The Underlying Mechanisms of Chronic Obstructive Pulmonary Disease

There is increasing evidence that chronic obstructive pulmonary disease, COPD, may be due to accelerated lung aging. In our research, we look at the underlying mechanisms of COPD.

For many years, we’ve been working on the underlying inflammation that occurs in patients’ lungs which affects the small airways and the spongy substance of the lung. We know that chronic smokers have inflammation in their airways, leading to increased mucus production or chronic bronchitis. In COPD patients, this inflammation is greatly amplified. Patients experience chronic inflammation over many years, which is thought to lead to pathological changes, emphysema and small airway fibrosis.

Photo by Antonio Guillem

We’ve also been examining the inflammatory cells and the inflammatory signals or mediators they produce in COPD. This is a very complicated matter as there are many such cells and more than 100 inflammatory mediators.

Pharmaceutical companies have also been trying to target this underlying inflammation. For example, individuals with asthma display chronic inflammation that is typically responsive to corticosteroids given via an inhaler. These corticosteroids stop the symptoms, prevent attacks and keep people from dying. Furthermore, most asthma patients feel much better when taking inhaled steroids because they suppress the airways’ underlying inflammation.

However, COPD patients experience a different kind of inflammation, and most fail to respond to steroids. This type of inflammation is described as steroid-resistant. We were working on why steroids are ineffective; however, that area of research is not leading to new treatments. Instead, we are now addressing the aging of the lung.

Accelerated Aging and Cellular Senescence

Everyone ages, but at different rates. Furthermore, the lungs age slowly over time, reaching peak lung function at around 25 years old and then slowly declining. In elderly people, you see lower lung function, but not low enough to cause symptoms like in COPD. Still, the lungs of elderly people display some of the features of COPD. They have a sort of emphysema and narrowing of small airways. This is also observed in COPD but to a greater degree.

We think that lung aging is accelerated in COPD, occurring much earlier in a patient’s life. When lung function begins declining, it drops much more rapidly until patients experience symptoms that progressively worsen. Indeed, the lungs of COPD patients look like the lungs of very elderly people.

They also have more aging cells, which are called senescent cells. Cellular senescence is the cellular process of aging, and senescent cells are found throughout the lung in COPD. In fact, it’s a very characteristic feature of COPD lungs, and we can measure the degree of senescence using different techniques.

An essential characteristic of senescent cells is that they don’t divide like normal cells, so they can’t repair damage. Normally when healthy lungs are damaged, they can fix this damage, but this can’t happen if their cells are senescent.

Yet, perhaps the most critical feature of senescent cells is that they’re not innocuous. Indeed, they’ve been called “zombie cells” because they release large amounts of damaging proteins and are not quite dead. In turn, these proteins can cause inflammation and further senescence. We think that the profile of these toxic molecules is the same as in COPD.

Inflamm-aging

Photo by sruilk

An interesting statistic is that of all the people who have ever lived to be 65 throughout human history, more than half are alive today. This provides some scope of the enormous increase in the number of elderly people susceptible to age-related diseases such as COPD.

The inflammation of COPD lungs is the inflammation associated with aging, which has been called inflammaging. We think this is an important mechanism of COPD and is one reason why COPD is becoming more prevalent – because more people live longer.

We’ve also been examining the features of cellular senescence and how they develop in COPD. We can use cigarette smoke to expose lung cells to the same conditions that a smoker would experience. We can thereby show that cigarette smoking leads to the aging of lung cells. As such, these cells become senescent and produce inflammatory proteins. We can also show that they exhibit markers of senescence, which indicates that senescence pathways are activated. This, in turn, allows us to study the molecular pathways involved.

Furthermore, we think smoking is an oxidative stress. This stress drives cellular senescence and leads to the inflammatory and structural changes that occur in COPD. We can then block this pathway at various stages with currently available drugs. Metformin, for example, is a widely used drug to treat late-onset diabetes but is also known to inhibit senescence in animal models.

