Why are women more vulnerable to cystic fibrosis?

• The average life expectancy for women with cystic fibrosis is 49 years compared to 56 for men, according to our partner

  The Conversation

  .

• Recent research reveals that the respiratory cells of women with cystic fibrosis produce fewer anti-inflammatory molecules than those of men.

• This analysis was conducted by

  Valérie Urbach

  , research fellow, INSERM researcher at the University of Paris-Est Créteil Val-de-Marne (UPEC).

Research on cystic fibrosis has made it possible to considerably increase the life expectancy of patients affected by this serious disease.

In 1945, before the start of patient care, the median age of survival was 4 to 5 years, it gradually increased to 20 years in the 1980s, and today it is 50 years.

Unfortunately, all patients are not equal in the face of the disease: some are not eligible for new therapies, others do not react to treatments in the expected way... Moreover, the mortality of women today remains even higher than that of men: their life expectancy is 49 years on average, compared to 56 for men.

Why don't the two sexes have the same chances in the face of the disease?

Our research at the Mondor Institute for Biomedical Research in Créteil aims in particular to answer this question.

We recently discovered a new lead that could explain, at least in part, the greater vulnerability of sick women compared to men.

​Inflammation, a central problem in cystic fibrosis

Our work has revealed that certain molecules involved in interrupting inflammation are produced in insufficient quantities by the respiratory cells of women with cystic fibrosis.

To understand the role of inflammation in disease, let's take a look at its causes.

In France, approximately 6,000 people are currently affected by cystic fibrosis, and each year, approximately 200 affected children are born with this hereditary genetic disease.

This condition mainly affects the lungs, but it also affects other organs, including those of the digestive system and the reproductive system.

It is caused by an anomaly of the CFTR gene, which normally makes it possible to manufacture a "channel" protein located in the cell membrane of the mucous membranes (respiratory, digestive, etc.).

This channel is responsible for the secretion of chloride ions to the outside of the cells.

In people with cystic fibrosis, this pathway malfunctions.

Consequences: the cells secrete less chloride and especially less water, especially on the surface of the respiratory tract.

This lack of water has important consequences.

Indeed, in normal times, the airways are covered with a thin layer of liquid and mucus, which eliminates microbes that have entered the body through the nose or mouth.

When this layer is dehydrated, the mucus becomes slimy and sticky.

It no longer fulfills its function correctly, which is why in patients with cystic fibrosis, bacteria and fungi therefore remain trapped in the bronchi.

The repeated infections that result from this situation result in the installation of a lasting inflammation in the lungs, which leads to their progressive deterioration.

This persistent inflammation is responsible for the difficulty in breathing and, in the long term, for the death of the patients.

When inflammation becomes harmful

The inflammatory response is usually protective.

It defends the organism against aggression, infection, trauma, injury… Once this mission is accomplished, in principle, it stops spontaneously, we say that it “resolves”.

It is when the inflammation persists, as in cystic fibrosis, that it poses a health problem.

Rather than preventing the onset of inflammation, a promising therapeutic avenue is to stimulate the resolution of inflammation.

The latter is orchestrated by various molecules called lipoxins, resolvins, maresins and protectins.

They all belong to the large family of

(or SPM), discovered in the 2000s by scientist Charles Serhan, a researcher at Harvard Medical School.

These "firefighters" are very important in extinguishing the fire of inflammation within our organism.

They are also involved in the repair of tissues that have been damaged during the acute phase of inflammation.

Why are men and women unequal when it comes to cystic fibrosis?

As we have seen, in people with cystic fibrosis, the thickening of the mucus leads to an increase in inflammation.

But this is not the only explanation of the disease.

Indeed, in these patients, the inflammatory reaction is ineffective and disproportionate;

it is even sometimes observed in the absence of microbial infection.

The observations made by our research team could explain this situation.

In particular, we have shown that several members of the family of inflammation-resolving molecules are produced in smaller quantities in people with cystic fibrosis than in others.

Several studies have also shown that, in the general population (therefore in people who are not affected by cystic fibrosis), women produce more PMS than men.

This observation could partly explain their higher longevity than that of men (in 2022, the life expectancy of women at birth is 85.5 years against 79.4 years for men).

Routine screening for cystic fibrosis at birth has revealed that the numbers of male and female newborns with cystic fibrosis are similar.

However, young female patients develop earlier and more severe lung disease than male patients.

This situation means that the life expectancy of women with cystic fibrosis is lower than that of men, contrary to what is observed in the general population.

The reasons for these differences are still poorly understood, but our work has revealed that the respiratory cells of women with cystic fibrosis produce less SPMs than those of men, which could be the beginning of an explanation.

We are now seeking to identify the molecular mechanisms involved in this anomaly, with the hope of uncovering new therapeutic avenues.

OUR “ILLNESS” FILE

This work could also help to better understand the situation of other patients.

Indeed, the study of the molecules of the resolution of the inflammation presents an interest which extends well beyond the only cystic fibrosis.

Abnormalities concerning them have indeed also been observed in the context of other diseases: chronic inflammatory diseases such as periodontitis (inflammation of the gums), multiple sclerosis, cardiovascular diseases, severe asthma, or Covid-19 are particularly concerned.

In addition, as we age, the body produces less and less PMS, which contributes to the vulnerability of older people.

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