My name is Steve Simpson. I'm your moderator, as it were, for this session, which is the Murray Kornfeld Memorial Founders Lecture. Murray Kornfeld, of course, is the founder of CHEST. He was not a doctor. He was an educator who perceived a need. And what he did was found the Federation of American Sanatoria, as you're probably all aware. CHEST was originally a TB organization, much like the American Lung Association and the American Thoracic Society were once TB organizations. That organization gradually became the American College of CHEST Physicians and then CHEST as we know it today. This particular award is conferred to a leader in pulmonary and critical care medicine, particularly in both infection and inflammation, whose developing therapies expected to guide medicine into the future, and that's what this talk is about. This year, it's my pleasure to present this award to Marilyn Glassberg. Dr. Glassberg is currently a tenured professor of medicine, as well as the John W. Clark Chair of Medicine at Loyola Stritch School of Medicine in Chicago, or Maywood. She specializes in pulmonology, as well as interstitial and rare lung diseases, and has done for over 20 years. Her research has focused on the pivotal role of inflammation and the onset and progression of chronic interstitial lung disease and the effects of mesenchymal stem cells and exosomes, sex hormones, and aging in the process. Within CHEST, she's been extremely involved in the Women in CHEST Medicine Group and is a member of the Diversity Inclusion Roundtable and the Women's Lung Health Network. She's been interested, as I am, in having more women in the specialty and promoting the women that are in this specialty for a long time. Dr. Glassberg has participated in many CHEST presentations that have educated many others on a whole lot of topics, including the one I just mentioned. She is quoted as saying that the CHEST annual meeting has continued to provide one of the most important and prominent events for women in the field for almost 30 years. Today, we honor Dr. Glassberg for her outstanding work and her dedication to CHEST. Please join me in welcoming Dr. Marilyn Glassberg to present the Murray Kornfeld Memorial Founders Lecture. Thank you. Thanks, everybody. I want to thank the CHEST Foundation and CHEST and Steve for many years of support. If I can tell a little anecdote, when I was at the University of Miami, I remember you inviting me to talk about lymphangial myelomatosis, and Joel Moss is in the audience. So way back when, when we were just starting to try to understand that disease, you recognized what we were trying to do, and I still remember that. So today, we're going to talk about inflammation. This is actually a part that references my road. There are many people in the audience from my time in Arizona that I'm very grateful for. I see you. And this is a scene you know, a very long highway in Arizona. And I think what we're going to see is that actually inflammation has shared highways, but they go to a similar destination. And when I would drive from Phoenix to Tucson, I would always say, when am I ever going to get there? And I would get there. There was a shared destination. I took this very long road. And on the right side, I show you the lung, and a lung that we worked on during COVID in Arizona to try to understand more about the role of inflammation and vasculature in producing interstitial lung disease. And so that's a cast from a paper we published in European Respiratory Journal with an algorithm to really look at the role, and further, we're continuing to look at the role of neanderthalium. So this is me. These are the objectives that you have. So we're going to talk lots about inflammation. And so when we think about inflammatory diseases in the lung, and we talk about sort of a generic approach to this, we really focus on T cells, B cells, but more importantly now, we recognize the role of the epithelium in the center of the slide as really interacting with these cells and leading to a lot of messages that are occurring downstream in terms of producing the inflammation. And if we tie that then sort of into the lung itself, we also know that there are lots of other cells that are residual cells that actually play a role in the inflammation. So we're drawn to the fibroblasts. We're drawn to, as I mentioned, the epithelium, but also the myofibroblasts and the conversion of the fibroblasts to the myofibroblasts, all contributing to this inflammatory cascade. So Peter Barnes, many years ago, tried to look at the inflammatory populations of different patients, both in the histology and the inflammatory patterns by comparing patients in asthma versus patients with COPD and those that had exacerbations. And what you can see by looking at this is that the asthmatics and the COPD all have inflammatory cells, but you can see the two columns aren't the same. And if you focus often on the, this is, look at the epithelium and the asthmatic, that's a shed epithelium versus a pseudostratified in the COPD. So what does that mean? If you look through the chart, these architectural changes are playing a big role in what happens in the inflammation. And then if you look to the right side of the slide with the inflammatory patterns, you once again compare