Chapters Transcript Inflammation in Bronchiectasis Course: Advances in Home Mechanical Ventilation: From the Iron to Artificial Lung Um, I'm gonna hopefully whiz through the topic of inflammation and bronchiectis cos there's nothing really exciting happening here, is there? Um. Now, this is, this is a really fun time to be giving this talk, uh, and particularly following on from the other two presentations. This is, uh, similar to, to Ken. I want to give a shout out to all of the people working in this field and, and making a difference. I'm gonna show quite a lot of data that's been done in collaboration with these, uh, colleagues, and we really appreciate that. We, we use the term paradigm shift too much, probably because we're always trying to get grants, right? But uh I think in, in bronchiexis we really are going through a period where we can claim that there is a proper paradigm shift going on. Uh, we're, we're really changing our concepts in terms of how we think about the disease. If I was giving this talk, maybe 5, 10 years ago, we'd show a vicious vortex or a vicious cycle as it was like this, and we'd be talking about antibiotic treatment, because that was what we were trialing 10 years ago and saying if we give antibiotics, we'll break the cycle, reduce inflammation. Improve mucociliary clearance, and we now know that that is not true, or at least not true for the vast majority of patients, uh, and we've had to really reconceptualize the disease, and we've made a lot of progress by thinking about bronchiois as an inflammatory problem. We've learned that we're, antibiotics make a difference and they're an important part of the way you manage your patients, but they are not the thing that is going to transform how the landscape of how we manage the disease, and we know that because we've tried antibiotic treatments in multiple ways. If you look at this meta-analysis of 20 studies of inhaled antibiotics, over 3500 patients, we can't say that we haven't tried. Small improvements in symptoms, variable, inconsistent improvements in exacerbations. Uh, and, uh, overall mixed results not resulting in FDA approved antibiotics, so we need a new way of thinking about the disease. Uh, and that way is to think that in fact, most of our patients don't have a CFTR mutation, most of our patients don't have PCD. What's the driver that ends up with mucociliary dysfunction? And infection. Pseudomonas is a late feature of the disease. Patients don't start with Pseudomonas. Something kicks this problem off, and in most patients, it's going to be inflammation. In most patients, patients, the starting point is going to be unresolved inflammation. And when we think about the patients that are doing badly in our clinics, what are the characteristics of those patients? Patients with high disease activity, purulent sputum, frequent exacerbations, lots of mucus production. We even have biomarkers now that can predict exacerbation, and they're all tied to inflammation. So the inflammation era of bronchiexis is acknowledging that this is a central feature of the disease, uh, and it's treatable. So I can't go through every aspect of bronchiectis immunology in the next 10 to 15 minutes, so I'm gonna just highlight a few interesting observations from recent studies that might flip a little bit from the inflammation angle, how we think about things. The first observation is this is not just an airway problem. So this is a study that we've recently conducted, 335 patients with bronchiexis against a matched control population, looking at blood transcriptomics, so systemic inflammation. And it's grossly abnormal in people with bronchiexis. Over 300 upregulated genes, over 300 down regulated genes, a lot of neutrophil pathways there, but also metabolic pathways, cell stress pathways. Why is that important? Because we think about this as an entirely airway related problem. Other conditions that are recognized systemic inflammation as a key feature incorporate things like cardiovascular risk assessment, osteoporosis, uh, management of comorbidities into those pathways because those are the consequences of systemic inflammation. A thought for you, do we need to start thinking about bronchisis not just as an airway inflammatory disease, but as a systemic inflammatory disease. What are the, what are the aspects of inflammation that are important in terms of outcomes for our patients? I can show lots of studies around this because we've done a lot of omic, multi-omic and biomarker studies. I'm gonna show you one that I think uh reveals a little bit around. Uh, the, uh, the importance of different pathways in the airway. There's a study we recently published in the Blue Journal. We took a cohort of patients with P pseudomonas infection, and that's the important point here, that all of these patients have the same baseline infection. So infection is essentially controlled for in terms of, uh, looking at prognosis. We did a series of, uh, proteomics and biomarker measurements and looked over a year at which patients had more exacerbations. And it reveals what I think we would now expect, uh, which is that even within a population that has the same history of exacerbation, they all had to have at least 2 in the previous year, the same bacteria, they've all grown pseudomonas at baseline, they've all got chronic pseudomonas, there's extraordinary inflammatory heterogeneity. The patients are very, very different, with different profiles of. Biomarkers in their sputum, we identified three clusters, uh, that are defined by different patterns of inflammatory process, and you'll not be surprised to hear that neutrophils are one of the dominant within there. Um, so driving clusters 2 and 3, the green and the orange cluster, is the