Advancing the treatment for respiratory diseases

“The irony will not have escaped your notice”, says Professor Steve Renshaw, Director of the Bateson Centre, “that I am a respiratory clinician working with a model with no lungs."

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"As my clinical colleagues delight in pointing out, how can you study lung disease in a fish?”

In answer to his own question, he points out that for more than a decade the source material for his investigations into the nature of inflammatory diseases has not even been mammalian. Instead, it is a very remarkable creature, the zebrafish.

Investigating the genetic mechanisms by which inflammation heals (or “resolves”) is impossible in humans.

“But the zebrafish allows us to make those genetic changes, and because it is transparent at the larval stage you can actually see every single immune cell, the whole process of inflammation,” he adds. “It was a revelation, and still is captivating, to see the whole immune system. In the one circle of the microscope lens you can see the entire immune system of the creature – it is a functional system working to protect the fish against infection. It is healing, right in front of your eyes.”

There has been much detail learned over the last decade, but two big findings stand out. “We thought from human studies that all neutrophils (white blood cells) moved into an inflammatory site, where there had been tissue injury or infection. They dealt with the problem and then they died in situ and were removed by macrophages. This does happen, but we have found another process, and one that is probably just as important.

"We have seen the migration of neutrophils away from inflammatory sites – we can clearly see this – some die in situ but probably 75 per cent move away and that dissipates the inflammatory burden. This is a component of inflammation resolution that we are unable to see in mammals so we are trying to work out a way of proving that that happens in humans.”

The second discovery is a drug, found in a screen in zebrafish that speeds up this process. “It increases healing by causing inflammation resolution and it does it by speeding the neutrophils exit by the process of reverse migration,” says Professor Renshaw.

“So that is the impact from this work: we have found a drug which is used in patients that could be repurposed for the treatment of inflammatory disease," says Professor Steve Renshaw.

With chronic obstructive pulmonary disease being the third biggest killer in the world, repurposing that drug is an important avenue to explore.

So that is the impact from this work: we have found a drug which is used in patients that could be repurposed for the treatment of inflammatory disease.

Professor Steve Renshaw

Department of Infection, Immunity and Cardiovascular Disease

The zebrafish also seems to be attracting the next generation of high-flying researchers to the Bateson Centre, including Vice-Chancellor’s Fellow and Wellcome Trust Sir Henry Dale Fellowship holder, Dr Phil Elks. His work on signalling responses to low oxygen levels in the host-defence mechanism against Tuberculosis in a zebrafish model is attracting great interest.

His colleague, Medical Research Council (MRC) Career Development Fellow, Dr Simon Johnston, is doing pioneering work into why our immune systems become vulnerable to the fungus Cryptococcus, which causes an estimated 600,000 deaths each year.

In addition, Dr Matt Towers, another MRC Career Development Fellow, is focusing his research on how patterning and growth are integrated during vertebrate limb development with implications for stem cell and regenerative biology. At the other end of the lifecourse biology spectrum, Dr Catarina Henriques is using zebrafish to explore tissue repair and immunity in ageing. Research, in other words, that spans the entire lifecourse.

“All these early career researchers fit really well with the science here and the lifecourse biology approach,” says Professor Renshaw. “So, while their work is different, it is also complementary. They all bring something to the network and gain benefit.

"We can generate lots of tools for studying immunity in zebrafish, so if someone wants to come and ask innovative questions about immunity in those systems, Sheffield is a great place to do it, because we can give them tools to push back the boundaries of lifecourse biology.”

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