteria and leads to cycles of lung infections and inflammation, which can eventually lead to damage of the lungs.

The study, published in the American Journal of Respiratory and Critical Care Medicine found that oestrogen limits the lung’s ability to respond to infection. Oestrogen was found to prevent the release of a chemical signal (IL-8) that triggers the influx of white blood cells (neutrophils) into the lungs to fight the infection when cells are attacked by bacteria.

Ireland has both the highest incidence of CF in the world at 2.98 per 10,000 and the highest carrier rate in the world with one in 19 individuals classed as carriers. The incidence of cystic fibrosis in this country is almost 4 times the average rate in other EU countries and the USA (1).

It has long been observed that female CF patients have poorer survival rates, poorer lung function and are more susceptible to lung infections than male CF patients.

In the lungs, a protective layer of fluid known as the airway surface liquid (ASL) keeps the lung’s lining hydrated and defends the lungs from infections. In CF sufferers this layer is thinner and previous research demonstrated that this protective layer is reduced even further at times of elevated levels of oestrogen during the menstrual cycle, so the likelihood of acquiring an infection is increased during this period (2).

Joint lead author of the paper, Dr Sanjay Chotirmall, Specialist Registrar in Respiratory Medicine in the Respiratory Research Division of RCSI, Beaumont Hospital commented: ‘This reduced response to infection combined with a greater likelihood of acquiring an infection in the first place, both caused by high oestrogen levels, goes a long way towards explaining how females with cystic fibrosis have more aggressive disease, particularly with the onset of puberty.

"Our research may contribute towards narrowing the gender gap in cystic fibrosis by identifying new potential targets for treatment, such as stabilisation of oestrogen levels, or more aggressively employing preventative strategies against infection during the one week of the four week menstrual cycle where oestrogen levels are at their highest. Our ultimate aim would be improving the quality of life and survival rate for female sufferers of cystic fibrosis," Dr Chotirmall continued.

The research has additionally been recognised by the Faculty of 1000 Biology, an online research service that highlights the most interesting papers published in the biological sciences as recommended by distinguished faculty. In their assessment, this novel work may reveal insight into why trials of most anti-inflammatory medications in cystic fibrosis patients have been unsuccessful with one large trial requiring premature termination due to the increased numbers of infections observed (3).

"Although uncontrolled chronic inflammation over a prolonged period can be damaging to the lungs, some degree of inflammation is required to fight off bacterial infections. Surges of acute inflammation during times of infection are fundamentally a protective response from the body," Dr Chotirmall concluded.

The research team from the Respiratory Research Division, Department of Medicine, RCSI Beaumont Hospital and RCSI Department of Molecular Medicine, included Dr Catherine Greene (joint lead author), Ms Irene Oglesby, Dr Warren Thomas, Professor Shane O’Neill, Professor Brian Harvey and Professor Gerry McElvaney. The research was funded through support from the Higher Education Authority PRTLI Cycle 4, through a Molecular Medicine Ireland Clinician-Scientist Fellowship Programme.

Reference: Chotirmall SH, Greene CM, Oglesby IK, Thomas W, O’Neill SJ, Harvey BJ, McElvaney NG. 17b-Estradiol Inhibits IL-8 in Cystic Fibrosis by Up-Regulating Secretory Leucoprotease Inhibitor. American Journal of Respiratory and Critical Care Medicine Vol 182. pp 62–72, 2010.

(1) Farrell PM. The prevalence of cystic fibrosis in the European Union. Journal of Cystic Fibrosis 2008 Sep;7(5):450-3. This study combined a variety of methods to determine the prevalence of cystic fibrosis in the European Union. The results of literature reviews, surveys, and registry analyses revealed a mean prevalence of 0.737/10,000 in the 27 EU countries, which is similar to the value of 0.797 in the United States, and only one outlier, namely the Republic of Ireland at 2.98.

(2) Coakley RD, Sun H, Clunes LA, Rasmussen JE, Stackhouse JR, Okada SF, Fricks I, Young SL, Tarran R. 17beta-Estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid volume in human cystic fibrosis airway epithelia. Journal of Clinical Investigation 2008 Dec;118(12):4025-35.

(3) Faculty of 1000 Biology: evaluations for Chotirmall SH et al Am J Respir Crit Care Med 2010 8 Apr: http://f1000biology.com/article/id/3828956/evaluation.