Equine Inflammation Research Scrutinizes Function of Two Peptides; Project Seeks Path to New Drugs, Fewer Side Effects

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A research project funded by Great Britain's The Horse Trust has made important discoveries about how two peptides regulate the inflammatory response in horses. This knowledge could help with the development of improved anti-inflammatory drugs, which are used to treat a wide range of conditions in horses.

Inflammation is the body's natural response to things that cause it harm.

However, sometimes the inflammatory response can be excessive, causing discomfort or pain and delaying recovery. Inflammation is associated with a wide range of equine diseases, including recurrent airway obstruction, laminitis and sweet itch. Although inflammation on its own is rarely life-threatening, if a horse has an inflammatory condition that cannot be managed, it may have to be euthanized.

Anti-inflammatory drugs, such as glucocorticosteroids, are regularly used in veterinary practice. These drugs mainly work by blocking the formation and/or actions of compounds produced in the horse's body that cause inflammatory responses. However, these drugs are not always effective and can have unwanted side effects.

This research, funded by The Horse Trust, aimed to find out more about two naturally-occurring peptides (chains of amino acids that are shorter than proteins) known as annexin-1 and CXCL8. Both have been shown to affect the inflammatory response but little research has been done on their effects in horses. In the long term, knowing more about these compounds could help in the development of new anti-inflammatory drugs with fewer side effects.

During inflammation, neutrophils (a type of white blood cell) stick to the cells lining blood vessels and migrate into inflamed tissue, where they ingest and break down harmful agents. Using techniques that mimic these events, CXCL8 was found to cause adherence and migration of horse neutrophils. However, when it was used in combination with another pro-inflammatory substance, neutrophil migration and adherence were markedly decreased. ?This suggests that attempts to reduce inflammation by blocking the actions of CXCL8 might not be as beneficial as had been thought.

At the start of the project, the researchers had no information about horse annexin-1, other than its gene sequence, so their first step was to develop a method to detect the peptide in white blood cells. They established that it was present and, as horse annexin-1 has not yet been synthesised, they used a synthetic peptide derived from annexin-1, Ac2-26, to look at the effects on horse neutrophils.

They found that Ac2-26 decreased neutrophil adherence and migration in response to other pro-inflammatory compounds, although at high concentrations the peptide itself caused some cell activation, thereby increasing inflammation. They also found that dexamethasone (a glucocorticosteroid) increased the levels of annexin-1 in cells, indicating that, as in humans, this class of drugs is likely to act in part through the formation of annexin-1.

These findings suggest that the use of compounds which mimic the actions of annexin-1 may have limitations as anti-inflammatory drugs. As glucocorticosteroids partly work by forming annexin-1, further research is needed in order to find out how annexin-1 will act in the horse's body and establish how its formation contributes to the beneficial effects of these drugs.

The research project was led by Professor Fiona Cunningham at the Royal Veterinary College in Hertfordshire and Dr Karen Rickards at the Donkey Sanctuary in Sidmouth, assisted by Dr Andrew Brooks at the RVC, and by Dr Kirstie Pickles, now at the Royal (Dick) School of Veterinary Studies in Edinburgh.

"This Horse Trust-funded research has resulted in some very interesting findings about how inflammatory cells are regulated in horses" said Professor Fiona Cunningham. "The receptors that annexin-1 and CXCL8 act upon could be targets for new equine inflammatory drugs, but more research is needed first to fully understand their actions and how they produce these effects."

The team's research has been accepted for publication by the journal Veterinary Immunology & Immunopathology.