Few would disagree that too much of a good thing is not such a good thing.

It's a conclusion some of Australia's brightest scientific minds are running with as they strive to advance treatments for asthma, bowel disease, COVID-19 and other conditions driven by a process called inflammatory cell death.

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The work of PhD student Daniel Simpson, Associate Professor James Vince and Dr Rebecca Feltham is concerned with a key biological messenger known as nitric oxide.

Not to be confused with the anaesthetic nitrous oxide or air pollutant nitrogen dioxide, NO is critical to the human circulatory and nervous systems.

In fact, the Nobel Prize in medicine was awarded for the discovery of its role as a cardiovascular signalling molecule in 1998.
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However in a finding with major therapeutic implications, the three researchers from Melbourne's Walter and Eliza Hall Institute have linked an overproduction of nitric oxide with correspondingly excessive cell death.

Although normally key to the immune response to infection, the team was able to demonstrate that uncontrolled cell death can also cause harmful levels of inflammation in otherwise healthy organs and tissue.

By implication, they found the potential to create drugs able to block a protein called caspase-8, which helps produce nitric oxide, could lead to new and improved treatments for people living with inflammatory disease.

Prof Vince says the realisation NO was a 'killer culprit' was surprising.

"Our research into the combined actions of pathogen and host inflammatory molecules in the cell death process led us directly to it," he said.

"This led us to discover how nitric oxide is the major driving force of cell death in this particular pathway."

Levels of nitric oxide ramped up when immune cells sensed viral and pathogenic threats. In other words, the more NO made, the more likely cells would die.

Mr Simpson says while preliminary, the data suggests the removal of nitric oxide in infection models stops cells dying and damaging tissue, highlighting the potential to use caspase-8 as a drug target.

DNA editing technology helped the team create gene mutations to determine which ones facilitated nitric oxide production.

"Coupled with our COVID-19 models, this ... allowed us to understand the exact role of caspase-8," Dr Feltham said.

"Being able to understand and manipulate key genes in this pathway could lead to exciting new treatment options for diseases."

The research involved collaboration with researchers from Monash University, Australian National University, the Hudson Institute of Medical Research and Germany's Cologne University.

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