This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.
Jeffrey J. Swigris, DO, MS: Hello. I'm Dr Jeff Swigris. Welcome to season 2 of the Medscape InDiscussion podcast series on idiopathic pulmonary fibrosis (IPF). Today we have a really great topic and I'm excited to talk to our guest, who's going to be educating all of us on circadian rhythms in IPF. Let me introduce Dr Isaac Sundar. Dr Sundar is an associate professor in the Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine at the University of Kansas Medical Center in Kansas City. Isaac, welcome to the Medscape InDiscussion podcast.
Isaac Kirubakaran Sundar, PhD: Thank you for this invitation. I'm glad to be part of this podcast.
Swigris: Tell us what piqued your interest in interstitial lung disease (ILD) and how circadian rhythms may play a role there.
Sundar: I started as a postdoctoral fellow in lung biology, trying to understand basic mechanisms that are related to chronic obstructive pulmonary disease (COPD) pathogenesis. My interest with respect to circadian rhythms came from the preclinical models of COPD. We did some initial studies with the circadian clock, coupled with lung cellular functions and COPD, in 2010. That was the initial stage where we started our studies and then that slowly evolved over time.
We moved on to try to understand the basic mechanisms of how the circadian clock regulates inflammation, how it regulates specific cytokine signaling processes, how it affects lung function and COPD, and then potentially also some other mechanisms, like DNA damage repairs, senescence mechanisms, that drive the pathobiology of COPD over time.
And then we started looking a little bit into the context of the similarities or understandings that we know from the models of lung disease to patients with COPD, because we know that patients with COPD have nocturnal symptoms and severity that is time dependent. So we were trying to really tie up the role of clock in lung function.
We thought there could be a lot of things that that clock does, not just regulating the biological processes that drive disease. It also has a lot of physiologic roles in terms of regulating many physiologic processes that drive these disease processes.
So then we moved on to asthma. That is my own independent research that I passionately started as an independent faculty, to look into the understanding of the circadian clock and asthma pathobiology. That also ties back with clock because asthma is also linked with a lot of nocturnal symptoms and severity, and a lot of immune cells play a very important role in a time-dependent manner in regulating asthma pathobiology as well.
That drives a lot of interest to me that it's not just COPD or asthma; rather, these clock dysregulations or circadian rhythms as a whole have a very broad role in a lot of chronic inflammatory lung diseases. That's where we thought to expand this knowledge — not just to asthma and COPD but also to ILD. Not much is known, so potentially there is a lot to explore in that angle to look at what clock is really doing at the cellular level and at the physiological level — how they are changing and contributing to the pathobiology of ILD.
Swigris: What a fantastic career and journey through chronic lung disease. Before we really dive into ILD and circadian rhythms and clock, and the potential effects there, let's level-set. Remind all of us what we're talking about when we use the term "circadian rhythm" or "circadian clock." What are we actually talking about?
Sundar: If you think about basic biology, people term the circadian rhythms as the natural processes that regulate the sleep-wake cycle as well as behavioral and physiologic responses in our body that are changed over every 24 hours. And it comes in a cyclical manner. So that's circadian rhythms.
But I think circadian rhythms play a very profound role in regulating a lot of things. One is the sleep-wake cycle, but apart from sleep-wake cycle, it also regulates a lot of physiologic processes and biological functions such as inflammation, body temperature, metabolism, and several other hormonal responses within our body; [all of these] are regulated in a very timed fashion.
This timing is very critical, such as when they are peaking, when they are troughing, when they have to really be present, when they have to be absent. They're very important in terms of dictating the physiologic processes that are normally functioning in our body. And we think they get dysregulated during disease. We know that these hormonal regulations — body temperature, lung function, and many other physiologic processes, like metabolism, inflammation, and immune response — all of these things get dysregulated because of imbalances in timing.
Swigris: I see. There's sort of a central, regulatory clock for our whole body, but then individual organs also have their own clocks. Is that right?
Sundar: Yes. The first study about clock and the lung was published in 2009. This 2009 study first identified the presence of these clock molecules in the bronchiolar epithelial cells of the lung, the Clara cells, which play a very important role in the airways of the lungs.
