What does melatonin, a hormone that regulates the sleep–wake cycle, have to do with asthma? Although she’s still unravelling the details, Haruka Sasaki, a dental anesthesiologist and assistant professor at Tohoku University in Sendai, Japan, is trying to answer this question.

Her research could lead to new, targeted therapies for nocturnal asthma, for which traditional asthma medications –– like inhaled corticosteroids and beta-receptor agonists –– have limited usefulness. 

Asthma, a chronic lung disease that affects both children and adults, is incurable. Pinpointing the cause of a person’s asthma is not always straightforward, but family history, allergies, smoking, and obesity have all been tied to its onset. Common symptoms include wheezing, shortness of breath, chest tightness, and a persistent cough, where weather changes, pollution, allergens like dust and pollen, and even exercise can all potentially trigger an asthma attack.

Among the hundreds of millions of asthma sufferers worldwide, hundreds of thousands die each year. According to the World Health Organization, most asthma-related deaths occur in low- and lower-middle-income countries, where under-diagnosis and under-treatment are common issues.  

Asthma attacks that happen at night, during sleep, are particularly tricky to control and account for most asthma-related deaths. Interestingly, those who suffer from nocturnal asthma have much higher levels of melatonin in their blood than healthy individuals. Sasaki’s efforts to uncover the mechanism behind their association has earned her international recognition.

In 2022, she received a L’Oréal-UNESCO Women in Science Fellowship and in 2023 was named one of the top 100 scientists by Asian Scientist Magazine. This year, she made Forbes’ 30 Under 30 Asia (Healthcare and Science) list.

Sasaki’s interest in asthma is personal. After experiencing a severe asthma attack in university, she’s been intent on developing therapies to help patients better manage the disease and prevent fatal attacks. She shared with us some of what she’s learned so far in her research.

What motivated you to study asthma?

Since childhood, I have been suffering from asthma and managing it with medication, which gave me a sense of control over the condition. However, a pivotal moment during my undergraduate clinical training completely changed my perspective.

I found myself face to face with the harsh reality of a life-threatening asthma attack while working in dental anesthesiology. This experience shattered my belief that asthma could always be controlled with medication and made me realize that, in some cases, this is just not true. I was shocked by the fact that asthma can be a life-threatening disease. It was this episode that inspired me to explore the pathophysiology of asthma and develop novel therapeutic approaches. To do this, we are working on identifying the receptors present in smooth muscle in airways and are investigating whether the activation of these receptors improves or worsens asthma symptoms.

Can a person develop asthma at any point in their life? What might trigger it?

Asthma is a chronic allergic disease that can develop at any time in a person’s life.  Various factors can trigger it, including indoor and outdoor air pollution, respiratory infections, exercise and hyperventilation, smoking, weather conditions, food and food additives, pregnancy, obesity, and so on.

Why is asthma often worse at night, when people are sleeping and inactive? How are asthma symptoms correlated with the body’s circadian clock? 

Several theories have been proposed to explain why asthma worsens at night. For example, it has been suggested that the activation of the parasympathetic nervous system [the network of nerves that relaxes the body] during sleep may make the airways more prone to constriction, or a decrease in the secretion of steroid hormones during sleep may worsen airway inflammation. However, these theories are all hypothetical, and the exact mechanisms remain unclear.

What role does melatonin play in asthma?

The main pathological feature of an asthma attack is the sudden constriction of the muscles that line the airways in the lungs. Melatonin exacerbates asthma by increasing airway smooth muscle contraction. Drugs called beta-receptor agonists are inhaled to relax the airway muscles during an asthma attack, but melatonin has been shown to reduce the effectiveness of these asthma drugs.

Do all asthma sufferers have higher melatonin concentrations in the blood at night? Why are melatonin levels higher in nocturnal asthma sufferers than in healthy individuals?

Whether all asthma patients have higher melatonin concentrations at night is currently unclear. However, previous studies have indicated that in patients with nocturnal asthma, peak serum melatonin levels are significantly higher than those in healthy individuals, which is associated with the overnight change in the amount of air a person can force out of their lungs. Nocturnal asthma attacks are one of the clinical indicators of poor asthma control, so it is possible that patients with poorly controlled asthma may also have higher peak melatonin levels. However, the reason for this remains unclear.

In a recent paper you mention that the effect of melatonin on asthma remains controversial. Why is this? 

We have demonstrated that melatonin exacerbates asthma by increasing the contraction of the smooth muscles in the airway. However, it has also been reported that melatonin administration does not actually affect asthma symptoms or lung function, but it does improve the quality of sleep in asthma patients. These different findings may be related to melatonin concentration, but the exact concentration that exacerbates asthma is currently unknown.

How is nocturnal asthma currently treated? How do the current medications fall short or fail?  

Nocturnal asthma symptoms are usually treated with a combination of inhaled corticosteroids and long-acting beta-agonists. During asthma attacks, oral or injected corticosteroids and short-acting beta-agonists are used. However, some patients continue to frequently experience nocturnal asthma symptoms (more than once a week), despite long-term treatment with inhaled corticosteroids. Currently, to treat these cases of severe, poorly controlled asthma, certain antibodies are used. Although they are mostly effective, there are still cases that are difficult to control. The fact that existing medications are less effective in nocturnal asthma attacks suggests the possibility of unknown factors that modulate asthma’s pathophysiology. We have proposed melatonin as a new factor that exacerbates asthma.

Should nocturnal asthma sufferers avoid taking melatonin supplements? 

High doses of melatonin may exacerbate asthma attacks by triggering the contraction of airway smooth muscle. However, melatonin have also been shown to have therapeutic effects in patients with cancer, cardiovascular disease, and psychiatric disorders, showing that high doses can be beneficial. Oral doses of 20 mg are sometimes used in cancer therapy to alleviate chemotherapy-related side effects, reduce depression, and improve sleep quality. Melatonin has also been reported to promote cancer cell death and autophagy, making cancer cells more sensitive to chemotherapy.

But the bioavailability of melatonin is low—varying from 10% to 56%—and after oral intake in its usual dose (1 to 5 mg), melatonin concentrations in the blood remain in the nanomolar range, which is still relatively low. Therefore, at these lower doses, supplemental melatonin is unlikely to have an effect on airway smooth muscle contraction.

What are your next research steps?

In addition to airway smooth muscle contraction, the pathophysiology of asthma also involves excessive mucus secretion and airway inflammation. We are currently investigating the effects of melatonin receptors on these aspects of the disease.