Defect in zinc supply mechanism affects pathology of intractable pulmonary diseases

December 29, 2017, Kumamoto University
In normal lungs, the transporter ZIP2 (WT-ZIP2: the bullet train, or "Shinkansen", on the left side of the figure) controls zinc transport and delivers zinc to lung epithelial cells. For this regulatory mechanism, it is important that the expression/function of CFTR (the tree in the figure) is normal and the expression/function of ENaC (tobacco at the bottom right of the figure) are low. On the other hand, in lungs with obstructive pulmonary disease, the expression/function of CFTR are low and ENaC expression/function is excessive. Credit: Associate Professor Tsuyoshi Syuto

Obstructive pulmonary disease is a collective term for refractory respiratory diseases with chronic airway inflammation and excessive mucus retention that are accompanied by airway obstruction. They include chronic obstructive pulmonary disease (COPD) that presents with chronic bronchitis or pulmonary emphysema, and cystic fibrosis (CF), an intractable hereditary disease characterized by mucus retention and chronic bacterial infection.

A main cause of COPD is cigarette smoke, and the global mortality rate for the now places it in third place. In Japan, the number of patients with COPD over 40 years old is estimated to be about 5.3 million people, making it a familiar disease with a high mortality rate. The onset and progression of the disease is caused by transporter proteins that allow ions to permeate ion channels into cells. COPD is thought to involve the overactivation of the epithelial sodium ion (Na+) channel (ENaC). CF, on the other hand, is a frequently occurring genetic disease in Western countries that is caused by genetic mutation of a chloride ion (Cl-) channel called the transmembrane conductance regulator (CFTR).

Excessive production of mucus-producing genes (such as MUC5AC) in the lungs is known to be important in the development of diseases such as COPD and CF. However, it was not clear why excessive production of these mucus genes occurs in these pulmonary diseases, particularly since they have such different causes, i.e., tobacco and heredity.

Pre-mRNA undergoes mRNA splicing which "cuts out" the information necessary for protein synthesis. In obstructive pulmonary diseases (right side of figure) abnormalities occur during mRNA splicing and cause abnormal (hyper-) mucus secretion. Credit: Associate Professor Tsuyoshi Syuto

In breakthrough work, researchers of Kumamoto University, Japan have now made it clear that abnormalities of the ENaC and CFTR reduce the body's ability to deliver zinc ions (Zn2+) to lung epithelial cells. (One of the zinc ion transporting factors, ZIP2, is an important mechanism for mRNA splicing to function correctly.) In addition, the researchers also revealed that COPD and CF lung epithelial cells have abnormalities in mRNA ligation, which, as a result, causes overproduction of mucous genes. In other words, the diseases developed due to an overproduction of mucus was, in turn, was caused by an insufficient zinc supply to lung epithelial cells.

In general, zinc is a very important element, not only for the lung but also for entire body. Until now, the importance of zinc in the was only understood from a nutritional aspect. The researchers believe that this discovery is the first in the world that clarifies how zinc is involved in the onset of pulmonary diseases, as well as its effects on the regulation of mRNA, one of the molecule responsible for life as we know it.

These results prove that there is abnormality in the zinc transport mechanism itself in obstructive pulmonary diseases. It also suggests that treatment for these diseases cannot be performed merely with supplements. A therapeutic approach that takes the transport mechanisms into consideration is also necessary.

Explore further: New mouse model helps in search for better COPD and CF treatments

More information: Shunsuke Kamei et al, Zinc Deficiency via a Splice Switch in Zinc Importer ZIP2/SLC39A2 Causes Cystic Fibrosis-Associated MUC5AC Hypersecretion in Airway Epithelial Cells, EBioMedicine (2017). DOI: 10.1016/j.ebiom.2017.12.025

Related Stories

New mouse model helps in search for better COPD and CF treatments

January 23, 2017
Researchers from Kumamoto University, Japan have succeeded in producing a mouse model that faithfully reproduces the pathologies of two intractable lung diseases, chronic obstructive pulmonary disease (COPD) and cystic fibrosis ...

New proteins to clear the airways in cystic fibrosis and COPD

July 13, 2012
University of North Carolina scientists have uncovered a new strategy that may one day help people with cystic fibrosis and chronic obstructive pulmonary disorder better clear the thick and sticky mucus that clogs their lungs ...

Repurposing heparin for inhalation may offer hope to millions with COPD

December 1, 2017
A drug used to thin blood has been found to also significantly improve the ability to breathe when inhaled by people with COPD (chronic obstructive pulmonary disease), for which there is no cure.

Scientists find gene linked to heightened mucus levels in lung disease

October 5, 2017
What if researchers could make breathing easier by changing how much mucus is in your lungs? Although healthy individuals have mucus in their lungs, mucus can be a major problem for people with chronic airway conditions, ...

Hope for chronic obstructive pulmonary disease

October 16, 2017
NUS pharmaceutical scientists have discovered that a naturally-derived compound is a potential drug candidate for chronic obstructive pulmonary disease (COPD).

Recommended for you

'Game changer' tuberculosis drug cures 9 in 10

October 22, 2018
A new treatment for a drug-resistant strain of tuberculosis can cure more than 90 percent of sufferers, according to a trial hailed Monday as a "game changer" in the fight against the global killer.

AI doctor could boost chance of survival for sepsis patients

October 22, 2018
Scientists have created an artificial intelligence system that could help treat patients with sepsis.

Consuming caffeine from coffee reduces incident rosacea

October 22, 2018
(HealthDay)—Caffeine intake from coffee is inversely associated with the risk for incident rosacea, according to a study published online Oct. 17 in JAMA Dermatology.

A guide to Acute flaccid myelitis (AFM), the rare, polio-like illness making young children sick

October 22, 2018
A fast-acting, polio-like illness has sickened 62 young children, with an average age of 4, in 22 U.S. states so far this fall.

Scientists in Sweden may have figured out one way acne bacteria defies treatment

October 22, 2018
Researchers in Sweden have discovered how acne-causing bacteria feed off their human hosts. The study, which was performed at KTH Royal Institute of Technology, could make it possible to find effective ways to treat severe ...

Home-based biofeedback therapy is effective option for tough-to-treat constipation

October 22, 2018
Biofeedback therapy used at home is about 70 percent effective at helping patients learn how to coordinate and relax bowel muscles and relieve one of the most difficult-to-treat types of constipation, investigators report.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.