By David N. Leff
You don't need a doctor's prescription to fight off histamine. There are precisely 50 pills and potions on the over-the-counter drug market labeled "anti-histamine."
They address the wheezes and sneezes, the drippy eyes and runny noses, that torment people with allergies — mainly hayfever and asthma. Histamine, the chemical perpetrator of these symptoms, is dispatched by the body's immune defenses to counterattack allergenic substances, such as plant pollens, mite dust and the monosodium L-glutamate (MSG) seasoning that causes Chinese restaurant syndrome.
To be sure, histamine has its redeeming features, as a cytokine-nudged factor that rushes to the scene of tissue injury to help honcho a therapeutic inflammatory reaction.
A ubiquitous population of immune-system mast cells is largely responsible for releasing histamine when injury or allergy duty calls.
Now a new and different indictment of mast cells' and histamine's claim to infamy has surfaced — literally — in the current Proceedings of the National Academy of Sciences (PNAS), dated July 21, 1998. Its title tells the story: "Mast cells mediate acute inflammatory responses to implanted biomaterials."
The paper's senior author is microbiologist John Eaton, in the pediatrics department of Baylor College of Medicine, in Houston, Texas. "Pediatricians," he told BioWorld Today, "are as concerned as any other arm of medicine with indwelling plastic prosthetic devices, because the really little kids that we see in neonatology have as many pieces of plastic in them as any part of the population, mostly in the form of intravenous catheters, and so forth.
"Not counting dental prostheses and contact lenses," he continued, "over four million people in the U.S. have long-term biomedical implants. And adverse responses to them — including blood clotting, chronic inflammation and infection — are frequent, and sometimes life-threatening."
Most of the non-metallic implants, he pointed out, are of plastic, notably polyethylene terephthalate, better known as Dacron. Knitted meshes of this polyester fiber are employed by cardiovascular surgeons to patch ruptured aortic aneurysms or replace blocked coronary arteries when transplanted veins from the leg are not available.
"Artificial breast implants," Eaton observed, "do cause a few real side effects, such as hardening and fibrosis. That process may likely stem from the kinds of responses we're talking about in this PNAS article."
He and his colleague Liping Tang, the paper's first author, "started out several years ago," Eaton recalled, "to find out why inert plastics, when you put them in the body, trigger an inflammatory response. Because these plastics don't have any toxins in them, they're not immunogenic, etcetera.
"So we began by making the assumption that probably the primary event was the adsorption of host proteins to the surface of the material. And that that somehow would determine later events — which turned out to be true."
Enter Fibrinogen, The Surface Spoiler
Eaton explained: "If you put a biomaterial into the bloodstream, let's say, or a body cavity, we found out, the predominant protein that sticks to its surface is fibrinogen, a clotting factor in the blood. If fibrinogen fails to stick to the prosthetic surface, then there is no inflammatory cell accumulation on the implant.
"What happens," he went on, "is the fibrinogen comes close to the plastic surface. And when it gets close enough, it becomes irreversibly adsorbed. That is, you can't get it off with powerful detergents. Then the fibrinogen exposes a little 13-amino-acid sequence that's ordinarily hidden in the soluble molecule. That little sequence, out of this really big protein, is the anchoring site for the incoming inflammatory cells.
"And the final mystery confronting us," Eaton recounted, "was: What host response triggers the influx of inflammatory cells? As this article reports, it's apparently due to the activity of mast cells. These are a type of cell that hangs around all the potential ports of entry to the body, like sentinels. And like sentinels, mast cells are programmed to fire when they see trouble. In the case of these biomaterials, we don't know yet what it is that excites them."
Eaton made the point that "mast cells release histamine, which causes blood vessels to dilate, and their walls to become more permeable to the incoming phagocytic [impurity-eating] cells."
He and Tang implanted tiny sterile polyester discs — a centimeter in diameter and half a millimeter thick — under the skin and in the abdominal cavity of mice born without the ability to deploy mast cells.
"These mice," Eaton said, "failed to show a normal inflammatory response to the implants. After we did a mast-cell transplant into the animals, once they had their mast cells back, sure enough, everything worked normally. The inflammatory response to the plastic implants was restored.
Alleged Perpetrators: Histamine, Mast Cells
"Our major finding so far," he summed up, "is that the activity of mast cells appears to be required for a full-blown inflammatory host response to biomedical implants." He conjectured that "by artificially modulating the response of the mast cells, one might change the host response to biomaterials. On the simplest level, one can do what we did with those helpless mast-cell-minus mice. That is, give the implant recipient histamine antagonists at the time the biomaterial goes in."
Eaton observed, however, "There's no really good evidence that that would do anything particularly useful in the long run.
"The alternative," he added, "would be to make biomaterial surfaces that did not spontaneously adsorb fibrinogen. We're working now on some kinds of materials like that. What we've done is display an albumin-binding dye on a large hydrophilic polymer. And the result is that when we put implants that have this kind of surface into the body, they selectively adsorb albumin, not fibrinogen. And those surfaces are passivated — by a protective albumin coating — at least with respect to not triggering blood clotting, as in intravenous lines, and not letting pathogenic bacteria stick to them."
This new departure is still in the preclinical stage, Eaton pointed out. "That is, we're still making model surfaces and putting them into animal models.
"What we're doing," he concluded, "is the non-glitzy end of bioengineering. We're trying to figure out the basic rules of the game of the host response to the implant. And the reason we're doing it is because few others are." *