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Resolving Inflammation

Resolving Inflammation

Inspired by nature, USC College chemist Nicos Petasis synthesizes compounds that help shed light on inflammation and offer a new approach to halting its damaging effects.

By Eva Emerson
August 2004

Even the tiniest paper cut kicks the immune system into action. Infection-fighting white blood cells, called neutrophils, rush to the site of injury and initiate inflammation.

Calling for back up, the neutrophils quickly recruit more of their kind to the scene, and commence to kill any bacteria they find. The skirmishes and casualties cause the skin around the cut to swell and redden until, victory in sight, the first wave of inflammation subsides. As the neutrophils retreat, the healing can begin.

Yet, these defensive forces have a dark side as well. Unchecked, raging inflammation can damage the very tissue the immune system is designed to protect. In fact, researchers have linked out-of-control inflammation to an ever-growing list of diseases, from clogged arteries and heart attacks to arthritis and cancer.

Over the last decade, USC College chemist Nicos A. Petasis has worked as part of a multi-disciplinary team studying the natural course of inflammation and what goes wrong in disease. Led by Harvard biologist Charles N. Serhan, the team’s research has altered fundamental ideas about the inflammatory response and revealed the role of biological molecules called lipoxins in regulating the process.

As part of the effort, Petasis and his group synthesized a number of powerful chemical compounds that mimic lipoxin’s anti-inflammatory, pro-healing activity. The compounds, called lipoxin analogs, are now being eyed as candidates for drug development, having shown great promise in quelling disease-associated inflammation in animal studies of dermatitis, asthma, and kidney disease.

In recent months, Petasis, a professor of chemistry, has co-authored reports demonstrating the potential value of the lipoxin analogs as new therapies in cystic fibrosis and gum disease.

Natural Inspiration

In his efforts to invent new materials and pharmaceuticals, Petasis, the Harold and Lillian Moulton Chair in Chemistry and member of the Loker Hydrocarbon Research Institute, looks to nature for inspiration.

Growing up on the island of Cyprus in the Mediterranean, Petasis was drawn to nature and using science as a tool to explore it early in life. In high school, he founded a chemistry club, and still fondly recalls doing his first experiments in the club’s lab. In college in Greece, Petasis was drawn to the field of organic synthetic chemistry because of its mixture of logic, creativity and relevance to the everyday world.

“Synthesis is where the action is, it’s at the heart of chemistry,” he says. He describes creating molecules from scratch, some that “no one has ever seen before, completely new,” as both intellectually challenging and incredibly fulfilling.

During his career, Petasis has built a stellar reputation in the world of synthetic chemistry, and is especially well known for developing improved tools and methods that have been adopted in academic labs and industrial manufacturing.

A Scientific Challenge

Finding ways to improve on nature’s designs was at the heart of the challenge when Serhan and Petasis began collaborating in 1993.

Serhan and Petasis had worked together earlier as members of their mentor’s teams — Nobel-prize winning Swedish biologist Bengt Samuelsson and preeminent synthetic chemist K. C. Nicolaou, respectively — who had joined forces to study leukotrienes, molecules that turn on the inflammation cascade.

Although Serhan discovered the lipoxins with Samuelsson in the 1980s, he wasn’t able to fully determine their function for years. A breakthrough came when he showed why lipoxins had resisted study. They circulated only a few minutes before enzymes broke them down.

“When Serhan discovered that, we started work synthesizing longer-lasting lipoxin-like molecules,” Petasis says. “My task was to protect the molecules from the enzymes without altering their biological activity.” It was a tricky prospect.

Petasis first conceptualized the kinds of chemical changes that might protect the molecule. With a rough design in mind, Petasis began his hands-on work. He would send his most promising molecules to Serhan to test for activity and metabolic stability. Going through a number of these loops, he created a few dozen promising analogs. Adding a fluorine atom to his best prospect, Petasis came up with what he was after — a potent lipoxin analog that lasts for hours.

Healing Molecules

Using the lipoxin analogs as tools, the team went on to reveal lipoxins worked as the immune system’s “traffic cops” to halt inflammation, among other key activities. Anti-inflammatory lipoxins, produced by neutrophils in the same biochemical cascade that initiates inflammation, signal other cells to retreat from an inflamed site and to begin the healing process.

The team’s research also led to a clearer understanding of how aspirin dampens inflammation. Scientists had known that aspirin works by blocking pro-inflammatory molecules, but Serhan was the first to show that aspirin also triggers the formation of a distinct, longer-lived form of lipoxin, which was first synthesized by Petasis. The team has gone on to show that lipoxins also promote the clean up of dead bacteria and cells, and trigger a transition to the less toxic chronic inflammation.

Promise for Periodontitis

As part of an NIH-funded Program Project, Petasis and dental biologist Thomas Van Dyke of Boston University joined Serhan and his team at Brigham and Women’s Hospital and Harvard Medical School to study the role of lipoxins in periodontal disease.

In December 2003, this group published a report showing lipoxin analogs helped protect gums and teeth in an animal model of periodontitis. Rabbits treated topically with the analogs had significantly less gum inflammation as well as less tissue and bone loss than an untreated group. These findings suggest that lipoxin analogs may prove helpful as a therapy for gum disease, the primary cause of adult tooth loss in the U.S.

A New View of Cystic Fibrosis

In the April 2004 issue of Nature Immunology, Petasis and a team led by physician-scientist Christopher L. Karp of Cincinnati Children’s Hospital, found that cystic fibrosis patients produce markedly lower levels of natural lipoxins than healthy people. The findings are the strongest evidence to date that uncontrolled inflammation, and not bacterial infection, initiates the destructive cycle in the lungs that eventually proves fatal for most sufferers of this genetic disease.

“People have thought of the bacteria as the main cause of lung damage in CF patients,” says Petasis. “But our results suggest that an overactive inflammatory response, which fails to resolve, may be the main culprit.”

The team also tested lipoxin analogs in an animal model of the disease. The airways of animals treated with the analogs showed less inflammation, fewer neutrophils and more successful clearing of bacterial infection than the airways of those receiving no treatment. Critically, those in the treatment group suffered less overall lung damage.

Scientists are targeting other diseases as well. In an earlier project done in collaboration with biomedical scientists, Petasis showed that lipoxin analogs may also be effective in kidney disease. Serhan’s group has published extensively on the potential of enhancing levels of natural lipoxins or using lipoxin analogs to prevent the build up of dangerous plaques in the arteries.

Petasis has developed a number of second-generation analogs that he has refined to improve their “shelf-life” or chemical stability. His first analogs were vulnerable to heat, humidity and other environmental factors, which made them harder to handle in experiments.

Future Directions

Petasis predicts that unraveling the whole story of inflammation — a tale both complex and redundant — will take time.

“Among many other issues, we still don’t know all of the mechanisms lipoxins and similar molecules use to halt inflammation, nor how they interact with other molecules in the pathway,” he says.

But some benefits from the research may arrive sooner.

If the results of animal studies are borne out in future human trials, Petasis’ pro-healing compounds may offer doctors a potent and unique new tool in the anti-inflammatory arsenal.

And that, Petasis says, would make a great ending to any story of chemical synthesis. “I tend to follow-up with what happens with the molecules I create,” Petasis says. “You care about them as if they were your offspring. If a molecule you create proves useful, you can have an enormous positive impact.”