Self & Other
8. Inflammation: The Double-Edged Sword
In the first century AD, a Roman physician named Aulus Cornelius Celsus, writing one of the earliest comprehensive medical texts in Western history, listed four signs by which a doctor could recognize that a piece of tissue was inflamed.
He wrote them in Latin, as everything was then. Rubor, redness. Tumor, swelling. Calor, heat. Dolor, pain.
These four signs are still listed in every medical school in the world today, in the same order, sometimes still in the same Latin. A second-century Greek physician, Galen, added a fifth: loss of function. The tissue that is red, swollen, hot, and painful also tends to stop doing whatever it normally does. A swollen joint cannot bend properly. A swollen throat cannot swallow easily. A swollen lung cannot breathe.
Celsus had no idea what was causing any of this. He had no microscope. He had no concept of a cell, or a bacterium, or an immune response. He just noticed, carefully, that injured tissue and infected tissue looked and felt the same way, and that the four signs went together. They went together because they were all parts of the same process, executed by the same cells, in response to the same kinds of trouble. We have a name for that process now. We call it inflammation.
Inflammation is not, in itself, a disease. Inflammation is what your body does when it is responding to something. The redness is your blood vessels widening to bring more cells to the site. The heat is the increased blood flow plus the metabolic activity of the cells doing their work. The swelling is the plasma leaking out into the tissue, carrying antibodies and complement and nutrients. The pain is the chemical signaling of damaged tissue, which is your nervous system being warned to protect the area. The loss of function is your body asking you to leave the inflamed tissue alone for a while.
Inflammation is not the problem. Inflammation is the response. We have spent the last seven chapters meeting the cells that produce it, the signals that coordinate it, and the systems that decide when to start it.
This chapter is about a different question. What happens when inflammation does not stop?
The Acute Version
In the normal course of things, inflammation has a beginning, a middle, and an end.
Something happens — a cut, a virus, a bacterial invasion, a sprain. The local tissue starts releasing the alarm signals we met in Chapter 2. Cytokines flood the area. Blood vessels widen. Macrophages and neutrophils pour in. The infection or injury is dealt with. So far, so good. This is acute inflammation. It is exactly what your body is supposed to do.
Then something equally important happens, which we haven’t really talked about yet. Inflammation, when it is working properly, also turns itself off.
This took immunologists a surprisingly long time to appreciate. For most of the twentieth century, the standard view was that inflammation simply ran out of fuel — the threat was gone, so the response petered out. Over the last twenty or thirty years, a different picture has emerged. Inflammation does not just stop. It is actively resolved by a specific set of signals and cells whose entire job is to bring the response to an orderly close.
When the threat is sufficiently dealt with, the cells at the site begin to produce a different family of signaling molecules — specialized lipids called resolvins and protectins, among others — which essentially tell the inflammatory cells: stand down. Macrophages switch from their attack mode to their cleanup mode, scavenging dead cells and debris. Neutrophils stop arriving. The blood vessels return to their normal dimensions. The plasma drains back. Tregs and other regulatory cells move in to maintain the calm. Within days, sometimes hours, the tissue looks normal again — perhaps slightly scarred, but no longer in a state of emergency.
This active resolution is, in some ways, just as important as the inflammatory response itself. An inflammation that ends correctly is healing. An inflammation that does not end correctly is the subject of the rest of this chapter.
When It Doesn’t Stop
Acute inflammation lasts hours or days. Chronic inflammation lasts months, years, decades.
Sometimes the cause is obvious: a smoldering low-grade infection that the immune system can’t quite finish off, or a continuous source of damage like cigarette smoke that keeps re-injuring the lung tissue. Sometimes the cause is autoimmune — the immune system has decided, wrongly, that some of the body’s own tissue is foreign, and won’t stop responding to it. And sometimes the cause is more subtle, and is one of the most actively debated subjects in medicine today.
What chronic inflammation does, regardless of cause, is wear tissue down. The same enzymes and oxidative chemistry that neutrophils use to kill bacteria, applied over and over to the same area for months or years, damage the tissue around them. The macrophages, instead of cleaning up and leaving, settle in and become a permanent feature. Cytokines that should be brief signals become chronic background noise. The tissue, instead of healing, slowly remodels itself — sometimes scarring, sometimes thickening, sometimes losing function.
The list of conditions in which chronic inflammation plays a major role is, by 2025, surprisingly long, and getting longer. Some of these are obvious: rheumatoid arthritis is, more or less, the disease of having chronic inflammation in your joints; inflammatory bowel disease is chronic inflammation in your gut; asthma is chronic inflammation in your airways. These have been understood as inflammatory diseases for a long time.