the asthma and the COPD columns, and you can see really that there are differences. So there are some of the same cells interacting, but their roles are different. So what about the pathology? Certainly we see tons of inflammation in both of these. This is a patient with, who died from asthma on the left and on the right, severe COPD. We can talk about smooth muscle hypertrophy, hyperplasia. We can talk about changes in the basement membrane, the development of subepithelial fibrosis and alveolar disruption, but you can see the two pictures don't look alike, and yet they have some of the same players. So why the differences make a difference? The nature and the sites of the inflammation differ between asthma and COPD, resulting in different pathology, clinical manifestations, therapies, and indeed response to therapy. We treat them sometimes with overlapping therapies because we're addressing the inflammation. There are multiple phenotypes that behave differently, and we've grown to recognize those. We know that the signature cells of the COPD exacerbation are neutrophils versus those of more severe asthma are actually the eosinophils. So there's some regulation of which cell comes to do the damage, right? And environmental and genetic triggers certainly are known to promote lung inflammation, including smoke exposure and allergy. But we give them anti-inflammatory treatments, and we know that we get a variable response. Sometimes it's pretty good, right? And some of those certainly in severe asthmatics when we treat them. But we also know we've gone through how many different versions of how we treat COPD exacerbations, and how much should we give them, and what should we do? So we recognize that we have a variable clinical response. In a very recent paper from GONAN that I encourage you all to look at, this is a pulmonary inflammation paper addressing various diseases. It's absolutely beautifully written and develops a lot of the thoughts very well. It's only a couple of weeks old. You can see that the different cell types are up at the top, and then we talk about these interactions. So let's look at this. So I don't think you can see the cursor, but I think this one will. No, it doesn't. Oh yeah, you can see it. So if you focus on the middle here and recognize all the players that you've known are being worked on in terms of antagonizing, drug antagonizing effects. So you have TGF-beta, some of the immune drugs, the VEGFs, looking at the role of the interleukins, the interferon gamma, the CCL25s. You can see that there are all these players that are potentially targets for us to treat these diseases. Well, that's a lot, right? And so determining who interacts with who first, and recognizing these players before the patient actually presents, being able to get some markers before they present would be key. Because when they present, this whole cascade is already going on. So then we're talking about, okay, how many drugs are we gonna give this patient? This is like oncology, right? We're gonna have to tackle so many different parts of the system here. In this one, then, in this figure, he compares the healthy lung tissue to acute inflammation and chronic remodeling. Let's look at this. So if you just look across at the airway, you can see that we know there are different cell types involved in here that certainly are involved, like when we talk about asthma with the goblet cells, but you see how they're changing in where they're sitting, right? Where they're sitting within the epithelium. And then with certainly within the remodeled tissue. Understanding what happens between this phase and that phase will be key. You can also see underneath with the extracellular matrix that there's this conversion to the myofibroblasts that are happening pretty early that's leading to what I'm going to then talk about, which is the fibrotic lung diseases. This is the unknown, right, that we're beginning to understand. There are several labs working on this. Nuncia Caporello and my group just published a paper in Nature that tries to describe the endothelium and understanding what factors the endothelium is making that then is triggering up here, as well as attacking these inflammatory cells. What's left with then is what you're seeing is changes within the architecture, and then as we'll approach it now in the IPF alveolus, we recognize serious changes, right, that appear to be irreversible. Now, for all of us that look at these CT scans, we can't argue that we see inflammation all the time, right? So these are always fun with the ground glass opacities and acute exacerbation of IPF, and certainly we see it in the upper lung and the lower lung, and these are patients with baseline IPF that is fairly significant, right? These aren't early patients. So these are patients that are already coming in, they're dry coughed, they may have a productive cough because they've got sputum. They have ongoing inflammation. So when they get sick, they get really inflamed. So the kitchen sink approach has been used for this, right, where we give them IV steroids, we give them the drugs, we do whatever we can to try to take care of this with the idea that it's a number line, right, that you're gonna progress from the inflammatory state to this honeycombing