Researchers Uncover Mechanisms Linking the Brain and Lungs in Asthma

As the English poet John Donne famously wrote in 1624, “No organ is an island.” Or at least, that’s what he would have written if he had been a psychoneuroimmunologist instead of a poet.

Today, researchers understand that different bodily systems are strongly interconnected and can affect each other in complex—and sometimes surprising—ways. Our mental states, for example, can have measurable effects on the function of our heart, lungs, digestive, and immune systems; stress, in particular can influence the development or progression of a laundry list of diseases, from multiple sclerosis to diabetes.¹ However, the biological pathways that connect stress with disease processes are still not fully understood.

It is precisely these kinds of questions that captured the attention of researchers like Melissa Rosenkranz, a neuroscientist at the University of Wisconsin-Madison. Since the beginning of her career, she said, “I’ve been really interested in wanting to understand the biology that is behind the connection between mind and body: How the contents of your mind can influence physiology in the body, and how the operations of the body influence how we experience the world.”

In a new study published in Brain, Behavior, and Immunity, Rosenkranz and her team made strides towards connecting the dots between psychological stress and lung physiology in the context of allergy-induced asthma.² They found that stronger cortisol responses to an experimental stress induction were associated with increased activity in threat-detecting brain regions as well as greater inflammatory responses to an inhaled allergen. This study sheds light on how pathways linking the brain, immune system, and lungs may drive stress-induced increases in disease severity and provides new targets to improve the management of asthma and potentially other inflammatory conditions.

“I was really impressed with this idea that they are going from the brain to circulation to what's happening in the lungs,” said Sonia Cavigelli, a behavioral neuroendocrinologist at Pennsylvania State University who was not involved in the study. “They're measuring biology at multiple levels.”

To study the effects of acute stress on asthmatic responses, Rosenkranz and her team brought several participants with mild asthma into the laboratory where they underwent the Trier Social Stress Test, which combines two of humanity’s greatest fears: public speaking and mental math. After running this emotional gauntlet, participants provided spit samples for salivary cortisol measurements and underwent positron emission tomography (PET) scans to assess their brain activity. Finally, the researchers used an inhaled allergen challenge to provoke a controlled asthmatic response and measured markers of inflammation in participants’ airways.

Surprisingly, researchers found that the stress test itself didn’t affect how participants’ lungs responded to the allergen. Instead, variation in individuals’ physiological responses to the stressor predicted differences in allergen-induced inflammation. People who had greater salivary cortisol responses also had greater increases in activity in brain regions which are involved in processing fear and social stress. These elevated stress responses were then associated with higher airway expression of the inflammatory protein interleukin-23A (IL-23A).

IL-23A is a component of the Th17 immune pathway, which has traditionally been associated with autoimmune diseases like lupus and rheumatoid arthritis. However, more recent studies have implicated the Th17 pathway in the pathogenesis of asthma as well, in addition to the Th2 pathway, which has long been associated with asthma and other allergic responses. This line of research linking stress, brain activity, and the Th17 pathway has several implications for improving the management of this disease.

“One of the things is that it allows us a pharmacological target,” said Rosenkranz. In the context of stress, she said, “Maybe drugs that are able to modify immune responses in the Th17 pathway might be more effective—rather than targeting the traditional Th2 pathway, which is generally what medications target.”

Another component of the Th17 pathway is the production of IL-17, a proinflammatory molecule that promotes glucocorticoid insensitivity.³ This could reduce physiological responses to naturally-occurring cortisol, but also to the corticosteroid medications used to treat asthma. “This is one of the reasons why it's problematic that stress is priming this Th17 response in the airway,” said Rosenkranz.

This ties in to Rosenkranz’s previous work on the effects of psychological interventions, like mindfulness training, on asthma symptoms and other types of inflammatory responses.^4,5 “Now what we want to do is try to understand if training in mindfulness has an impact on lung biology through [this pathway]—by reducing stress, we're also reducing the priming of the Th17 response, so that we're not promoting this glucocorticoid insensitivity, and that the medications that are traditionally used to treat asthma will be more effective.”

Cavigelli is interested in other questions as well. Given the large body of literature on sex differences in the responses to acute and chronic stress, as well as differences in immune function, Cavigelli said she was curious about whether the processes explored in the paper differed between males and females.^6,7 “I think we need to know that stuff, especially if we're thinking about treatment,” she said.