Metformin has also been shown to have beneficial effects on some aging diseases. A very large study underway in the US is examining the impact of metformin on normal aging to understand whether it delays dying from age-related diseases. If shown to be effective, metformin could potentially be used to treat COPD. Other available drugs like rapamycin have also been shown to work on age-related diseases.

Targeting microRNA

More importantly, however, new therapeutics in development may be more effective on these aging pathways. One particular area that we’ve been studying is a type of RNA called microRNA.

RNA, produced by the DNA template, codes for proteins but also has sequences that regulate genes. These microRNAs are very important because they regulate different pathways.

We found that two microRNAs are markedly increased in COPD, both of which inhibit a key anti-aging molecule called sirtuin 1. Sirtuin 1 is a very, very important molecule that counteracts the aging process and is known to be drastically reduced in COPD lungs and cells. From our previous work, it appears that this loss of sirtuin 1 could be the major mechanism leading to accelerated aging. Furthermore, it may be produced by microRNAs activated by the senescence pathways, which are themselves activated by smoking and oxidative stress.

This might be a critical pathway that could be blocked in the future. We’ve also shown that if you block these RNAs, you reduce aging in COPD cells collected at surgery. These pathways, when blocked, can lead to overcoming senescence and rejuvenating cells.

Naturally, this is a very exciting possibility for new therapies in the future, although it remains to be determined how such molecules could be efficiently delivered to the lungs of people with COPD. I think studying aging pathways will lead to a better understanding of the disease process. More importantly, we may develop new treatments that reduce the progression and mortality of this disease.

Future Therapeutics for an Aging Population

Photo by Microgen

The aging process is relentless. More people live to old age because they’re not dying of diseases, particularly infections, which formerly had poor prognoses. We’re also making good progress in reducing mortality from heart disease, cancer, diabetes and many other chronic diseases. However, the longer people live, the more they are exposed to risk factors like smoke and air pollution and are more likely to develop age-related diseases like COPD.

I hope that current research will lead to treatments that stop aging or even reverse it. That’s why we need to understand the pathways and how we can block them safely. Of course, treatments may not be safe in the long term, so their effects on reducing disease progression will have to be carefully assessed. If safe treatments can be developed, they would best be given early in COPD before patients lose a lot of lung function.

Moving forward, it will become essential to diagnose patients at an early stage, perhaps before they have symptoms. Take, for instance, blood pressure. Although high blood pressure doesn’t have symptoms, it is used as a marker for developing strokes and heart attacks. We treat blood pressure to prevent those severe diseases.

I hope that we will have a similar situation in COPD. In smokers that lose lung function but are unable or unwilling to stop smoking, we may then be able to intervene with a treatment that prevents lung aging. Such treatments may also work in other age-related diseases because there are common pathways between these diseases.

Furthermore, it may be that you could use a combination of approaches to get the best outcome with the fewest side effects. Still, the approach we currently find the most attractive is to target the reduction of sirtuin 1, which can be achieved in several ways. As mentioned, this important anti-aging molecule is reduced in COPD and other age-related diseases.

Blocking specific microRNAs is another approach. For example, there are drugs like resveratrol that are known to increase the level of sirtuin 1. Resveratrol comes from the red skin of fruit and is found in wine. It can increase sirtuin 1 and has anti-aging effects, but is relatively weak and is not very well absorbed. Researchers have developed related molecules that are better absorbed, so many are looking at that approach.

Finally, other drugs block the pathways that lead to a reduction in sirtuin 1. Therapeutics may also be able to deliver sirtuin 1 or the RNA that codes for it. This approach of restoring sirtuin 1 is particularly attractive because it returns something abnormal to its normal value.

Discover more about

Accelerated aging of the lungs

Barnes, P. (2016). Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. The Journal of Allergy and Clinical Immunology.

Barnes, P. (2018). Cellular senescence as a mechanism and target in chronic lung diseases. American Journal of Respiratory and Critical Care Medicine.

Reverting the aging process