Why NSAIDs damage the tissue that lines the gastrointestinal tract

Jun 23 2007

New versions of drugs like buffered aspirin and Vioxx could produce fewer harmful side effects thanks to research being done at Kansas State University's College of Veterinary Medicine.

K-State researchers are examining how nonsteroidal anti-inflammatory drugs, or NSAIDs, damage the tissue that lines the gastrointestinal tract. James Lillich, associate professor of clinical sciences, is leading the research. He said NSAIDs are some of the most commonly used prescription and over-the-counter drugs for relieving ailments from headaches to arthritis.

The research being done at K-State will benefit animals like horses that require NSAIDs for ailments related to their athletic activities.

"We treat horses the same way we treat humans, and horses get the same side effects," Lillich said.

NSAIDs work by blocking a type of enzyme called cyclooxygenase, or COX, which is needed for healthy cellular function. When tissue becomes inflamed, isoforms of the enzyme produce naturally occurring compounds called prostaglandins, which are responsible for the pain associated with inflammation. Although drugs inhibiting COX-2 reduce inflammation, their targets can spill over and also inhibit the gastrointestinal tract's ability to heal itself, leading to problems like ulcers.

"NSAIDs are doing more than just inhibiting COX," Lillich said. "You're going to have to deal with side effects with any drug."

In the intestines, healthy epithelial cells move toward damaged cells to repair wounds in a matter of minutes to hours.

"The epithelial cells in the GI tract are the barrier between your body and the outside world," Lillich said.

He said NSAIDs inhibit this migration. To find out why, Lillich took an intestinal cell line and exposed it to NSAIDs. He then used wounding assays to assess cell migration over a period of four hours.

"Wounding assays are a way we can look at, basically, the behavior of cells," Lillich said.

In the wounding assay, Lillich said cells are seeded on a base that resembles the substance they would normally anchor themselves to in the body. The cells lay themselves out as a flat, single layer, known as a monolayer. The cells are treated with NSAIDs, and then a portion of the monolayer is removed and examined to see the response over a short period of time.

"Basically we are looking at cell migration as they move to re-establish the monolayer," Lillich said. "We do this over a four-hour time frame, so we know it is migration and not the cells dividing or proliferation."

Lillich and the researchers found something they didn't expect -- that in addition to blocking COX, NSAIDs also are affecting other important enzymes called calpains that are required for cell maintenance. These calpains are vital to white blood cells in epithelial cell migration. Lillich said calpains have become the focus of the research at K-State.

"Calpains are a good starting point, because they play important roles for a variety of cells, and you're not just looking at one or two cell types when it comes to ulcer formation," Lillich said. "This will teach us about wound healing, cell migration and what the white blood cell does."

Lillich said the research he is doing at K-State will lead to better treatment for patients requiring nonsteroidal anti-inflammatory drugs.

"What we're trying to do is get better at drug design," Lillich said. "The manufacturers will be able to make drugs that inhibit some isoforms of COX but without inhibiting calpains. Manufacturers will be able to make a drug with fewer harmful side effects."