state, and we can't fix you. So the anti-inflammatory treatments were deemed ineffective in a very seminal trial, the PANTHER trial many years ago. A little information came from the azathioprine that was added in that trial that maybe we were helping with infection, but we certainly weren't reversing this problem. And then what about other anti-inflammatory treatments? So more recently, the STRIVE trial being done out of Alabama, an NIH-sponsored trial, addresses the use of rituximab and plasmapheresis. They've enrolled patients at about seven sites now with acute exacerbations and really have some very interesting data, hard to enroll because of COVID. So we all have to be patient while they complete the enrollment. So what have been the attacks? If we switch over now completely to fibrosis, we talk about where have we attacked, what have we tried? Well, we've worked on the fibrocyte monocyte recruitment, we've worked on angiogenesis and growth factors. I think Dave Zistman is in here, where we fooled around with Sedanofil, tried to look at walk tests, figure out what went on there to see if we could get a patient-reported outcome that would make a difference. We've dealt with reactive oxygen species and oxidative stress, also a little bit with NAD, and intercellular signaling, CTGF. This is now a recently failed trial where we tried to antagonize connective tissue growth factor, it didn't work. Took almost 15 years to prove that one. And then more on the TGF-beta pathway, and we're gonna see more. I'm gonna talk about the LPA antagonist, as I think that's an interesting approach. And then fibroblast activation, epithelial activation, T-cell and cytokine production, and B-cell activation. What I think is most important about this chart is if I talk to you about some of these drugs, lapruzumab or PAR antagonists, you're not necessarily gonna be thinking about epithelial activation. So one of the benefits of all these trials in IPF has been that we have learned a lot about the disease. From the drugs, right? We designated them as antifibrotics, but we've seen certainly with nitetinib and profenadone that these drugs have other effects. We need to better understand the inflammatory effect, but the downside is on the clinical trials, we haven't looked. So now we're beginning to look at imaging, and trying to look earlier on using some of these algorithms with artificial intelligence to be able to see how early can we actually see these changes? And can then we get biobanking to go with our imaging to understand what early disease really is? Because I think for all of us, treating chronic fibrotic lung disease is not gonna be the solution. The solution is trying to identify it earlier. So one of the other diagrams in this paper that's particularly interesting is talking about other aspects of these drugs after this chart, is that they also turn out to do something very interesting, which is to destabilize the extracellular matrix. That's a problem, right? Because we need to stabilize the matrix and rebuild it. But we also recognize that they're inducing apoptosis, inducing cellular senescence, targeting intercellular signaling. People have now started to talk about using CAR-T cell therapy here to produce repair, and inhibiting growth factors. That we know, right? And whether we agree which growth factors might be inhibited doesn't really matter. The point is that they do antagonize certainly some of the key players. TGF-beta, PDGF, VEGF, FGF. They're certainly doing that. And then importantly, they're also working on the signaling. So yesterday I talked about lymphangial lymimotosis, and I talked about patients that are being treated with mTOR inhibitors, but also about ones that have AKT problems. So this pathway with the P38 is really one you're gonna see and continue to explore. So let's talk about LPA, because I think this is an interesting target. Bristol-Myers Squibb has sort of led the direction on this with two recent phase two trials that have been positive. And why LPA? What do we know about LPA? We know that the levels increase in lung injury and activating the receptor promotes the fibrosis. So if we can block it, right, then we might certainly, we did show clinical benefit, but if we block it, then we're stopping this whole vascular leak. We're stopping the fibroblast proliferation. So we have a drug that's working a little bit differently, right, within the system. So we wanna modify the fibroblast behavior. And as this is a group at Mass General, they talk about plugging the vascular leak. That maybe what's going on here is really, the inflammation is being triggered at the level of vasculature, and that's starting the process. I don't know that this drug alone will do the job, but we can imagine with using what we know from nitetinib or profenadone plus using LPA, right, that we might be able to do some cool things here in terms of stopping fibroblast turnover and stopping this leak. I draw your attention also to this other paper that I mentioned before from NUNCIA, which I think is a really good profile that she just, this paper's Amgen Respiratory Solomio. She also has a paper in Nature. And I think her work in the endothelium is very, very challenging. You know, it's hard to do. It's like, what cells are you