Viagra could help Crohn's disease

Crohn's disease may be caused by a failure of the immune response, contrary to the commonly-held view that the disease is caused by excess inflammation, a new study by UCL (University College London) scientists has found.

The findings, published in the Lancet, suggest that Crohn's sufferers could be given Viagra to boost blood flow to an infected site, thus improving the body's inflammatory response to infection.

Crohn's disease (CD) is a chronic inflammatory disorder of the bowel, where lesions and ulcers form on the bowel walls. It can lead to severe gastrointestinal symptoms (sometimes requiring surgery) and chronic ill health. Many causes have been suggested for the disease, including infection with tuberculosis, other bacteria or viruses thought to trigger an excessive inflammatory response.

In the UCL study, Professor Tony Segal and colleagues investigated whether the disease is instead caused by impaired innate immunity. They found a defective immune response in Crohn's sufferers, based on a lack of white blood cells sent to destroy bacteria. Normally, when the immune system identifies an infection or injury, it produces cytokines which summon the most common form of white blood cells - neutrophils - to the infection site. When the neutrophils encounter bacteria they engulf, kill and digest the bacteria. Pus then forms, made up of dead neutrophils and other cell debris.

Professor Segal's team measured cytokine production (interleukin-8 or IL-8) and neutrophil recruitment at injury sites in the bowel and skin of CD patients and a control group of healthy individuals and patients with other types of inflammation. Biopsies were taken from the bowel, and 'skin windows' were created in the arms by sandpapering the skin to produce inflammatory cells and hormones, which were then measured. In a separate experiment, the left and right forearms were injected with heat-killed E.coli (a gut bacteria) to study blood flow and the immune response to bacteria.

In the skin and bowel, they found that CD patients had abnormally low levels of neutrophils and IL-8 at trauma sites. In the infected arms, they found a much lower blood flow response in CD patients compared with control subjects, where increased blood flow would normally carry the neutrophils to the infected sites. The team used Viagra (sildenafil) to artificially correct the blood flood response to normal levels. Applying IL-8 to the skin windows corrected for neutrophil recruitment. Applying muramyl dipeptide (MDP), another immune enhancer, also boosted neutrophil migration in some cases.

The findings suggest that in CD sufferers, a weak immune response is failing to or severally delaying the elimination of bacteria in the bowel because of an ineffective neutrophil response. Instead, macrophages (another form of white blood cell) are containing the bacteria in granuloma (clumps of debris) which accumulate in the intestines, resulting in secondary, chronic inflammation. Stimulation of blood flow with drugs such as Viagra could help to compensate for the lack of neutrophil activity by carrying more neutrophils to the infected areas.

Professor Tony Segal (FRS), of the UCL Department of Medicine, says: "The wall of the bowel is normally an effective barrier against the bowel contents, but sometimes the barrier is broken by an infection or injury and the bowel contents, which include large numbers of bacteria, penetrate into the bowel wall.

"Normally, an acute inflammatory response would kick in to remove the bacteria and return the condition of the bowel to normal. But in Crohn's disease, we think that the acute inflammation fails to kick start, leaving bacteria to fester in the bowel wall which in turn triggers chronic, secondary inflammations.

"Inflammation in our healthy volunteers was associated with the production of nitric oxide, a similar mechanism to that which induces the penis to become erect. We therefore used Viagra to correct the poor response in Crohn's sufferers, where the drug amplified the effects of nitric oxide to return inflammation levels to nearly normal."

Notes for Editors:

1. For more information, please contact Jenny Gimpel at the UCL Media Relations Office on tel: +44 (0)20 7679 9739, mobile: +44 (0)7990 675 947, e-mail: j.gimpel@ucl.ac.uk.

2. 'Defective acute inflammation in Crohn's disease' is published in the Lancet on 25 February 2006, embargoed to 0:01 GMT Friday 24 February 2006.

3. Images and film footage are available from the UCL Media Relations Office, contact details as above.