Protecting tissue from inflammatory attack.

Protecting tissue from inflammatory attack

A surgeon finishes the delicate repair of damaged cardiac tissue and signals an assistant to restore blood flow to the fist-shaped heart muscle. To their shock, the medical team realizes the heart has gone rigid, refusing to pump.

The deadly "stunned heart" phenomenon -- caused by inflammation of heart tissue following the restoration of blood flow -- was once an all-too-common aftermath of open-heart surgery. Today, surgeons avoid it by chilling the heart and bathing it in a chemical cocktail during surgery. This is a complicated and laborious procedure, and medical researchers admit they don't really know how it works. But the threat of catastrophic inflammation compels surgeons to accept an imperfect solution.

Now, in animal and in vitro studies using genetically engineered versions of proteins found in the human body, two research teams say they have found new ways to prevent or dramatically suppress the culprits behind inflammation. This work, they say, could have implications for a whole range of debilitating, inflammatory conditions -- from rheumatoid arthritis and cystic fibrosis to skin burns and stunned heart.

The inflammatory culprits are some of the same blood-borne proteins and white blood cells that fight infection. Activated by an initial tissue injury, the normally helpful proteins -- part of a network of substances called complement -- attach to blood vessel walls at the damaged site. The activated proteins, in turn, attract white blood cells called neutrophils. As large numbers of neutrophils congregate outside the vessel walls, they begin eating away at surrounding connective tissue, destroying the very cells they were intended to protect.

Using a protein known to bind and inhibit the action of key members of the blood-borne complement network, researchers at the Johns Hopkins University School of Medicine in Baltimore and T Cell Sciences, Inc., in Cambridge, Mass., have blocked the cascade of events leading to the neutrophil invasion.

The recombinant protein, known as complement receptor type I (CR1), is a soluble form of a substance normally anchored to certain cell membranes in the body. CR1 strongly suppresses complement activation in vitro, Douglas T. Fearon and his co-workers report in the July 13 SCIENCE. Moreover, when the researchers clamped and reopened the coronary artery in rats -- simulating a human heart attack and its aftermath -- CR1 injections nearly halved the amount of heart muscle that died, they say.

These findings identify CR1 "as a potential agent for the suppression of complement-dependent tissue injury in auto-immune and inflammatory diseases," the researchers say.

In a separate effort, William G. Rice of Emory University in Atlanta and Stephen J. Weiss of the University of Michigan in Ann Arbor are working to halt inflammation by interfering with the neutrophils' tissue-degrading enzymes. In the same issue of SCIENCE, they describe in vitro experiments using a recombinant form of a human protein known as secretory leukoprotease inhibitor, or SLPI. This substance, normally found only in mucus, prevented neutrophils from attacking fibronectin and elastin -- major components of connective tissue.

Rice and Weiss suggest that SLPI's newly discovered function might lead to the development of a novel class of anti-inflammatory agents. In experiments with hamsters, other researchers have shown that SLPI can prevent inflammatory damage to lung tissue. And human testing may not be far behind. Biochemist Robert C. Thompson of Synergen Inc. in Boulder, Colo., which makes recombinant SLPI, says his company plans to seek FDA permission this winter to administer the experimental compound to emphysema and cystic fibrosis patients.