By Jessica Martin, PhD
The other day, my first-grader son fired off a long series of questions about the lungs, kindly pointing to his chest in case I was uncertain where they are found. “Mom, what do the lungs do again? What is asthma? One of my friends at school has asthma.” As a further multimedia aid, he gave me sound effects in the form of a long, slow, noisy inhalation and exhalation. Of course, his general demeanor indicated that he knew some of the answers and was just checking to see if I knew, too.
From a very young age, we come to understand our bodies by breaking the whole into smaller compartments with different functions – the various organs and organ systems — and after awhile we only focus on the ones that really hold our interest. This process of compartmentalization continues up the chain of education all the way to the top, culminating in our “specialist” medical doctors and scientists. We have allergists, pulmonologists, dermatologists, endocrinologists, neurologists, urologists, cardiologists, and the list goes on. Ask a dermatologist a question about the heart and they will quite likely shrug and defer to the cardiologist. What is the first thing that comes to mind when hearing the word “asthma?” I know that I instantly answered my son’s questions with an explanation of the lungs, what they do, and what happens to breathing during an asthma attack. But here’s the thing: asthma that is triggered by allergens is typically treated and monitored by an allergist (asthma-like symptoms are often treated by a pulmonologist). While we may think of asthma as the immune system going haywire in the lower respiratory tract, asthma is not the offspring of an unhappy marriage between two bodily systems (i.e. immune and respiratory). Asthma is the product of a love triangle with additional partners likely to be discovered. Other specialties may have something to contribute to the conversation.
A recent paper published in the Proceedings of the National Academy of Science (Tränkner et al., 2014) highlighted the essential role that the nervous system plays in allergic asthma. And they weren’t just any old cells of the nervous system. These were “my” neurons – the very same ones that I spent over 5 years of my life studying. Occasionally worlds collide. While asthma is recognized as an inflammatory condition stemming from a skewed immune system, many of the hallmark symptoms, such as bronchoconstriction (a decrease in size of the airway openings), are in fact mediated in part by the cells of the nervous system (i.e. neurons). The lungs contain nerve cell endings that can sense chemical irritants. If a chemical activates these neurons, the information is relayed and integrated into the central nervous system, which can then send a signal back through a different set of neurons to the muscles lining the airways. The muscles are commanded by these neurons to contract and airways constrict. For a person with asthma, the same amount of a chemical irritant causes a much greater airway constriction than someone without asthma. Thus, an asthmatic’s airways are said to be “hyperreactive” and wheezing ensues.
The scientists wanted to know what role a population of sensory neurons that detect chemical irritants in the lungs plays in allergic asthma. Even more interesting is that these neurons house the receptor (TrpV1) that is activated by capsaicin, the active ingredient in chili peppers! The difference between say a habanero and a banana pepper lies entirely in the concentration of this stuff – as quantified on the Scoville scale. (Wear gloves while you chop habaneros!) In the taste buds of our mouth, activated TrpV1 tells us muy caliente – in other words, TrpV1 can be activated by heat alone or capsaicin (among many other physical/chemical stimuli), and the end result is the same “hot” sensation. The precise function TrpV1 plays in the sensory neurons of the lungs is still being studied. Nonetheless, the scientists in this particular paper used TrpV1 as a way to identify a population of sensory neurons in order to study their role in allergic asthma, using mice as subjects.
The scientists left the murine allergic immune system unchanged, but removed or inactivated the TrpV1-containing sensory neurons. They wanted to know if removing these neurons could stop airway constriction in allergic mice. The answer was yes!
They also tested whether the reverse was true. Instead of removing or inactivating the TrpV1 sensory neurons, they selectively activated them. They expected that the activated sensory neurons would cause a hyperreactive airway response in asthmatic mice (e.g. more bronchoconstriction) compared to mice without asthma. Right again.
Clearly, something from the immune system of allergic mice was signaling the nervous system to overreact when irritated. They found one potential candidate. The immune system cells can release a chemical called sphingosine-1-phosphate. Interestingly, the sensory nerve cells have a receptor that recognizes this chemical – in other words, the structure was in place for communication between these two different systems to work as allies if threatened! If in fact sphingosine-1-phosphate could tell the nervous systems of asthmatic mice to overreact, then it might also cause hyperreactive airways in non-allergic mice. Again—hypothesis confirmed; this is in fact what they observed.
What does this mean clinically? We know that controlling inflammation is critical to controlling asthma. That being said, controlling inflammation isn’t always enough to completely avoid symptoms. Just ask anyone who uses Flovent as directed. Would it make sense to not only control inflammation, but also selectively control the sensory nervous system component and disrupt communications? Whether this could be done in a very specific way in humans (only affecting the lung sensory nerve cells in a non-invasive way) is a great question, but certainly one worth exploring. This study relied on genetically engineered mice and highly invasive procedures. Hard to duplicate with people.
Thus, we come back to where we started – talking about compartmentalization and specialization of our bodily systems. While certain diseases such as asthma, are currently viewed as the domain of an allergist, what this example highlights is that disease is not confined to our self-imposed classifications and the myriad of the specializations based on those classifications. This is also true of other allergic disorders such as food allergies, which are also a function of the digestive system.
To move our understanding of the field forward – ultimately leading to better treatments or even a cure – researchers must get out of their comfort zones and think beyond their own specializations. Multisystem diseases require multisystem collaboration. The different bodily symptoms already have a lingua franca, an “international” biochemical language that allows them to work together, sometimes for good and sometimes not. Our researchers must do the same.
Reference Tränkner, D., Hahne, N., Sugino, K., Hoon, M.A., and Zuker, C. (2014). Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways. Proceedings of the National Academy of Sciences 111, 11515-11520.
Jessica Martin earned a Ph.D. in Neuroscience from Oregon Health and Science University in 2011. She lives in the Portland, Oregon area with her husband Jason and their sons where she teaches undergraduate biology and anatomy and physiology at Portland Community College. Although not currently engaged in cutting-edge laboratory science, she continues to actively research current findings in allergy and immunology, where she writes about some of those findings on her blog, The Food Allergy Sleuth. She aspires to eventually return to the trenches of doing laboratory science in allergy and immunology, but for now, her life is happily filled to the brim with being a Mom, an educator, a writer, and as most food allergy sufferers and parents already know, part-time cook.