actually studying? How is that working? But combined with imaging, I think it's going to be very beneficial. So let's look overall at IPF. This is an old diagram, right, but it really sort of says the whole story that this blood vessel problem here and what the leak might be is affecting a bunch of stuff in the interstitium and leading to changes in the epithelium in the alveolar space. Where we stop this cassade, I think becomes the most important thing. And as I've mentioned, I think we have to go back here because if we can develop factors that we can identify in patients as biomarkers or plus or minus imaging, then we would stop the entire process and then potentially think about being able to remodel the airway. So just to draw attention a little bit to COVID-19, it wasn't ignored that COVID-19 actually, there were some therapies that targeted neutrophils that could be important. I just show you some of the drugs that were tried in COVID-19 early on. This was when these patients were coming in where they had myocardial infarctions, they had embolisms and we were all going, what's that all about? Why is that happening? It turns out that really there was a big vascular leak, right, and plugging that vascular leak was important. But it's tied into the neutrophil in these drugs that were tried, much like some of the therapies that have been tried in terms of looking at COPD. So the recovery trial, as everybody knows, demonstrated an anti-inflammatory benefit in non-intubated patients so that we could, when we were talking about neutrophils, use steroids, right, and use them effectively. So what's the problem? The problem is the need for definitive predictive biomarkers for identification and characterization of clinical course for any lung disease, right? Wouldn't that be great? The need to be able to predict when somebody's gonna get worse, as well as when they're gonna get better. When the patient says to you, what's gonna happen to me, doctor, right? For all of us that take care of these interstitial lung disease patients, it's terrible. What do you say? I don't know. You don't know what the course is gonna be. And then finally, the need to know the precursor to the anti-inflammatory cascade. By the time we see them clinically, I think it's too late. And so how do we attack this by trying to see it earlier? So we've been interested for many years. This started back in work at the University of Miami, and Tanira's here and probably remembers me doing this, working on mesenchymal stem cells, and now more recently on exosomes, which are contained in mesenchymal stem cells. Why bother with an MSC? So MSCs block inflammation really well. So they come from your bone marrow. They're not hematopoietic cells. They're mesenchymal cells. They lack MHC class two. So they're not seen by the body as foreign. Very good for patients who, you don't wanna immunosuppress them. You wanna give them some therapy where they can tolerate it. They won't get infections. It's not even worse, like their five-year survival at best, right, with IPF. So this looks very promising, and we went back, this was in the mid-2000s, starting to work on this, and more importantly, in animal models, which we all know don't always necessarily happen what in human, they induce repair. So here's the MSC, and now the product of that, the contents inside that MSC is an exosome carrying all kinds of things that really do block inflammation and induce repair. More importantly, what they do is they change this M2 polarization of macrophages, from M1 to M2, which is promoting anti-inflammation. So we know that there's important contents in these things that allow this shift to occur. They do carry pro-inflammatory factors. So when the exosomes are packaged in our body, they're packaged with pro-inflammatory, anti-inflammatory, pro-fibrotic, anti-fibrotic, and so the challenge has been now sort of, if you think about it, to make a designer exosome, right? That has the contents to be given to patients to discharge basically what they need through IV infusions and correct it. So we aren't at the patient point yet, folks. We're still in animals, and I'm gonna show you some of the animal data. But this M2 macrophage, keep your eye on it. It's a very important mediator in inflammation in several diseases noted here. So it also has a very intricate role in innate and adaptive immunity as diagrammed here. You're noticing some overlaps in the figures, some of the same players that are listed when I talk about inflammation are clearly listed here. And you notice the MSC is sort of positioned in the middle, ready to attack on all levels. But think of the MSC on the left-hand side, just of all of its functions and what it can do to really be able to essentially stop inflammation and promote repair. So this is the trial we published in 2017, the ETHER trial. We had a very small trial. This is a safety trial, 11 patients. You can see how they were separated out. And basically gave three cohorts different dosages of mesenchymal stem cells, modeled this a lot based on cardiovascular trials. So two million, one million, 200 million. And completed follow-up were seven. You can see how they did. And this cohort three was problematic because the longer they stayed within the study, the more