Sep. 3, 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 tissues 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 chemist Nicos A. Petasis has worked as part of a multidisciplinary 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 have 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, kidney disease and now gum disease and cystic fibrosis.
In his efforts to invent new materials and pharmaceuticals, Petasis, holder of the Harold and Lillian Moulton Chair in Chemistry in the USC College of Letters, Arts and Sciences and member of USC’s Loker Hydrocarbon Research Institute, looks to nature for inspiration.
Finding ways to improve on nature’s designs was at the heart of the challenge when Serhan and Petasis began collaborating in 1993.
The pair had worked together earlier as members of the teams of their mentors – Nobel-prize winning Swedish biologist Bengt Samuelsson and preeminent synthetic chemist K. C. Nicolaou, respectively – who had joined forces to study other aspects of inflammation.
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,” said Petasis, “My task was to protect the molecules from the enzymes without altering their biological activity.”
It was a tricky prospect.
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.
Doing this, Petasis created a few dozen promising analogs. Adding a fluorine atom to his best prospect, he came up with what he was after – a potent lipoxin analog that lasts for hours.
Using the lipoxin analogs as tools, the team went on to reveal that 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.
As part of an NIH-funded Program Project, Petasis and dental biologist Thomas Van Dyke of Boston University then 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. Their findings suggest that lipoxin analogs may prove helpful as a therapy for gum disease, the primary cause of adult tooth loss.
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.
Unraveling the whole story of inflammation – a tale both complex and redundant – will take time, said Petasis.
But some benefits from his 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.
“I tend to follow up with what happens with the molecules I create,” Petasis said. “You care about them as if they were your offspring. If a molecule you create proves useful, you can have an enormous positive impact.”
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