Carbon dioxide has a bad name: too much of it in the atmosphere and it acts as a greenhouse gas, while too much of it inside our bodies can be a harbinger of disease and death. Yet such notoriety is not fully deserved, it seems, as papers published recently highlight CO2’s promise as a new anti-inflammatory agent.
"In the past, CO2 was considered simply a waste product of metabolism, but recent work has highlighted the important role that CO2 plays as a signal molecule affecting multiple processes including inflammation," says Eoin Cummins, assistant professor of physiology at UCD.
Inflammation is a term given to how the immune system responds to the presence of an irritant or disease-causing agent in the body. Typically, specialised cells of our immune system, the neutrophils, arrive first at the site of an infection. They work to neutralise the invader, causing pain, swelling, warmth and redness in the process.
A wealth of scientific evidence has linked excessive inflammation – caused by the body’s immune system overreacting to an invader and attacking itself – to a huge range of diseases including asthma, eczema, irritable bowel disease, cancer, heart disease, type two diabetes, obesity, rheumatoid arthritis and Alzheimer’s disease.
The two types of drugs currently used to treat inflammation are the prescription-based corticosteroids – synthetic molecules that mimic human hormones – and the non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen which are available over the counter. The corticosteroids come as tablets, sprays, injections or creams to treat conditions such as asthma, eczema and hay fever.
There are potentially serious side effects from corticosteroids including high blood pressure, mood swings and weight gain. NSAIDs, meanwhile, which are effective in reducing the pain of inflammation in, for example, arthritis, can also come with side effects – albeit milder – such as indigestion, headaches and dizziness.
"We're still using a lot of the steroids and immunosuppressants that have been employed to very good effect for a number of years," says Cummins, "but it would be tantalising to think that we could identify some new pathways to potentially tap into."
In 2019, Cummins along with Prof Martin Cann of Durham University in the UK and Dr Vicki Linthwaite, a postdoctoral researcher also at Durham, secured funding from the Royal Society to co-host a meeting of leading researchers studying CO2 in biological systems.
It brought leading CO2 biologists together for the first time. One of its most interesting findings –published in February by the Royal Society Journal Interface Focus – concerns its role in controlling excessive inflammation, including that which can occur during a potentially deadly so-called “cytokine storm”.
Cytokines are cells that promote an immune response; when they become too abundant immune cells begin destroying healthy tissues. Blood vessels can be ruptured, lungs fill up with fluid, blood pressure drops, blood clots form and organ damage and death can follow.
“There’s significant evidence, looking at cell and some animal models, that CO2 has the ability to suppress inflammatory pathways and inflammatory cytokines; things that are known to fuel cytokine storms,” says Cummins. There is evidence too, he says, that higher CO2 levels in the blood protects damaged organs. For example, he says, when the lungs of patients in ICU are hyper-ventilated this raises their blood CO2 levels and protects them from lung damage.
It is tantalising for scientists that an entirely new pathway for the development of anti-inflammatory drugs and therapies – one based on a greater understanding of CO2 physiology –could open up. One of the hurdles scientists face is the reluctance of clinicians to conduct clinical trials to test the potential benefits of hypercapnia (build-up of CO2 in the blood) on critically ill people in ICU who might benefit.
“There are relatively few clinical trials examining the impact of administering additional CO2 to patients in the context of disease,” says Cummins. “One small study looked at the effect of therapeutic hypercapnia on inflammatory responses in [lung] lobectomy patients and found that therapeutic hypercapnia dampened the inflammatory response and improved respiratory function.”
“More research is required to identify the diseases in which elevating CO2 might be of clinical benefit,” Cummins adds.