advanced their disease got. So we know IPF patients are not very stable, like they're always sort of smoldering. This group, two of them actually developed pulmonary hypertension. So the data I'm gonna show you is based on the first two cohorts, if it moves forward. There we go. And this shows you the percent-predicted FEC, the percent-predicted DLCO, and the six-minute walk test distance. So it's a 60-week trial. They got one infusion at the beginning here. And this shows you the overall between these cohorts. You can see they had stabilization of their FEC, stabilization of their DLCO. And their six-minute walk test, though, had these dips, which has led us to investigate what was going on with these groups of patients. And it's very hard, because there were very few patients. So we've done things like look at quantitative lung fibrosis, and try to map out what was going on in those lungs. And you can see here that the fibrosis score, which is the blue and the red little squares here, and the ground glass, which is the yellow. And what you can see as you go through these, as these patients were treated, that they're still having quite a bit of inflammation. And when you quantitated this, which I'll show you in the next slide, you can see here this is cohort one, and this is cohort two, right? Cohort one did much better. But the individual changes were different. And maybe what this suggests is that giving one dose wouldn't work, right? That if we wanted to sustain something longer, we would have to treat them more. And what we ended up doing with this was then asking what were these cells actually doing? What were the contents? So in that trial, the donors of the stem cells were from their bone marrow. They were age 18 to 26, young males. Most of them were either medical students or lab techs, healthy, no other diseases. And they donated their bone marrow. They were paid to donate their bone marrow. But they were considered young MSCs because they were younger than 26. When we did these experiments though, and we used old mice. So if you use a mouse that's like 18 months old, that's like a 77ish year old, you may go down to a 14 month old mouse and you get some mouse that's like in his late 60s, and they're male mice. We're trying to mimic the human disease. So what you're looking at is data from these male mice. And we asked a couple of questions, like what would happen if we gave old MSCs, right? What would happen to them in terms, and this is the bleomycin model that everybody loves, and can we make them young again, right? Could we change them by giving them young cells versus old cells? And would that help us then in designing a new trial when we didn't want to just give one infusion, we would want to give more? And indeed it did. These are real pretty H&E pictures with some serious red thrown in there. But if you look down here in B and C, you can see the collagen content. Here's what's going on here, is that we're able to bring down the collagen, right? And bring down the TNF, and basically say that the old cells by themselves were triggering fibrosis. So we did the right thing using young cells, but then we needed to understand what was in the old cells. We used a skin model then to be able to quantitate what would happen if you gave old cells versus young cells. This is old. If you activate, so you make them younger, this is caspase. You can see that the wound heals. Here it doesn't, here it doesn't, and here it has a different one. These are the control old cells. So to promote the healing, you really have to change what the old cell is doing. So you have patients that go to these stem cell clinics. They go and they get their own cells, right? They get these autologous infusions in these clinics. You might say, why? If I show you this kind of data, you would think that the old cells are probably making them worse. Remember that we don't have a full phase two or phase three in this, so these stem cell clinics are operating. I've written a lot about this. It's a pretty dangerous space when we don't have any data. So a decrease in oxidative stress is shown to you with this activator. Modifies catalase. We used CRISPR-activated plasmids in the old MSCs to enhance the therapeutic efficacy. So if you ask, can you make them young again? Yes, you actually can in the sense that you reverse the activity that's been against what the process is, which is the catalase. So these are some more studies to look now at getting, can we get exosomes that are from humans that are fibrotic and put them in the same model? And will they act like old MSCs or old exosomes? And indeed they will. If you focus on the last one here, this is the, these are ones that are non-fibrotic exosomes. You can see the lung looks pretty good, but here are ones that are from the old ones. You can see it's much more fibrotic. Here's some with control exosomes from younger patients that don't have any other disease, but they're controlled exosomes. This is now not the whole cell, but the exosome. And then you can see the baseline is the bleomycin. So very interesting is if you can re-engineer the exosome, you can re-engineer the pathology. This is mice, not human. And these are just the standard scores for Ashcroft, for fibrosis, collagen content, and then looking