July 13, 1998 MANHATTAN -- A blocked blood vessel means a medical emergency. Doctors must act quickly, usually within minutes or hours, to restore blood flow to endangered tissues beyond the blockage.
Modern technologies: inflatable balloons within the blood vessel or "clot busting" drugs have made quick relief for blocked blood flow fairly common.
It's one of the ironies of late 20th century medicine that tissue damage can also occur once blood flow resumes.
"Even with these modern methods, a doctor is put between a rock and a hard place," says a Kansas State University scientist. "Blood brings in nutrients and removes waste from tissues, so a blockage will damage tissue," says Chris Ross. "But the technologies to open the vessels and restore blood flow can put the doctor in the position of creating tissue damage, too. That's because a very complex biochemical process closely resembling inflammation takes place once blood flow is restored."
In medical parlance, the blockage is known as ischemia; the process of blood flow restoration is reperfusion.
Ross and colleague Frank Blecha study reperfusion injury, a condition that's a major contributor to coronary artery disease and stroke and many other important disease syndromes. They have discovered a substance, a very small protein called PR-39, that suppresses production of the toxic oxygen metabolites that contribute to the inflammation-like response characteristic of reperfusion injury.
The worrisome mechanisms of reperfusion injury could have evolved as part of the body's response to invading microorganisms, says Ross. In the case of a blocked blood vessel, the body's response mechanism becomes accidentally triggered even though no microbes are present.
The most prominent cell contributing to tissue damage is the neutrophil. It produces toxic oxygen products ordinarily made to kill microorganisms and fight infection. Those products can be very damaging to tissues in reperfusion injury. "It's sort of the price we pay for being able to make potent antimicrobials like free radical oxygen," Ross said.
One of the more toxic metabolites is hypochlorite -- "that's the active ingredient in household bleach," says Blecha, professor of anatomy and physiology.
Neutrophils of some animals, including pigs, produce a second substance that suppresses or down-regulates toxic oxygen metabolite production. In 1995, a K-State graduate student isolated PR-39 from pig neutrophils, and in subsequent experiments he discovered PR-39's ability to block the neutrophil oxidative activity. Jishu Shi worked in the labs of Blecha and Ross at K-State's College of Veterinary Medicine.
He found that adding PR-39 to isolated neutrophils blunts their ability to produce free radical oxygen to 30 percent of normal production level. "That 'down-regulation' was a critical finding," said Blecha. "That's when we started to wonder: Could PR-39 fight inflammation?"
The KSU researchers have acquired collaborators who are extending the research from cellular studies to using animal models. PR-39 continues to look very promising.
Dr. Tom Leto, National Institutes of Health Laboratory of Host Defenses, has helped define PR-39's molecular mechanisms of action. "Dr. Leto is an acknowledged expert in the neutrophil enzyme system that generates the free radical oxygen," Ross said.
Said Blecha, "The fact that Dr. Leto and others have repeated our work and extended our results adds a great deal to the credibility of this project. Their efforts make this a collaborative study involving some very well-known scientists."
Another collaborator studies biochemical and cellular events during reperfusion injury. Dr. Ron Korthuis, Louisiana State University School of Medicine, Shreveport, has demonstrated in an animal model that PR-39 can completely prevent reperfusion injury. He uses a real-time video technique to observe events when a tiny artery is first blocked, then opened.
The presence of PR-39 does several important things, he found: it prevents the generation of the toxic oxygen products and the tissue damage that usually follows; it also blocks neutrophils from adhering to the blood vessel walls and subsequently migrating into the tissues, the typical inflammatory sequence.
"Demonstrating that PR-39 blocks multiple sites in the biochemical pathway of reperfusion injury is a very exciting finding," say the K-State scientists. "That suggests that PR-39's overall effectiveness in an actual disease situation might be bolstered and, if so, then it might be enlisted for use in human medicine someday."
They point out that it will be years before PR-39 can be developed into a drug treatment for human diseases.
"It is always a long time from drug discovery and our first understanding of a substance's basic biochemical activity to the day when human patients benefit from such research," they say. They acknowledge the excitement of being involved with a compound like PR-39 that has potential to make a real difference in treating some rather devastating illnesses.
Working with the KSU Research Foundation, Blecha, Ross and Shi have applied for several patents involving PR-39 and its anti-inflammatory and antimicrobial activities. Several grants from the Kansas Affiliate of the American Heart Association have supported the research. Shi now is a postdoctoral researcher at UCLA Medical School.
Kansas State University researchers and colleagues have published five papers and 17 abstracts to date about PR-39. Proceedings of the National Academy of Science published the 1996 paper, "PR-39, a proline-rich antibacterial peptide that inhibits phagocyte NADPH oxidase activity by binding to Src homology 3 domains of p47phox."
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