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The intricate history of a long-familiar companion of tissue injury

Yale Medicine Magazine, 2020 - Winter


Inflammation has captured the interest of generations of distinguished clinicians and researchers.

Rubor, calor, tumor, dolor: Dating from the early first century CE, these Latin words form an incantation that medical students recite to this day. They come from the Western world’s first known description of inflammation, authored by one Aulus Cornelius Celsus, a Roman who observed that the condition manifests as redness, heat, swelling, and pain.

The Romans weren’t the first to mention the phenomenon, though. The ancient Egyptians wrote about pus collections and ulcers, while in the fifth century BCE, Hippocrates repeatedly brought up inflammation in connection with such ailments as hemorrhoids, superficial skin infections, and ulcers. For patients with leg wounds, the great Greek physician made this chatty recommendation (one that suggests he may not have taken deep vein thrombosis into account): “If a person ... at first betakes himself to bed, in order to promote the cure, and never raises his leg, it will thus be much less disposed to inflammation, and be much sooner well, than it would have been if he had strolled about during the process of healing.”

Hippocrates’ suggested herbal treatments included boiled mullein, fig and olive leaves, and “linseed ... moistened with the juice of strychnos [the source of the poison strychnine] or of woad, and applied as a cataplasm.”

Galen, a Roman medical authority and personal physician to Emperor Marcus Aurelius, who was revered for over a millennium after his death in 216 CE, believed inflammation allowed blood to escape the arteries. His many misconceptions were taught until the Renaissance. Eventually, though, anatomists began to glimpse the actual inflammatory process thanks to the invention of the microscope.

The Dutch medical professor Herman Boerhaave (1668–1738) peered at blood vessels in inflamed tissue, decided they were too small to conduct blood, and proposed that calor arises from the blood’s generating friction. His German-born student Hieronymus David Gaubius (1705–1780), whom history will also remember as the discoverer of menthol, correctly linked inflammation to coagulation. The Scottish surgeon John Hunter (1728–1793), another careful observer, wrote a book (published by a colleague in 1794) comprising detailed discussions of inflammation and its connections to such colorful ailments as “putrid and jail-distempers,” gout, and ringworm.

Henri Dutrochet, a French botanist and physiologist, watched white cells escaping through vessel walls in 1824; and Rudolf Wagner, a German anatomist, described leukocyte rolling in 1839—processes by which inflammation delivers cells to the site of injured tissue. In 1867, the pathologist Julius Cohnheim realized that changes in vessel walls allow white cells to cross, alliteratively describing a typical cell as a “colorless, matte-shining, contractile corpuscle.” Ilya Ilyich Metchnikoff in 1893 described different white cell types and observed that the engulfment of harmful agents by amoeba-like phagocyte cells is central to the process of inflammation. He shared the 1908 Nobel Prize in Physiology or Medicine for his work on immunity.

In an irony that persists today, battlefield experience increased the West’s understanding of infection, inflammation, and healing. Surgeons in the Roman army—the first army to have a dedicated medical corps—emphasized the importance of keeping surgical instruments clean and promptly evacuating wounded men. In 16th-century France, an era when gunpowder weapons complicated traumatic inflammation and even minor wounds could lead to tetanus, Ambroise Paré challenged prevailing Galenic notions after engaging in an accidental experiment. One day in 1537, after running out of the usual gunshot-wound dressing—excruciating and injurious boiling oil—Paré applied a soothing ointment to such wounds, to far better effect. He went on to be known as the father of military surgery.

Dominique Jean Larrey, a surgeon in Napoleon’s army and the inventor of field triage, broke with a tradition of delayed amputation by performing it promptly to reduce the risk of inflammation and infection; in 1809 he amputated the shattered leg of one of Napoleon’s marshals in less than two minutes. His technique for treating abdominal gunshot wounds also avoided the inflammatory complications that had beset those of his predecessors. Larrey also insisted on retrieving wounded men and tending to them behind the front, reviving the long-defunct Roman practice. Trailblazing, trousers-wearing American Civil War surgeon Mary Walker clashed with her colleagues against the overuse of amputation, arguing that it is often unnecessary. These surgeons contributed to a move away from indiscriminate amputation of wounded limbs on the grounds that the practice increases the risk of inflammation rather than lowering it.

In the 19th-century, to the classical list of inflammation’s four signs was added a fifth sign—functio laesa, or loss of function of the affected body part—by Rudolf Virchow, the 19th-century German pathologist. (Legend has long held that Galen did so, but in his 1991 book The Healing Hand: Man and Wound in the Ancient World, physician-historian Guido Majno argues persuasively that it was Virchow.) Far ahead of his time, Virchow also linked inflammation to atherosclerosis.

The 20th-century saw repeated milestones in the study of inflammation, and we now understand the basic steps of the process. Blood vessels dilate, leading to redness and heat; they become leaky, causing swelling as fluid and cells cross their walls; and pain arises from pain receptors in the inflamed tissue.

Today, researchers believe subtle, chronic inflammation contributes to many diseases of modernity, including heart disease, obesity, depression, cancer, and even dementia. Even the gradual attenuation of bodily functions that accompanies growing older is thought to be powered in part by inflammation, a process called “inflamm-aging.”

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