What Causes Inflammation And Why It Occurs

Surely, inflammation is half a billion years old, since even the lowly starfish may experience it. Virtually every human being who ever lived has suffered from it, perhaps dozens or hundreds of times. But why? And what is it? Pathology textbooks take refuge in rolling Latin, describing inflammation by its signs: rubor, calor, tumor, dolor (redness, heat, swelling, pain). It is the reaction of a part or all of the body to injury. In its later stages it includes the processes needed to repair the injury.

Clearly, such a universal phenomenon should have commanded intensive research attention. In fact it has not, and until recently there has been so little research that 90% or more of today's knowledge about inflammation has been gained in the past ten years. Not until a fortnight ago did the International Inflammation Club convene its first symposium. The club is an amorphous group with no officers or formal organization. Conceived by Biochemist John C. Houck of Children's Hospital in Washington, D.C., it drew together 80 researchers as guests of the Upjohn Co. at Brook Lodge in Michigan.

Total Mobilization. Some of them had interests so specialized that even other scientists could not understand their presentations. Houck had expected this. He had wanted the meeting to build bridges of communication between men who had never heard of one another's work, and that it did. And the scientists concurred on some basic aspects of the subject that will be important in the treatment of patients--some, admittedly, in the distant future, but others perhaps immediately.

Inflammation, all agreed, is one of nature's most basic defenses against injury. As such, Dr. Houck pointed out, it has to be enormously versatile because the injury may be a stabbing or abrasive wound, a burn, or invasion by infectious microbes. Even a sterile, uninfected wound summons inflammation to its aid. Since nature cannot construct individual defenses against an infinite variety of attacks from innumerable sources, said the Upjohn Co.'s Dr. E. Myles Glenn, it mobilizes everything at hand--the immune and clotting mechanisms, the blood-forming and lymph systems, the liver, and many others. Sometimes it overreacts to the injury; sometimes it damages the very system it is seeking to defend, as in autoimmune diseases.

"We visualize the overall inflammatory process," said Dr. Glenn, "as a wave or chain of cellular destruction." The first result of injury is to cut cells open, in the case of a stab wound or burn, or to weaken their membranes, in the case of many infections or poisoning by plants or animals. Either way, powerful chemicals that had been locked inside the cells, some in leakproof packages, spill out.

They start a chain reaction by breaking down other parts of the damaged cells and releasing more active substances, such as histamine. At first these constrict the blood vessels, to minimize bleeding, and initiate the clotting process. But they damage the vessels' walls, causing dilation and rubor, and letting out white cells and antibody proteins. Fluid oozes from blood vessels into the tissues, causing tumor and dolor. Biochemical signals sent through the blood and lymph systems call for the production of more infection-fighting white cells and antibodies. If the threat has been great enough, the inflammation suffuses the whole body, creating a generalized calor--fever. In its final stages, inflammation stimulates the production of new capillaries and connective-tissue cells, and scar formation.

Sucked In, Sealed Off. Especially important among the cells' inflammatory chemicals are enzymes, the organic catalysts that mediate reactions between other body substances and, in some cases, destroy them. Perhaps the most potent are the acid hydrolases, some of which dissolve proteins and nucleic acids. Where they were kept was a mystery until 1955, when Dr. Christian de Duve at the Catholic University of Louvain deduced from their behavior that they must be stored in some particles inside the cells. Though nobody had yet seen the particles, he named them lysosomes (dissolving bodies).*

Electron microscopists have since photographed lysosomes, and Dr. de Duve, now at Rockefeller University, has figured out some of the ways they work (see diagram). In a typical case, a foreign particle (it may be a virus, a bacterium or a chemical) reaches the side of a cell and is sucked in, sealed off by a piece of the cell's own membrane. Standing by inside the cell is a lysosome, packed with enzymes. Lysosome and invader, now packaged in a phagosome, are drawn together and fuse. In the resulting sac, called a vacuole, the foreign substance is digested.

Usually, that is good; the harmless debris may be either left in the cell or expelled from it. But in the case of some viruses, the effect may be to bare the virus particle's nucleic acid and leave it free to infect the cell. Moreover, as New York University's Dr. Gerald Weissmann reported in Michigan, some virus particles can survive a spell in a digestive sac, and emerge from it with their infective powers intact. By another mechanism, lysosomes can be directly harmful: they may, for reasons not yet guessed at, attack part of their own cell's natural contents, and destroy it.

Clots & Aspirin. What makes lysosomes and their enzymes so important in the study and treatment of disease is their major role in cases where the inflammatory process overshoots. The overshooting has long been clear in the case of extensive burns, when the body builds too much scar tissue, and in rheumatoid arthritis, when the inflammation becomes recurrent and does permanent, crippling damage. Reports at Brook Lodge also implicated an overzealous inflammatory reaction in some kidney diseases, and made it a suspect in two still commoner diseases, diabetes and even atherosclerosis.

Moreover, Dr. James F. Mustard of Hamilton, Ont., asked for a new look at the phenomenon of clotting inside blood vessels, including coronary arteries. In the past ten years, he said, it has been shown that formation of a thrombus that will plug an artery is a complex process following an inflammatory reaction and involving an aggregation of platelets, the smallest solid elements in the blood. It may be possible, he suggested, to use anti-inflammatory drugs to control or prevent some kinds of thrombus formation. But by the same token, it may be unwise to give such drugs--even aspirin--to a patient taking anticoagulants, since they may depress the coagulability too far, and lead to dangerous bleeding.

Inflamed Red. That opened up the whole question of anti-inflammatory drugs, how they work and which are best. How they work on some cells at some times seems clear: the cortisone group of hormones strengthens the lysosome membrane, making it less likely to spill out its enzymes. But the field is booby-trapped with paradoxes. If a rat is given a local injection of histamine, a notorious cause of inflammation, it has a strong reaction. But if the rat first gets a histamine shot into its abdominal cavity, said Dr. Glenn, a later local injection will have little effect.

Dr. Houck noted that three drugs, hydrocortisone, oxyphenbutazone (Tandearil) and indomethacin (Indocin), when injected into animals, all cause the release of an enzyme which is itself inflammatory--though all are prescribed as anti-inflammatory medicines in arthritis. This, he declared, is puzzling to the point of being "intellectually unpleasant." Dr. Arthur Bogden of Worcester, Mass., made the paradox still sharper. If hydrocortisone and aspirin are given to laboratory rats under certain conditions before they have arthritis, both have anti-inflammatory action. But after the rats have their arthritis, the hydrocortisone raises a certain enzyme level used as a measure of drug activity, while aspirin pushes it down. How to determine, in advance, what effects a new drug will have on human beings is still a puzzle.

The symposium experts admitted that they were bewildered by the complexities of inflammation. If they were red-faced, it was appropriate. As U.C.L.A.'s Dr. Carl Pearson pointed out, the redness of measles is not a direct result of the virus invasion but a consequence of the inflammatory reaction by which the body tries to cure itself.

* Not to be confused with lysozyme, an enzyme found in egg white and tears.

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