Thinner collagen linked to lung fibrosis

What role does a thinner, more heavily cross-linked form of collagen play in the progression of pulmonary fibrosis?
24 August 2018

Interview with 

Mark Jones, University of Southampton


Connective Tissue: Loose Areolar


Scientists at Southampton University have some good news about the problem of lung fibrosis, where patients’ lungs become stiff and gas exchange is severely impaired. Prevailing wisdom was that this was caused by a build up of excessive connective tissue and indeed you can see that in end-stage disease. But by studying biopsy specimens from patients early in the disease course, as Mark Jones explains to Chris Smith, he's discovered that the structure of the collagen in their lungs is different. And he thinks he can intervene with drugs to retard the progression…

Mark - I'm a lung doctor and one of the conditions that I see a lot of is lung fibrosis and in particular a type called idiopathic pulmonary fibrosis. Unfortunately we don't have very effective treatments and one of the questions I really wanted to start out to address was to understand exactly what's happening at the time that fibrosis develops. So how does it start and what progresses over time. And the thing that we chose to focus on was collagen.

Chris - Now if one looks at the lungs of a person diagnosed with fibrosis, what do you see, both macroscopically but also down a microscope?

Mark - We can look with a CT scan. We see that the bottoms of the lungs are scarred so you see lots of little white dots on the scan which shouldn't be there and there's just far too much protein there. And we think that that's extracellular matrix. If you look even closer down with a microscope you see more and more of this, these changes, but we really don't understand why they start.

Chris - And when you look at the composition of those proteins the building up is it just more of what we should have there, or is the distribution and the different concentrations of the different components wrong?

Mark - So we don't really know. There's a concept that collagen, which is really thought to be the main building block of the lungs, from a structure point of view, is increased over time. But one of the challenges is how you relate that to other components. We don't have a very good way of measuring and comparing.

Chris - So what did you actually do then who did you study, and how did you try and get to the bottom of what is actually causing this?

Mark - We wanted to look at collagen, and it's quite complicated in the way that it can assemble. So you can start with an individual "brick" - or collagen fibril as we can call it - and each of those is around one 1500th of a human hair - when they then join together they get bigger and bigger. And so when we want to look at it, one of the questions we can ask is "well, is there more collagen there, or is actually how the collagen are joining together changed? And one of the things you can look at is cross-linking.

Chris - Because, obviously, these diseases are complicated and what starts the process may not actually be where you end up, as in you could end up with lots of collagen in someone who has end-stage disease but that wasn't what caused the disease to start happening in the first place. So can you get a handle on that?

Mark - Exactly. So one of the ways that we can diagnose fibrosis is by taking a surgical lung biopsy we were able to use the tissue which wasn't needed for diagnosis to actually look at the changes which had happened in the lungs at time of diagnosis. Normally studies have looked at very much end stage tissue. So we were very fortunate to be able to look at this tissue at time of diagnosis. What we found actually the amount of collagen hadn't increased, but when we looked at each collagen fibril there seemed to be fundamental differences. They're smaller and the way that a join together seems to be more intricate - so they have more cross-links. One of the reasons that that's important is actually that can affect how stiff the lungs become; and we know that the stiffer an area is, the more likely fibrosis is to progress over time. And so the question then is what's driving those changes?

Chris - That's interesting isn't it? So the collagen - almost the recipe that's being used in the way it's being assembled - has changed between a healthy lung, or someone at the very beginning of this disease and someone who's got end stage disease. It's not the overall amount of collagen, it's the way it's wired up?

Mark - Exactly and that's kind of a really important concept to think about, because actually when we then look at treatments for fibrosis very often in the studies that we're doing before we looking at trying a drug in patients we need to think well what are the measures we need to look at? Very often we actually look at the amount of collagen as being proof that yes there's a possible drug and it possibly might actually work in patients. What we saw was that actually that amount of collagen seems far less important and what we really need to focus on is how is the colalgen structure changed. Because we think that might actually be something which might have far more benefit from a treatment point of view.

Chris - Apart from finding that the strands are physically different - in the sense they're are a bit smaller and they are stiffer - how have you managed to unpick - or untwist if you like - the strands to work out why they are like that?

Mark - One of the kind of challenges when it comes to studying something like fibrosis is that we can look in the tissue. But we know that's just one time point and really to try and unpick what might be the underlying mechanisms of this we need to be able to look in models where we can look at changes over time and so we were able to use cells from patients and actually start to grow little areas of fibrosis and we can look at the colalgen over time. We were then able to work with pharmaceutical companies with drugs which targeted some of the changes that we identified, and were able to then start to unpick how those changes might relate back to the patient.

Chris - So do you think this is almost a bit like a prion disease in the sense that you get an abnormal folding of a protein that then makes more of the same and that once the collagen starts to abnormally behave it then encourages more colleges to behave badly?

Mark - Exactly yes. I think this type of feedback loop which is self-perpetuating process is definitely something that we saw from our data and other groups have shown and pharmacology that you think you can throw at this.

Chris - How does it work and is it very effective?

Mark - We were able to look at specific types of cross-links that we thought were altered and we can use a specific drug which is able to inhibit those cross-links and I think the studies that we did it works very well and we seemed to get a resetting of fibrosis. But the next step is really to translate those treatments from our studies into human studies. And so the very first part of that - the Phase 1 trials - are in progress at the moment. So hopefully there is the potential for this to be of real benefit to patients in the future...


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