COPD or when our lungs are unclean

December 08, 2016

COPD stands for chronic obstructive pulmonary diseases. It is characterized by the difficulty to breathe properly. Unfortunately, this pathology develops and never reverses, that’s why it is called a progressive disease (NIHBI website). In 2002, 5% of deaths were due to COPD, mainly occurring in developing countries (WHO website, 5th cause among dead people). However, it is thought that in 2030, the number of COPD casualties will dramatically raise (included developed countries) due to more exposure to polluted air and more consumption of tobacco among people (especially women, WHO website). This makes this pathology a world public health issue.

COPD: what is it?

First of all, before explaining COPD in details, it is better to have a refresh of how our lungs are functioning. The lungs are the organs allowing our body to breath. They are connected to the outside by our mouth and our nose, which are connected to the trachea. The trachea is linked to the lungs by the bronchus which divide themselves in small tubes called bronchioles. These bronchioles lead to small bags called alveolus where exchange of oxygen and carbon dioxide take place. These alveolus are really crucial for our well being as they allow us to breath, to remove the dust that we receive thanks to immune cells called alveolar macrophages. However, accumulation of unclean material, due to polluted air, cigarette smoke (active and passive), dust exposure, results in too much work for our cells, which fail to complete it. Exhaustion of these cells leads to their destruction, followed by the serious damage of the alveolus and the accumulation of impurities in bronchus, which are obstructed. This results by the emphysema (destruction of lung tissue) and the bronchitis (obstruction of the bronchus) which characterize the COPD (COPD Review update 2014, Lancet).

There are different stages of COPD evolving from moderate to severe. Unfortunately, the main issue is that most of the people living with COPD are not aware of theirs critical conditions (COPD Review update 2014, Lancet). That means that it is often late, while diagnosed. Indeed, COPD can lead to complications which are responsible for heart failure, diabetes, pneumonia, lung cancer and dementia (Stephane Faris, healthline website, 2012). Worst, no effecient treatment is available currently.

Nrf2, the solution against COPD?

Multiple treatments are available to limit the damage of COPD, with arguable efficiency. They can be based on the reduction of the lung volume (surgical or not). Drugs like azitromycin, cortiscostreoids or bronchodilatators are available also as a treatment (COPD Review update 2014, Lancet). But there is one molecule on which researchers and clinicians are putting their hopes, namely Nrf2. Nrf2 stands for Nuclear factor (erythroid-derived 2)-like 2. It is a nuclear factor which functions is to activate genes in the nucleus of a cell. Cells are briefly composed from a cytoplasm and also the nucleus in which the DNA is kept. Nrf2 is usually kept in the cytoplasm, sequestrated by another protein called Keap1 (Itoh et al, Genes Dev, Jan 1999). Under stressed conditions, Nrf2 is released into the nucleus following the destruction of Keap1, and activates target genes. Among these genes:

- NqO1, NAD(P)H quinone oxidoreductase 1, which is involved in detoxification (Venugopal R, Jaiswal AK, Proc. Natl. Acad. Sci. U.S.A., Dec 1996).
- Gclc/Gclm (Glutamine-cysteine ligase catalytic/modifier), a group of antioxydants (Solis et al, Biochem. Pharmacol. 2002).
- SRXN1 (sulfiredoxin 1)/TXNRD1 (Thioredoxin reductase 1), which detoxify reactive peroxides (Neumann et al, Cell Signal, 2009; Soriano et al, Mol Cells, 2009).
- HO1 (Heme Oxygenase 1): an anti-inflammatory agent giving the antioxydant biliverdine (Jarmi T, Agarwal A, Curr. Hypertens., 2009).

This case is observed while our immune system is able to control the oxidative stress reactions. On the other hand, while our system cannot face these reactions coming from outside (ROS, electrophiles, xenobiotics, cigarette smoke…), Nrf2 is kept in the cytoplasm, unable to stop the accumulation of oxidative reactions, resulting therefore in COPD (Boutten et al, Trends in Mole Med, 2011).

Therefore, supply of Nrf2 in COPD patients could maybe limit the damages or slow down the progression of the pathology.

To conclude, COPD is a major health public issue that can affect everybody (smoker or not). The best way to prevent this disease is to adopt the healthiest lifestyle.

Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (January 1999). "Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain". Genes Dev. 13 (1): 76–86. doi:10.1101/gad.13.1.76. PMC 316370. PMID 9887101.