We all know that clock genes are not just present in the lung in one cell type, but rather every cell type of the lung has their own clock genes and they have their own function. And they maintain their normal homeostasis in terms of regulating their functional readouts in those cell types. Understanding clock, not just in one cell type, but in different cell types of the lung, is where we need more insight, because currently there is not much information on how these clocks are different in different cell types and how they are contributing to the overall clock function in the lung.
Swigris: So can we bring that into the discussion of ILD? I recognize that there is a limited amount of data here. But if we think about what normal clock mechanisms are at work and normal timing of different things in the lung, what is aberrant or what is abnormal, if we know, in clock mechanism, in clock genes, in ILD?
Sundar: In terms of perspective, I would like to say what I know and what we know from the literature. Not much is known in this space. But we do know some things about where we are at in terms of understanding the role of clock in ILD. Currently we know that when we say "clock dysregulation," the alteration in clock genes that over time can be either upregulated or downregulated, we know from our existing literature that these clock genes are not in sync with their normal regulation, which means they are not rhythmically seen as you see in a normal lung.
Rather, in ILD, you see an exaggerated rhythm or you see dampened rhythms at specific times of the day. It's very important that these clock genes are altered in a time-dependent manner. So we need to be very careful when we look at animal samples vs the human tissue or outcomes that are measured in human samples.
From the snapshot of what we see in animal models, we can easily time them because we can conduct studies using one time point vs another time point. So you can understand whether clock dysregulation is altering these genes on a level higher than what they are normally or lower than what they are normally. But in the disease context, it's very complex because the tissue samples are not collected all at the same time. We do know from the single-cell data from IPF and ILD [that the data are] clearly showing that not all the cell types are significantly affected in terms of clock genes or their proteins, but there are specific clock genes and proteins that are affected in specific cell types of the lung.
I would say that the type II cells of the lung, the alveolar type II (AT II) cells and the lung fibroblasts, are the predominant cell types, which are profoundly affected at the cellular clock level in these tissues. Understanding what clock is doing in these type II cells, what it's doing in the fibroblast, and how they are different in the normal lung vs diseased lung could provide us with better insight in terms of understanding about how clock genes play a very important role in regulating some specific biological processes and functions within those cell types that drive the pathobiology of ILD.
Swigris: In a minute I'm going to [address] if those genes are dysregulated, what patients might do to potentially turn those back to normal function. But first, do you think the dysregulated clock genes in the lung potentially play a role in the progression of ILD and fibrotic lung disease in particular, or do you think the dysregulation is a manifestation of the fibrosis being present?
Sundar: It's a very good question, but I think it's very complicated as to whether this comes first or that comes first. It's very easy to say that in a cellular model you can clearly perturb the cells and say that when you perturb the cells with TGF-beta, and then you look at the responses, you can say that TGF-beta–mediated epithelial-mesenchymal transition or fibroblast-myofibroblast transition is dysregulating clock function.
But in the context of a disease, there is so much complex signaling already driving this disease process — for example, inflammation, oxidative stress, extracellular matrix remodeling and things like that. They are all simultaneously happening in a complex cellular system; that makes it more complex to say whether the altered clock comes first or whether those things drive the disease and then comes the alteration of clock. I would say it goes hand in hand: Altered cellular processes drive circadian dysregulation and also contribute to the pathophysiology of these phenotypes. And I would say the other way around is true as well: If you disrupt clock and you treat them with certain agents that can activate certain signaling, then you can also perturb that to cause the disease process.
Swigris: Very complex for sure. You're more on the basic side of research. I'm much more on the clinical side. And if we're going to try to bring this line of inquiry into the clinical realm, what do you think are some important studies or steps that we need to take to improve our understanding of clock and clock genes in patients with ILD? And then we could bring that data to bear on therapeutic maneuvers. Lay out the roadmap here for us.
