By Wallace Ravven

In experiments with laboratory mice, a team of American, Canadian and Italian
researchers have discovered a cause and potential treatment for painful colitis
and other forms of inflammatory bowel disease.

The often painful conditions can arise from the action of one of the body’s
signaling chemicals, a peptide called substance P, released by sensory nerves
in the intestines and known to be involved in other inflammations.

The scientists had earlier determined that bowel inflammation restricts
production of an enzyme that would otherwise break down substance P. In the
current study, they found that colitis was up to five times worse if mice
lacked the enzyme, known as NEP. When they reintroduced NEP into these mice,
the bowel inflammation subsided, they report.

Their study shows that loss of the NEP enzyme fuels inflammation because
substance P doesn’t break down and so continues to cause colitis. The finding
also shows that breaking this cycle - either by administering the NEP enzyme or
blocking substance P with a drug - can dramatically reduce the inflammation.

Substance P-blocking drugs are already under development to treat depression,
asthma and other conditions. If studies show that NEP and substance P play a
similar role   in humans as they do in the mice, then drugs already in the
pipeline could prove effective against colitis, said Nigel Bunnett, PhD,
professor of surgery and physiology at the University of California, San
Francisco and designer of the study

The research results are published in the current issue (Sept. 26) of the
Proceedings of the National Academy of Sciences (PNAS). 

Inflammations of the pancreas and skin also appear to be aggravated and
controlled by the NEP/substance P cycle, Bunnett said, and these too may be
treatable with substance P blockers.

Current first-line treatments for inflammatory bowel disease often have limited
effect or carry serious side effects such as osteoporosis and mood shifts, said
co-investigator Steven Collins, MD, professor of medicine and head of the
division of gastroenterology at McMaster University in Ontario, Canada. Surgery
can effectively treat some, but not all, cases.

For unknown reasons, some patients don’t respond to conventional
anti-inflammatory therapies, and these patients may be particularly prone to
the nerve-related mechanisms of inflammation that was this study’s focus,
Collins said.

The researchers examined the mechanisms that control colitis by studying
“knockout” mice that lacked the gene for NEP, and therefore could not normally
degrade substance P.  They found that NEP knockout mice had twice as much
substance P in the intestinal wall than normal mice. The NEP-deficient mice
also showed a four-fold greater “leakage” of proteins and immune cells from
the blood into the wall of the colon, which may predispose the animals to
develop inflammation, the scientists reported.

The researchers were able to counter both the more severe colitis and this
abnormal leakage by giving the mice either a genetically engineered form of NEP
or a drug to interfere with the action of substance P activity (a “substance P
receptor antagonist”).

Colitis causes often severe abdominal pain and bloody diarrhea, Collins said.
As many as one person in 2,000 suffers from some form of inflammatory bowel
disease at any time and the treatments are sometimes inadequate or too burdened
by side effects.

Sergio Sturiale, MD, research fellow at the University of Messina, Italy, is
first author of the PNAS paper, based on research he did at McMaster
University with Collins and colleagues.

Co-authors on the paper, along with Suriale, Collins and Bunnett, are Giovanni
Barbara, MD, assistant professor at the University of Bologna; Bosheng Qiu, 
MD, a postdoctoral fellow at McMaster.

Other researchers include Michela Figini, PhD, postdoctoral fellow, and
Pierangelo Geppetti, MD, professor, both at the University of Ferrara; Norma
Gerard, PhD, and Craig Gerard, MD, at Harvard Medical School; and Eileen
Grady, PhD, assistant professor of surgery at UC San Francisco.

The research was funded by the National Institutes of Health, the Crohn’s and
Colitis Foundation of America, and NATO.