The end of inflammation? New approach could treat dozens of diseases.
Cancer, aging, and severe COVID-19 have all been linked to damage from inflammation. Now scientists are flipping their focus to find new drugs that may revolutionize treatments.
BYCONNIE CHANG / National Geographic / MARCH 4, 2022
Bilateral X-ray of the hands and wrists of a 54 year old patient with rheumatoid arthritis. On the right hand (left), there is arthritis in the wrist joints. There is a loss of bone space and the bones are beginning to fuse. On the left hand (right), there are bony growths in the left fi...Read More
Growing up in Atlanta, Georgia, Lauren Finney Harden had always had allergies. But after she moved to New York City for her first job in 2007, inflammation just exploded throughout her body.
I had insane full-body rashes and strange gastro issues. Id get massive burps that made me feel like I needed to throw up, but nothing would come up but air, she says. Eventually, she was diagnosed with lupus, a disease in which the immune system attacks the bodys own tissues and organs. She was put on a drug called prednisone, a corticosteroid that tamps down inflammation.
But the cure, at times, felt worse than the disease. I looked four months pregnant all the time, Finney Harden says, and Id get cold sores every other week; my body could not fight off anything.
Finney Hardens experience is unfortunately a common one with traditional autoimmune treatments like prednisone. A broad immunosuppressant, prednisone works by disabling the production of pro-inflammatory molecules that are crucial for the body to mount an immune defense. So while prednisoneand drugs like itare adept at quickly snuffing out inflammation, they leave the body vulnerable to any bug it encounters, and they can come with toxic side effects.
Simply stopping inflammation is not enough to return tissue to its normal state, says Ruslan Medzhitov, a professor of immunobiology at Yale School of Medicine. This approach ignores the other side of the inflammation coin: resolution. Resolving inflammation is an active, highly choreographed process for rebuilding tissue and removing the dead bacteria and cells. When that process is disrupted, inflammatory diseases arise.
In the early 2000s researchers began to recognize the role of inflammation in conditions as varied as Alzheimers, cancer, diabetes, and heart disease, prompting them to recast inflammation as the unifying explanation for a myriad of ailments, including those we develop as we age. Even aging itself, and its associated pathologies, is driven by persistent inflammation.
Until relatively recently, we believed that inflammation just stopped, says Molly Gilligan, an internal medicine resident at Columbia University who studies how the immune system impacts cancer development. Immunologists thought that products of inflammationmolecules that trigger it and dead cells and tissueare eventually metabolized, or spontaneously dissipate on their own.
The reality is more complicated, and recognizing that could have game-changing effects on how we treat a wide swath of diseases.
Why is inflammation dangerous?
Inflammation evolved to serve an important function: It rids our bodies of stuff that doesnt belong, including foreign invaders like bacteria and viruses, tumor cells, and irritants like splinters.
A classic example of inflammatory onset is the bee stingthe site becomes hot, red, swollen, and painful, says Derek Gilroy, a professor of immunology at University College London. This response comes from a series of biological changes: blood vessels dilate to deliver white blood cells to the site of injury, making tissues turn red. Fluid also floods the site, causing swelling. The molecules that trigger these vascular transformations precipitate the itching, pain, and fever associated with inflammation.
White blood cells, the bodys first responders, then swarm and kill the invaders. Under normal circumstances, this carnage is contained, with the initial inflammatory response subsiding within 24 to 48 hours.
When inflammation becomes chronic, though, the chemical weapons deployed by front-line immune cells often damage healthy tissue, and our bodies become collateral damage. The price exacted includes worn joints, damaged neurons, scarred kidneys, and more. Autoimmune diseases like rheumatoid arthritis and lupus, characterized by pain and worsening disability, have long been associated with persistent inflammation.
In extreme cases, such as the cytokine storms associated with sepsis or severe COVID-19, inflammation can destroy and disable multiple organs, leading to catastrophic system failure and death.
What happens after inflammation?
Medzhitov likens an infection to a broken pipe that has flooded an office with water. Fixing the pipe might stop water from streaming in, but it doesnt restore the office to its previous, functional state. Similarly, inflammation has a clean-up phase known as resolution, and it proceeds in a series of highly coordinated steps.
Like inflammations onset, its resolution is orchestrated by an army of signaling molecules. Among the most intensely studied are the specialized pro-resolving mediators, or SPMs, which were discovered in the 1990s by Charles Serhan, a professor of anesthesia at Harvard Medical School. Serhan was inspired by his postdoctoral mentor, Bengt Samuelsson, who uncovered how fatty molecules called lipids trigger inflammation. Serhan was searching for similar molecules when he identified lipoxin. But to his surprise, rather than inciting inflammation, lipoxin seemed to hamper it.