patterns of neutrophilic inflammation, including things like neutrophil elastase that we've got used to. And we know from other studies that that predicts exacerbation. So we looked over the course of a year at these patients, at which patients then have had exacerbations, uh, on the study, uh, and there are proteins that predict exacerbation. Many of the ones that are positively associated, LSP one's a good example, are neutrophil associated, so they're just what we've seen in other studies. Lots of neutrophil proteins. But I'm really interested in the proteins that are associated with protection from exacerbation. So there's certain proteins, when they're high, you're less likely to. Have exacerbations. And a lot of them actually were immunoglobulins, so Ig here, uh, IGK, IGLV, these are fragments of immunoglobulin. So the more immunoglobulins you have in the airways, uh, the more B cell cytokines you have in the airways, the more likely you are to be protected from exacerbation. And of course these things are not independent. Your neutrophils are chewing up the immunoglobulin. And we've shown neutrophils actually suppress cytokine production from, uh, your, uh, your adaptive immune system. So we're starting to get an idea that there's a balance between excessive neutrophilic inflammation and what you would consider your normal way of controlling infection, which is having a, a strong immune response involving T cells, B cells, uh, and making neutralizing antibody. There's a talk later about eosinophils, so I'm not going to dive too deep into the inflammatory part of eosinophils, apart from to say about 20% of patients have some evidence of eosinophilic inflammation in their airways. We've recently measured this directly using a mass spec assay, and there are some weak relationships. Between various eosinophil proteins like galactin 10, ECP, uh, etc. and lung function and severity of disease, but they are weak, and I think we still don't know exactly how big a player the neutrophil granule, sorry, the eosinophil granule proteins are in terms of important outcomes. We need their clinical trials of depleting eosinophils before we'll know how important they are in terms of the proportion of exacerbations, um, but eosinophils certainly are there. The big, the big revolution in terms of understanding the uh the role of neutrophils is having therapeutics that can modulate them. We can have all the association studies we like, but we can't prove one thing causes another until we have an intervention that can change the, the situation. There are talks later in this conference on DPP1, so I'm not gonna go through the DPP1 data in great detail, uh, the clinical data, but I'm gonna show you some of the translational data because it helps us to understand the nature of inflammation. Uh and. A lot of this data comes from the Phase 2 Willows Study, which was the first study of renzicaib in bronchiectasis. And that established, firstly, the, the first study to establish efficacy of DPP1s, but also did biomarker work to look at the fact that within 4 weeks, you can gross, uh, massively suppress neutrophil elastase, cathepsin G, and protease 3. And I'm going to show you some data from the Samples from those studies. Uh, there are a number now of other, uh, phase two trials, including Verducatib, which has now entered phase 3 clinical trials, showed similar, uh, results in phase two with a 30% effect on exacerbations of the two effective doses. Uh, and as you know, there is a positive phase 3 trial with Brenza-Katib that's led to FDA and now a couple of weeks ago, EMA approved. So using samples from the, uh, from trials that we've done with DPP ones, we've been able to uh uh look at the, uh, effect on the immune system of modulating the neutrophil inflammatory response. Uh, and this is the first of those studies I want to show you. In this study, we took neutrophils from the peripheral blood of patients who'd taken renzakib for 28 days. Uh, and we looked at what changed in the cells, and we got a surprise because we were expecting neutrophil elastase, proteinase 3, and cathepsin G to be the things that are reduced. That's what every textbook will tell you. And the protein that was most reduced was one called azurocybin 1, which had not previously been described as a DPP1 target. It's structurally very similar to neutrophil elastase, so it maybe shouldn't have been a big surprise, but it doesn't have a protease domain. Uh, but it is shown in sepsis to be really damaging to endothelial cells. We've now confirmed that in the Willow trial, that over, over 6 months you can show that renzaid massively depletes this protein called azurocybin 1. why should we care about that clinically? Well, in COPD exacerbations, spikes in azurocybin 1 are predictive of the development of exacerbation. So it seems to be highly involved in the development of an exacerbation, so dropping it may explain. The strong effects on exacerbations. So we took this back to the lab and said, OK, what does this do? We added azuroyin to epithelial cells and got a signal in epithelial cells of severe cellular stress on transcriptomics, suggesting this was causing a lot of damage to airway epithelial cells. So we took that a bit further and looked at what we think is important in bronchiexis, which is mucociliary clearance, and you can see reductions in trans uh epithelial electrical resistance. This is the junctions between the cells that stop bacteria invading, that's damaged by azurocydin. We looked at ciliary beat frequency, which is markedly reduced by azurocydin, and we looked at epithelial disruption, and it really destroyed the epithelial barrier. So this is something that's in the airways of our patients at very high concentrations, it