Sundar: Yes, definitely. It's a very complex roadmap because we are in two different phases. There are basic biologists working on one aspect of it in terms of understanding the disease process using complementary animal models and preclinical models that are very important to understand the disease process biology, and how you could intervene on this biology by using some therapeutics and stuff like that. But when we talk about patients, it's even more complex that you can do the sampling in patients so as to better understand how clock biology or biomarkers of circadian rhythms can be used as a prognostic marker or a diagnostic marker, or even a predictive marker, of ILD.
We need to see how, as basic researchers and clinicians, we can work together to have a framework of putting this into perspective to identify models that can be translationally relevant. We know that ILD is an aging-related complex chronic lung disease. So we need to use complementary aging-related animal models that resemble what you see in terms of patients with ILD.
Those models could help us understand how this disease progression is happening and the role of clock in this disease process. Can you really modulate clock function and can you better understand the disease process? Can you reverse this disease process completely? Or to what extent can you prevent the disease process?
On the other side of it, when you look at the patient perspective, I still feel like we should be thinking about coming up with some realistic timelines to see how we could do sampling at at least one or two time points, at a specific time of the day, and try to look at the circulatory biomarkers that are relevant clock biomarkers to see if we can learn anything from these diseases as they are progressing. Initially, where are these biomarkers expressed and how are they different as the disease progresses? And at a later stage, how are these disease markers the same or are they changing over time?
I think those kinds of understandings will give us better insight in terms of whether these clock markers drive this disease or whether they are just a consequence of the disease that we already see. I think these understandings will really help us in terms of moving this to the next level to bring our understanding both from the clinical perspective as well as from the basic science perspective, to put together how we could develop novel therapeutics.
I don't think a single drug would be a way to solve this complex disease. Potentially we need to think about complex multidrug therapies. In a way, a clock modulator combined with a fibrotic drug could be a potential way to look at it. We need to start thinking about this because clock modulators are profound in regulating specific biological processes and functions. When you combine these two things, maybe it could have better efficacy in providing long-term, beneficial health effects in terms of reducing their mortality rates, and then life expectancy will be further increased by using these kinds of approaches as we take it forward.
Swigris: Absolutely. And I think most clinical experts in the ILD field would agree with the statement that the complexity of fibrosing ILD is going to necessitate multiple drugs in combination, inhibiting multiple different pathways. Up to this point, I don't think many people have thought about altering clock and medications that might alter clock genes. So that just opens up another avenue, certainly worth pursuing. I'm sure you would agree with that. Does the circadian clock wane as we age? Do we know that?
Sundar: Yes. There are some studies, from preclinical models at least, that have clearly shown that over time, the rhythmic expression of these genes is getting blunted. That implies that as we age, our clock is also aging in some way in terms of affecting functions and outcomes. So potentially that will have a direct role in these age-related lung diseases.
Swigris: If we looked at the general population, if clock is dysregulated, you mentioned sleep and hormonal manipulations, and exercise; are there things that we know that we can do in terms of lifestyle modifications that will turn a dysregulated clock mechanism into a regulated clock?
Sundar: That's a very interesting question. At least from the preclinical model perspective, I think the literature supports that if we can do things like exercise endurance, if you perform some kind of regulated feeding regimen and then fasting, feeding, and trying to have a time to administration of drugs given in animal models, that has been shown to have a very profound role in regulating those processes. So I still do feel like having a very good sleep-wake cycle and then having a very good exercise pattern tailored to the needs of the patients, depending on their illness, might be a potential way to look at how they could regularly have a schedule of sleep-wake, and then regularly exercise and also diet.
We all agree that food is our medicine. So I think even having a proper diet that is balanced, tailored to the needs of the patients and their health status, will also really have a profound role in regulating the normal function of the circadian rhythms in our body that will also influence the progression of disease in terms of slowing the progression of disease. And that will enhance the cellular functions that drive the protective response in our body to mediate protection against those chronic inflammatory lung diseases.
Swigris: Well, I'm a big proponent of time-restricted eating. And I know that there are various definitions of that. As a clinical researcher who knows very little about nutrition science or the effects of time-restricted eating or feeding, it just makes sense to me that putting what I term "metabolic stress" on fibroblasts, these sick cells in fibrosing ILD, fasting puts some sort of stress on those cells that, again, in my naive view, they don't like. And it just seems like it would be something potentially beneficial for patients with lung fibrosis.
