June 2009

A Friend in Platelets? Not When It Comes to Inflammatory Bowel Disease

Small and irregularly shaped cells floating in our bloodstream called platelets play several important roles in our health and development. They're essential to stop bleeding. They release a multitude of growth factors integral to the repair and regeneration of tissues.

But new evidence suggests that platelets are unwitting contributors to the chronic inflammation that causes inflammatory bowel disease. IBD includes a variety of debilitating diseases, including Crohn's disease and ulcerative colitis, that afflict 1.4 million people in the United States and 2.2 million in Europe .

Of interest is how platelets interact with hyaluronan (HA), a common sugar compound found throughout the body. Increased levels of HA is part of the body's normal inflammatory response to injuries, and HA serves as a type of temporary bandage for injured tissues – it's rapidly produced, holds water to guard against dehydration of the tissue, and serves as a “matrix” until permanent repairs can be made.

The key is how long HA remains at an injury site. It needs to disappear for permanent healing to occur. If HA overstays its welcome, real repair and tissue regeneration will not happen.

One way for HA to be assimilated by the body is for enzymes to cleave, or chop up, the strands of HA into smaller pieces. This process requires two enzymes called hyaluronidase 1 (HYAL1) and hyaluronidase 2 (HYAL2) – one to cleave the HA strands outside the cell, and the other to chop up the smaller pieces inside the cell.

Carol de la Motte, PhD, Pathobiology, found that platelets are players in this inflammatory balance. In fact, they might actually promote HA production in the blood vessels, leading to the characteristic “hit/skip” placement of lesions throughout a patient's colon.

According to Dr. de la Motte's observations, an initial injury or stimulus activates the endothelial cells that line the inside of the blood vessels that nourish and support the large intestine. In turn, the endothelial cells produce strands of HA.

Platelets and monocytes (the latter a type of white blood cell) bind to these strands, starting the initial inflammatory response. Here's where platelets contribute to perpetuating the inflammation.

Platelets only produce HYAL2, which degrades the HA strands. Because platelets lack the second enzyme (HYAL1) needed to thoroughly dismantle HA, the smaller strands are free to bind with monocytes – a joining that sends signals to the body that an inflammatory response should continue and that more HA is needed.

And the cycle of HA creation and inflammation needlessly starts over again.

“Platelets are not only involved in the earliest step in wound healing, but we've shown they are also important in the signaling of subsequent inflammatory steps,” Dr. de la Motte said. “We think that aberrations in these sequential steps can promote chronic inflammation, as we've found in inflammatory bowel disease. Platelets may be a connection between initial acute and long-term and unnecessary chronic inflammation, wound healing, and the subsequent creation of excess fibrous tissue that can be part of tissue repair.

“We next want to explore whether or not IBD patients are more prone to having excess hyaluronan, whether their platelets have an excess of the HYAL2 enzyme, and how any platelet defects might influence hyaluronan's ability to continue triggering inflammation,” she said.

The research also might further our understanding of blood vessel growth and blood clotting. For example, endothelial cells bind to the smaller HA fragments and promote proliferation, migration and release of growth factors that are essential to blood vessel development.

Additionally, excess HA that collects on the lining of blood vessels can spur minute blood clots called microthrombi. IBD patients frequently have elevated numbers of platelets and platelet clumps circulating in their blood. “If you get a lot of HA, you could get unnecessary clotting, or produce these clumps that circulate. Ideally, you want to keep the surface of the inside of the blood vessel clean so blood flows freely,” she said.

Dr. de la Motte's coinvestigators include Claudio Fiocchi, PhD, Hyunjin Rho, and Sean Kessler, PhD, all of Pathobiology; Amit Vasanji, PhD, Manager of the Institute's Biomedical Imaging & Analysis Core; Julie Nigro, PhD, of the Commonwealth Scientific and Industrial Research Organisation, Victoria, Australia; Silvio Danese, MD, PhD, Istituto Clinico Humanitas, Division of Gastroenterology, Milan, Italy; and Robert Stern, MD, Faculty of Medicine, Al Quds University, East Jerusalem. The research appears in the American Journal of Pathology ( http://ajp.amjpathol.org/, June 2009; 174,6:2254-2264).