UCD researchers are finding ways to get oxygen to deprived tissues to fight inflammation, writes Dr Claire O'Connell.
Some diseases have a knack of kicking you when you are down. For example, in bowel conditions such as Crohn's disease, inflamed tissue runs low on vital oxygen. This in turn can make the inflammation even worse, setting up a vicious cycle.
Researchers at University College Dublin (UCD) want to break that cycle, and they are shedding new light on how low oxygen levels feed into inflammatory bowel disease. They have also teamed up with an Irish biotechnology company to develop ways of delivering therapeutic drugs specifically to the inflamed cells that need them.
"Basically we are interested in the cellular impact of oxygen deprivation," explains Dr Cormac Taylor, who heads the research group at UCD's Conway Institute. In conditions such as Crohn's disease or ulcerative colitis, regions of the gut wall can become inflamed and damaged, and because the blood vessels break down they can no longer deliver oxygen efficiently to cells.
This means patches of gut tissue can become hypoxic, a condition where the supply of oxygen does not meet the tissue's demands, explains Taylor.
The UCD group is now looking for biochemical links between oxygen deprivation and inflammation, which often occur together in disease states. Their focus is on the epithelial cells that line the inside of the gut.
"It's the layer just one cell thick that separates the internal compartment from the external compartment," explains Taylor, who says we rely heavily on these cells not to leak. "If that layer is compromised then the contents of your gut start spilling into your blood and immune system and you get a chronic inflammatory situation."
To recreate this critical gut barrier in the lab, the UCD group grows sheets of human colon epithelial cells and carries out experiments in an oxygen-controlled chamber. Their results show that the cells are more sensitive to inflammation if they are depleted of oxygen.
"We have found that when cells are exposed to hypoxia it has the potential to amplify other inflammatory states that are going on," says Eoin Cummins, a PhD candidate in Dr Taylor's lab.
The group has also shed new light on how an enzyme called prolyl-hydroxylase contributes to inflammation in the oxygen-starved cells, according to Cummins, who presented the results at a recent prestigious Keystone Symposium in Colorado. He says the enzyme could provide clues for developing new drugs to treat inflammation. However, any current or future therapeutic drugs first need to be delivered effectively to the damaged tissue. "There are all these great drugs but if you can't get them into the place you want to get them, it's not much use," says Dr Taylor.
This is why Science Foundation Ireland has funded a two-year, "grassroots" collaboration between his lab and Dublin-based Sigmoid Biotechnologies, which has developed a new drug delivery system called LEDDS. The technology formulates non-water-soluble drugs into easily swallowed mini-capsules, explains Sigmoid's CEO, Dr Ivan Coulter. The LEDDS micro-capsules can then be specially coated so they get past the stomach and distribute well through gut.
Coatings can also control the drug's release over time, says Coulter. "It's about getting the drug to the right place in the right quantities," he explains.
Pharmacist Dr Fergal Seeballuck will now test LEDDS formulations of anti-inflammatory agents on the UCD gut model to find out how the oxygen-starved, "leaky" cells take up the drugs. The aim is to find the optimum formulation that gets taken up selectively by inflamed tissue, explains Dr Taylor. "If you could get more efficient delivery of these drugs to the inflamed tissue, you could get more effective therapies."
And the applications don't stop there. "The beauty of the LEDDS system is that you could apply it to any drug, from aspirin to Zantac," says Dr Taylor. "What has also become apparent in recent years is that tumours are quite hypoxic and inflamed," he says.
"It's amazing how similar inflammation and cancer actually are and the argument is that inflammation feeds into cancer quite significantly. So the technologies and the information that we develop could be applied to cancer chemotherapy too in the future."