at some other microRNA parameters. So then you say, well, do I have to draw blood from patients? Do I have to do bronchial alveolar lavage from patients, or can I just look at their urine? Is it a systemic disease? And indeed, it is. So urine and serum fibrotic exosomes carry the same fibrotic signature. I can show you some of them here. You can see the Let7D, the microRNA29A, 199A, miR8, miR192. And these are really interesting because you can see the differences in the levels between control, which are non-fibrotic males, and then the IPF patients. And across the board, there are differences in the urine exosomes that are obtained from these patients that map out and mirror the blood. So urine and serum exosomes derived from the same individuals with the same fibrotic lung disease express similar microRNA profiles, and we've patented now these divine exosomal signatures. Can you use the normals to treat the fibrotic patient? And I guess that's the next question we have to address. You can in mice. We have to do it in man. So we wanted to know, we went back to the ETHER trial. We had samples that we had banked at Miami, and we asked the question if the changes in the microRNA signature pre and post nine months infusion in those subjects. So you remember it was 60 weeks. We took those two time points. We measured to see if there were differences. And the idea that when they were treated, could we explore in a small group of patients whether or not they had any quote unquote repair or differences, and yes they did. So these are just some of those highlighted for you. And I wanted to also highlight some of the inflammatory ones that you can see, like the cell adhesion and leukocyte activation are also different. They don't reach statistical significance, but they're going in the right direction. So in Nonan's paper, he does a beautiful job of summarizing the therapeutics that are targeting lung fibroblasts and acute and chronic pulmonary disorders and relates them to inflammation. So in IPF in the past, we looked at immunosuppressive agents, corticosteroids, azathioprine, cyclophosphamide. We know we failed there. In the present, we have the two approved fibrotic agents, and then of course lung transplant. We know that there's an entity in lung transplant called bronchiolitis obliterans syndrome, right, BAS and RAS, that are very similar to a fibrotic process. So we're thinking about what happens with lung transplant rejection. Is that a parallel to the fibrotic pathway? And then certainly under evaluation, this is quite a long laundry list, right? Some have failed since this paper was published, but the CTGF has failed. The galactins have failed. I don't know if they're on this one. Yes, the ototaxin failed. Heat shock proteins, unfolded protein responses. We're trying everything to figure out where in that complicated pathway we can intervene. In ARDS, we've looked at surfactants, statins, and interferon-beta-1-alpha, immunosuppressive agents, and then look at the cascade now of where we're looking in terms of even signal transduction inhibitors and MSCs. There were several trials that have been done now with patients in ARDS headed up by Mike Mathay, and then certainly in COVID, several different groups published on using MSCs to address the ARDS or the acute inflammation in viral infections. And then finally in asthma, we're still sort of using this same kind of approach, right, but we're modifying it because we're tailoring our treatment to the inflammatory population of those diseases, right? We all look for eosinophilic asthma, right? We write for treatments for those patients. We're starting to understand that it's not just one group and that we can tailor our therapies. And then lastly, look at what's going on here. We're even looking at aldehyde species inhibitors. We're looking at inflammasome inhibitors. This is a really booming field to try to understand the isolation characterization of inflammasomes with exosomes to try to understand how those two parallel each other. So in summary then, I think there are shared inflammatory highways for acute and chronic lung disease. The earlier identification of the initiating markers will lead to disease-altering therapies, but we have to get better at figuring out how to find them. Understanding these pathways in other organs will enhance our approachments to treatment of lung disease. And right now, we're really approaching multi-drug therapies certainly in pulmonary fibrosis. We're recognizing that it's not gonna be a one-drug day. It's gonna be a multi-drug approach or some type of mix of therapies and maybe staggered also. But they're needed because our problem as clinician is the late identification. By the time that patient presents to us, that disease is already on a roll, right? And we can't intervene. MSCs and exosomes and their contents I think hold promising anti-inflammatory therapies. But the problem is the applications are limited really due to a lack of trials and getting them funded because you have to do trials like the pharmaceutical industry does with large groups of patients. You have to do 60-week trials, right? We're trying to look at shorter trials and we're getting burnt, right? These latest trials that have failed in IPF were 26 weeks. It's not long