damages cilia, it impairs mucociliary clearance, uh, it damages epithelial cells, and it's virtually eliminated by these new drugs. A novel, uh, target and a novel way to understand how these drugs may be able to help us, uh, and help our patients. Mucociliary clearance, I think, is incredibly important as the downstream effect of inflammation. Uh, I think a lot of our anti-inflammatory drugs, both the ones that are now in clinical practice, but that we're now testing, will have their major effect by modulating mucociliary clearance. Uh, I've shown you the azurocybin example of that. The more classical example is that neutrophil proteins are known to drive hypersecretion of Mach 5 AC in vitro. So we're really keen to know, does that happen in vivo in patients with bronchi. X is treated with these drugs. Uh, and again, this is, this is data that's recently been published in the Blue Journal. We found that MUC 5AC, the major pro-inflammatory mucin, is significantly reduced over 6 months by treatment with renzacatetib. Uh, and it's interesting that the magnitude is much greater with the 25 mg dose. We know from a number of studies now that the 25 mg dose has the lung function benefit, and most recently we've presented some data at chest showing radiological mucus plugging. predominantly by the 25 mg dose. So the higher level of neutrophil elastase inhibition that you get with the 25 mg dose may well therefore translate into more mucus effect. Uh, on the other side, some things go up when you, when you inhibit inflammation, and those are things that are either suppressed or cleaved by proteases, and SLPI is one of your body's natural antibiotics, and that's also rescued, uh, by treatment with DPP-1 inhibitors. Loads of really interesting, um. Uh, research questions come out of this. Uh, what happens to bacteria or bacterial load when you're on these drugs long-term if your body's natural host defenses are being enhanced with these antimicrobial peptides going up? Those are questions we really need to know the answers to. What happens to Pseudomonas, uh, what happens to NTM over the long, over the long term. With the mucus signal, you know, is this going to impact on progression, because we think a lot of progression, new bronchiectis happens through mucous plugging of healthy airways that then become dilated over time. If this is reducing mucus plugging and reducing nuisances in the airway, will that have an impact on long-term progression? The the anti-inflammatory revolution means that we're getting lots more anti-inflammatory therapies coming into clinical trials. This is a schematic from a paper we published 18 months ago, looking at the various things that are in clinical trials. If you were to update this now, there would be another 6 or 7 compounds on this slide, uh, because, uh, large numbers of anti-inflammatory therapies are now coming into clinical. studies, um, enciphentrin PDE3, PD4 currently in trials, anti-IL 33 currently in trials, inhaled immunoglobulin currently in trials, alpha 1, we're doing a trial and there's a, another coming. Uh, so this is a really busy trial space, um, because of the recognition, uh, as I've talked about, that, that inflammation is central to the pathogenesis. One example of an early story that looks quite encouraging, this is inhaled immunoglobulin. I showed you that data from the orbit study showing low immunoglobulins associated with exacerbation. Immunoglobulin's part of your major host defense against infection. This is a small All 6 patients in each arm, phase 1 study, but with encouraging results showing that inhaled immunoglobulin for 14 days was able to reduce bacterial load compared with the placebo, which is shown here, and that's now transitioned into a phase 2 clinical study. Um, and the other side of antibody therapy, the previous one is, is non-specific. Specific antibody therapy against pathogens is also coming, uh, and you'll see a presentation tomorrow, uh, from Marretta Long in my group on the results of the phase two antibody study, uh, using, uh, a, a drug called dromubumab, which has quite. Encouraging results. So, understanding what's going wrong in the immune response is going to lead us to significant, uh, advances in terms of new therapies, new ideas, new targets, uh, as well as new ways of thinking about how we manage our patients, such as thinking about, uh, such as thinking about systemic inflammation as a target. So we are moving from the broad spectrum antibiotic era into the anti-inflammatory and disease modification era, and I think that's a really good thing. The future of treatment is going to be about immunomodulation uh and trying to break the vortex uh at what I think is the source. Uh, we have lots of really important research questions to now navigate, such as what does disease modification look like, uh, what happens if you can suppress mucous hypersecretion over the long term. Um, so this is a really exciting time to be involved in bronchiectis, but also an exciting time to be involved in translational research, and a lot of what I've shown you is the value of incorporating biosampling and translational research into the clinical studies that we're doing. Uh, and my final slide then is on that theme, uh, we have a massive. International biobank that is open to translational researchers. If there's anybody in the room that really wants to look at their favorite target in bronchiectasis, um, the Bridge Biobank is available, the website is there. Uh, please do use these samples to dig into some of these important questions because that's where we're going to make, uh, our biggest progress. And with that, thank you very much. Published December 2, 2025 Created by
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