Over the next several years, Serhan and his colleagues identified additional SPMs. These molecules are derived from essential fatty acids such as those omega-3s famously found in cold-water fish like salmon and sardines. But they are difficult to study in the lab. One of the main challenges is that they have short half-lives, so the body metabolizes them very quickly, Gilligan says. Because of this, researchers who work on them often turn to synthetic versions of the molecules, or mimetics, which are simpler, more stable, and cheaper to produce.
Catherine Godson, a professor of molecular medicine at University College Dublin, has long been interested in diabetes, given its impact on global public health as the most common cause of kidney failure. When she learned of SPMs, she was excited by the idea of encouraging resolution to treat diabetics, a population with a particularly high risk for infection.
In mice with diabetic kidney disease, scarring from kidney inflammation gradually destroys the organ. Her team is testing the therapeutic potential of a lipoxin mimetic in these and other animal models. Theyve also looked at the mimetics effect in human tissue in lab cell cultures taken from patients with atherosclerosis, an inflammatory disease of the blood vessel wall. In both cases, inflammatory factors plummeted when the mimetic was introduced; for the mice, the kidneys recovered their function in a stunning reversal of established disease.
Gilroy notes, however, that the story on SPMs is incomplete. While lipoxins are present at levels in the body that indicate that theyre important in resolution, other SPMs such as resolvins require more evaluation, he says.
Scientists speculate that one way lipoxins and other pro-resolution molecules work is by interacting with immune cells called macrophages.
Because theyre so abundant during inflammation, macrophages have traditionally been thought of as pro-inflammatory cells, says Gerhard Krönke, an immunologist and rheumatologist at the University of Erlangen-Nürnberg. But a paradigm shift in the last decade or so suggests that macrophages are pivotal players in the resolution of inflammation.
Gilroy agrees, calling macrophages linchpin cells at the juxtaposition of inflammation and resolution: It can go one way if were healthy and the other way if were not.
Initially, when the danger posed by invaders is at its peak, the macrophages drawn to the area are inflammatorysecreting pro-inflammatory cytokines and amping up production of antimicrobial agents. But this balance shifts as the tide of the confrontation turns. After the number of viruses declines, the debris left behindviral remnants, dead immune cells, and other wastemust be collected and cleared away before it sparks another cycle of inflammation. Thats when the macrophages switch gears.
Attracted by eat me signals expressed on the surface of dying cells, macrophages readily engulf and clear cellular corpses from the environment. But its not just about clearing the wreckagethis act also flips a genetic switch, reprogramming macrophages to restore balance to the system and heal the tissues.
Macrophages start to produce factors that tell the local tissue, Dont recruit any more inflammatory cells here, or, Lets proliferate and start repairs there, says Kodi Ravichandran, an immunologist at Washington University in St. Louis whose research focuses on how dead cells are cleared from the body.
Clearing away cellular debris
Now consensus is building that many of the illnesses attributed to inflammationboth chronic and acutecan be traced to a failure in resolution. Often that translates into a failure to clear away dead cells.
If you knock out receptors in the macrophages of mice that recognize dying cells, for example, they become incapable of eating up these cells, resulting in a lupus-like disease, with symptoms such as arthritis and skin rash, says Krönke.
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Your immune system sends out its first responders: inflammatory cells and cytokines (substances that stimulate more inflammatory cells). These cells begin an inflammatory response to trap bacteria and other offending agents or start healing injured tissue. The result can be pain, swelling, bruising or redness.
- Load up on anti-inflammatory foods. ...
- Cut back or eliminate inflammatory foods. ...
- Control blood sugar. ...
- Make time to exercise. ...
- Lose weight. ...
- Manage stress.
Inflammation Treatment. Treatment for inflammatory diseases may include medications, rest, exercise, and surgery to correct joint damage. Your treatment plan will depend on several things, including your type of disease, your age, the medications you're taking, your overall health, and how severe the symptoms are.
Resolution of inflammation is driven by a complex set of mediators that regulate cellular events required to clear inflammatory cells from sites of infection or injury to restore tissue function. However, recent studies suggest that resolution is not the end of innate mediated immune responses to infection/injury.
The four cardinal signs of inflammation are redness (Latin rubor), heat (calor), swelling (tumor), and pain (dolor). Redness is caused by the dilation of small blood vessels in the area of injury.
Inflammation is the immune system's response to harmful stimuli, such as pathogens, damaged cells, toxic compounds, or irradiation , and acts by removing injurious stimuli and initiating the healing process . Inflammation is therefore a defense mechanism that is vital to health .