enough for us to be able to measure what it is. So we wanna save money, but we're not getting the efficacy that we need. And there are no shortcuts, right? To developing safe and effective therapies. I think the FDA is right in a lot of ways. I was just in a meeting there a few months ago in really addressing rigorous therapies but allowing us to do multiple trials at the same time maybe with the same drug using different approaches to how it's given even if we use an aerosolized approach and an IV approach but allow us to be testing things at multiple times instead of waiting for one trial to give us an answer before we go to another. We need to speed it up. You know, the world, if you think about pulmonary fibrosis, it's, you know, we started at the end of the 90s and we're not where we need to be yet. We're certainly a lot further thanks to, you know, the definitive trials that we did. But there's much more to do. So I'll stop and be happy to take your questions. Questions? Yes. Has anyone looked at the impact of omega-3 fatty acids on this inflammatory process? The reason I ask is because there's some data in the neurologic literature that showed a clinical, significant improvement in some chronic neurologic diseases with high-dose omega-3s. And I haven't heard anything about it at these meetings with respect to our organ system. So I can tell you people give them, but there's no randomized controlled trials. So that's where our problem is. There's a lot of stuff. There's some interest in vitamin D, right? We don't have a trial. So part of it is doing the rigorous trial to make the answer, but it's been looked at. You know, the role of diet and environment. The last paper that I think looked at environment and IPF was probably in the 80s. And it wasn't even IPF then. So we don't have answers for it. Isn't it time for some kind of... There's a lot to do. Trials that are less expensive and maybe easier to do. Well, maybe not, though, so easy to do. Think about how you have to enroll that and what you have to control for when you're giving somebody that, right? Those are design problems. I mean, we all work on them. But design and making sure that patients are compliant in these trials is very difficult to do. Yes, Dr. Zisman. Thanks, Marilyn, for an outstanding talk. And congratulations on your well-deserved award. You know, as you well know, since Moises Selman came up with that paradigm of, you know, and I'm not saying, it's probably right in some respects is that there is epithelial cell damage and that there's communication between the epithelial cells and the fibroblasts. That he proposes bypasses really all the inflammation and that is maybe why we've not been successful at treating IPF with anti-inflammatory therapies. But, you know, it's hard to imagine really that there can be scarring without inflammation. So, you know, I still think that there's got to be inflammation. There's certainly inflammation in acute exacerbations and whatnot. Do you think that that model maybe applies to a later stage and perhaps we're just not capable of? Absolutely. Recognizing early disease? I'm in the camp. You know, we have like splitters, whatever else. I'm in the camp that I just don't a lot of times see the inflammation. But for my ICU colleagues that get these patients that come in immediately with the acute exacerbation, I think they would all tell you that that certainly, we're not arguing about that one. That's inflammation. I think for these patients that we see clinically that are sort of smoldering along, that they have chronic inflammation. But I think because they have so much architectural change fairly early on that we haven't picked up when that starts, that when we try to come in like in the Panther trial with the anti-inflammatory, we failed. Because it's like the ship sailed, right? It's gone on. But I think it's going to be interesting what we get from the rituximab plasmapheresis trial. That could give us some markers that maybe we can go back and look earlier and see what happened to that group because they're all IPF patients. And see if we can maybe, because they're doing a lot of biobanking on the trial, we can maybe look and see. It may also be too late, but there are a group of those patients that have sort of like, they're early exacerbators. So they aren't people that have had frequent necessarily exacerbations. There are not a lot of them though in the trial. So you're going to have a numbers problem. Yes, thank you. Or maybe looking at the familial group perhaps and the relatives that may have. Maybe. Subclinical disease. If we can figure out what to look at, right? I think the problem is that the animal studies don't give us necessarily the markers that we need for the human studies. So we're trying to do some more profiling of IPF exosomes to try to look at some more sequencing things to see what we can find. Thank you so much. Yep. Dr. Ferreira. As usual, brilliant lecture. Congratulations. Thank you. Can you comment on NAD and if there's a role to using in conjunction with antifibrotic therapy? So, you know, it's been looked at the acetylcysteine was looked at in the trial, right? And there's, I think, a group of pulmonologists who would probably tell you, David's nodding, that we think that there may be