You mentioned diet. Are there foods that we know are better for clock regulation or types of diets that we know are bad for clock regulation?
Sundar: If you think about the [foods] which are good in terms of maintaining the regular sleep-wake cycle, the foods that give you a good hormonal balance, those foods that really make you go to sleep at the right time, not like caffeine, not like having alcohol during the night — those kind of things will affect your hormones that have to peak and trough at specific times of the day so as to regulate your sleep-wake cycle.
If we have a very good lifestyle in terms of having good fibers, good vegetables, good fruits, and then those foods which are rich in antioxidants, we already know that they help us in terms of regulating our normal sleep-wake behavior. So I think integrating those forms of food into our regular practice would really help us in terms of having the regulation of sleep-wake, and that could profoundly influence all the processes that are regulated by our circadian rhythms and outcomes.
Swigris: Before we wrap up, I want you to just get really theoretical and hypothetical for us. Just based on your gut. And I want to remind listeners that this is not based on absolute human science or phase 3 randomized placebo-controlled trials or anything. But what does your gut tell you about what patients with lung fibrosis ought to be doing in terms of their lifestyles to best regulate their circadian clock?
Sundar: As you cautioned, it's definitely not fully validated science that we are talking about here, but potentially it will have a profound role in terms of their overall health and well-being. I still feel like if they have good sleeping habits and then a regulated time of physical activity, when it is needed, not like every day, every time, but rather tailored to the needs of the patients, [that helps]. And then the exposure of light is very important in terms of entraining our body to that physical environment. I think maintaining the daily routine over time is equally important. That ultimately will have a very good impact on well-being. And that's not just for the patients; people like us who would like to have a very healthy lifestyle also should practice these things. I think they will definitely have a profound role in regulating the circadian rhythm.
Swigris: Outstanding. Does it make sense that drugs, whether for lung fibrosis or any other condition, should work better or should be administered at certain times? Do we know about that?
Sundar: We know that from the point of COPD and asthma, specific administration of corticosteroids or bronchodilators at specific times of the day has a more profound influence in regulating those exacerbations as well as the inflammatory outcomes that we see in patients.
Potentially, not all drugs are going to work effectively when given at any time. We need to learn from the existing literature from chronic lung disease, where there are studies specifically tailored to the needs of patients and given at specific times of the day, in terms of intervention and what they learned from that.
If we take those lessons, if we can try to implement something in our ongoing studies and future clinical trials about administering the existing drugs that are used for the treatment of ILD, I think we could learn whether these are the ways to go in terms of giving the drug at specific times, when it is needed to regulate those processes that are robustly regulated in our body. It could have a profound role in controlling those processes, thereby having a protective response.
Swigris: Absolutely fascinating. We have talked to Dr Isaac Sundar, who educated us all about the topic of circadian rhythms and the circadian clock and its vital role in regulating the sleep-wake cycle, hormonal balance, nutrition, and so forth. He reminded us that we have so much more to learn with respect to the role of the circadian clock in fibrosing ILD.
He talked to us about a roadmap for the future in terms of research and how we might begin to think about and integrate either medications or lifestyle modifications that could potentially regulate a dysregulated clock in fibrosing ILD. Many more questions than answered, but a fascinating topic nonetheless. Isaac, thank you so much for joining us. It was a real pleasure having you here today.
Sundar: Thank you very much for having me here. I'm happy to share my ideas.
Swigris: And thank you all for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on IPF. This is Dr Jeff Swigris for Medscape InDiscussion.
Listen to additional seasons of this podcast.
Resources
Idiopathic Pulmonary Fibrosis (IPF)
Circadian Clock-Based Therapeutics in Chronic Pulmonary Diseases
Interstitial Lung Disease: Pathophysiology and Genetic Predisposition
Circadian Timing in the Lung; A Specific Role for Bronchiolar Epithelial Cells
Medscape © 2024 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: Understanding the Role of Circadian Rhythms in Idiopathic Pulmonary Fibrosis - Medscape - Jul 23, 2024.
Comments