a role, right, that you could use those. The sort of attacking the oxidants. There's certainly plenty of oxidative injury in these lungs. There's no question. And we can look at a variety of these reactive species. You know, we got all these little kits now we can play with, and there's tons of them. We have not been treating patients with that because of the trial published in the New England Journal. So we don't give them acetylcysteine. As I say, I think there's a group that still believes that there's probably a subgroup that would respond, but we don't use it. Yes, Dirk. How are you? Hey, Madeline Dirk. Good. Great, great talk. I had a question on trials. Most of our trials that we see, they focus on fibrosis and not on inflammation. How would you design future trials showing that compounds have also anti-inflammatory effects and not only anti-fibrotic effects? So, you know, some of, when I showed you that little chart, right, that's all come post facto, right? That's stuff that people went back and looked. You know, we've become very interested in the imaging end of it, right? Trying to look at patients, like, early on in the clinics when they enroll, using, you know, very cool algorithms to get down, further down. Like, what, how much can you get out of that CT scan? And I think that might, with, we draw samples at those different times, but really design trials to go out and get those earlier patients. But do the imaging and the markers together? Then we might be able to get some kind of composite because we know from all of our trials, right, and you've been involved in all of them, I think it's too late, right? And so what we're looking at, even though we're getting some data now that shows us all these, you know, factors, the cytokines and all that, we don't know where we are in the cascade of their disease. So we have to have some way to stage them. Like, how much impingement of the vasculature is there at this point and stage them and define them so that we actually know who we're studying? Because we've come so long, I mean, certainly in a lot, thanks to Boehinger and Genentech, too, right, is that we understand so much more about the disease because of the natural history from the control group, right? I mean, we would have not even ever been having these conversations if we hadn't had all of our flunky trials. You know, I think our problem now with the failed trials is our design. It's not because we aren't necessarily looking for the right kind of patients, but I think we have to pair a different way to find the marker, I think. Uh-huh. Yes. Hi. Good morning. Good morning. Hi, Dr. Osberg. It's nice to meet you earlier. But I had a question. My name is Cindy from Upstate Medical University. Yes. So for your trial, and you're looking at the biomarkers, how would you target which patient populations to be able to evaluate these biomarkers for? Would it be those who had a genetic component for IPF? And if so, would you start treatment earlier with these patients? I was wondering for, I know I'm like thinking probably so far in the future. It's a great question. I don't think we're there yet, though. You're ahead of us. Because we need to know which biomarker would actually be impactful with the treatment. Right. And we don't know that yet. Right. But like, would you be looking into the MSC, like exosome as a biomarker in patients with a genetic component to IPF? Like let's say a father who had IPF, would I test the son for MSC exosomal and then start treatment earlier? It's a really good idea. So what we're doing now, it's a very good idea. You're very smart. So profiling MSC exosomes in families, right, and looking at familial fibrosis, which you mentioned. It may be a very beneficial way. What we're trying to do now is do large populations of IPF patients. We've done about 200 of them. So that's how that signature thing came about, is that those seem to be the most reproducible, repeatable microRNAs. I think it's interesting, though, to think about being able to both treat with them as well as diagnose. And that's something in the pipeline to do, which will be really critical. Yeah, just a food for thought. Because as you said, people who are presenting with symptoms, it's already too late. So I'm wondering, how do we get to them before they come to us with their symptoms? Yeah, the other population to think about with this would be the autoimmune lung disease population, right? The patients with rheumatoid arthritis, who develops lung disease, who doesn't develop lung disease? Yeah. We don't have any clues. Ah, this may provide the clue, right? Is that if we could find that specific signature. So we're working now with the rheumatologist, and scleroderma, right? We know something about the autoantibodies, right? The immunoprofile of the scleroderma patient. But can we come up with more predictive indexes for them? Because as we develop treatments that would work earlier, it would be important to be able to identify those people to treat them earlier. Right. Yeah. Thank you so much. Sure. Thank you. It's a great, great comment. Anybody else? Okay, Steve.

inflammation

lung diseases

interstitial lung disease

idiopathic pulmonary fibrosis

mesenchymal stem cells

exosomes

clinical trials

predictive biomarkers