It is absolutely true that if inflammation does not arise in the human body, it will die. Inflammation is a hero as well as a villain…and each of its roles depends on the context in which it appears.
Instead of eliminating it, modern medical science is trying to redirect inflammation with new therapeutic techniques. Inflammation is one of the body’s natural superpowers. It helps us fight infection and heal wounds. “If you don’t have inflammation in your body, you die,” says Ed Ranger, a professor at the University of Birmingham, UK who researches chronic inflammation. It’s as simple as that. But if this temporary reaction persists for months or years, it becomes chronic inflammation. This condition then leads to liver disease (cirrhosis), rheumatoid arthritis (RA) and heart disease.
In the past, doctors tried to completely suppress inflammation to treat many diseases, but this led to dangerous side effects and often this treatment was not effective. Scientists are now developing treatments that don’t completely eliminate inflammation, but instead create changes in the cells that exacerbate the condition.
In cancer, for example, tumors hijack the healing aspects of inflammation and use them to their advantage. Newer treatments take the opposite strategy … that is, they want to push inflammation back into a “warrior state” to enable it to attack cancer cells. Depending on the context, inflammation can be both beneficial and harmful. But thanks to new medical research, it’s now possible to control both.
Inflammation is the body’s natural response to physical injury, infection, or toxic effects and has been recognized by physicians for centuries. “Inflammare” is a Latin word meaning: “to set on fire”. In the second century AD, Galen, physician to the Roman emperor Marcus Aurelius, described five basic symptoms of inflammation: “Heat, redness, swelling, pain, and loss of function.” These were the characteristics that indicate “acute inflammation”.
Redness and warmth are caused when blood vessels dilate to deliver the body’s repair substances to injured tissue. Hormones such as prostaglandins, on the other hand, cause pain and swelling by releasing substances. To fight infection, our immune system releases chemicals called “pyrogens” that stimulate the body to make more prostaglandins and cause fever. “The main purpose of inflammation is to contain the infection, stop it from spreading and then start the healing process,” says Robert Anthony, associate professor of medicine at Harvard University.
During acute inflammation, injured cells send out “danger” signals that draw immune cells to the site of attack. Among the first to arrive are the amoeba-like macrophages that ingest the offending bacteria. And also neutrophils (neutrophils) cells that kill enemies by trapping them in their net. When these cells are activated, they release chemicals called cytokines that further increase inflammation. Thus a “positive feedback loop” or positive feedback loop is formed.
When acute inflammation is at its peak, the immune system of a person or any organism is targeting the enemy in a more effective and specific way. According to Anthony, acute inflammation usually peaks seven days after a bacterial or viral attack and begins to subside after about three days. At the same time, certain cells begin to heal the wound by releasing inflammatory or anti-inflammatory signals and promoting the formation of new blood vessels and connective tissue.
Scientists still don’t fully understand how the body turns off acute inflammation. But sometimes, for example, when our immune system can’t completely control the infection, the inflammation doesn’t go away…that’s when it turns from a positive process to a harmful process. “If the process doesn’t stop around day 10 after the illness, that’s when it enters the chronic phase,” says Anthony.
In chronic inflammation, neutrophils, macrophages, and other white cells remain at the site of inflammation. These cells continuously release cytokines and increase inflammation. Inflammatory cells also produce “growth factors” that increase cell division and make enzymes that damage tissue. As a result, more “danger” signals are generated and the vicious cycle begins.
Chronic inflammation plays a role in the development of many diseases such as: Rheumatoid arthritis (RA): which affects the joints. *Cirrhosis: In which the liver becomes scarred. * Atherosclerosis: It means the appearance of obstructions in the blood vessels which can cause heart attack or stroke. Furthermore, chronic inflammation causes rapid cell division and mutation. Thus, an environment is created in which the risk of cancer is strongly exposed.
In the past, doctors tried to completely eliminate inflammation during treatment. For example, in the 1950s, scientists discovered the anti-inflammatory effects of naturally occurring compounds called “steroids,” which “silence” the immune system as a whole. Steroids then became a mainstay in the treatment of chronic inflammatory diseases such as rheumatoid arthritis. But since they completely suppress the body’s immune system, they also have side effects such as:} high blood pressure (hypertension)} stomach ulcers} mood swings.
In the 1990s, pharmaceutical companies introduced drugs called “Biologics”. Most of these drugs work by silencing various cytokines, that is, by turning off the chemical signals that increase inflammation. But like steroids, biologics often suppress large parts of the immune system, which can increase the risk of infection. For example, tofacitinib, a drug used to treat rheumatoid arthritis, targets a signaling pathway shared by many cytokines. As a result, patients using this drug may suffer from herpes zoster virus, pneumonia and urinary tract infections. Then, for unknown reasons, biologics may not be effective in every patient.
That’s why scientists are looking for more targeted methods to give a new direction to harmful inflammation… usually they adopt this process by reprogramming immune cells. Stuart Forbes, a medical scientist associated with the University of Edinburgh, United Kingdom, is researching the role of macrophages in the process of forming “scar tissue” (hard tissue of the wound) in liver disease (Liver Fibrosis). Research by him and other researchers has shown that there are actually two types of macrophages:
* Harmful inflammatory type known as “M1”.
The second type, called “M2”, reduces inflammation and helps in tissue regeneration.
Stuart Forbes’ team filtered cells called monocytes, which are precursor cells of macrophages, from the blood of patients with severe liver disease at his institution’s hospital. Then in the lab, the team uses chemical signals to transform these monocytes into M2 regenerative (repair) macrophages. These “reprogrammed” macrophages are then reintroduced into the patient’s body. “The goal of our treatment is to stimulate liver regrowth, which means removing scar tissue and turning inflammation from a negative state of damage to a positive state of repair,” says Forbes.
The method was shown to be safe in a phase I clinical trial on nine patients. “Encouraging results” from a large phase II trial (on 50 patients) were presented by Forbes at a meeting of the American Association for the Study of Liver Diseases. The team discovered that the macrophage treatment significantly reduced the number of fatal liver-related complications in patients during a one-year trial.
However, to treat the underlying problem of inflammatory diseases, it is important to identify the key cells in the specific affected tissue. This point is emphasized by Dr. Chris Buckley, who is Professor of Translational Rheumatology at the University of Oxford, United Kingdom. For example, in rheumatoid arthritis, white blood cells that are part of the immune system often mistakenly target joint tissue. These white blood cells also activate macrophages and fibroblasts cells that form connective tissue and thus increase inflammation in the joints.
Common treatments for rheumatoid arthritis usually target these “rebellious” white cells. But the truth is, only 50 percent of rheumatoid arthritis patients make a full recovery. Some time ago, Buckley and his colleagues discovered that one type of fibroblasts in joints increases inflammation in rheumatoid arthritis, while another type damages bone and cartilage in another bone disease, osteoarthritis. This made it possible to treat both diseases by targeting the specific fibroblasts that play different roles in each disease. His research has been published in a famous American journal, Nature.
If both white blood cells and fibroblasts are targeted together in the treatment of rheumatoid arthritis, it is possible that “one hundred percent” of patients with this disease will achieve complete recovery, according to Dr. Chris Buckley. This treatment is still in its early stages. However, in 2021, a drug called Seliciclib, which suppresses the growth of fibroblasts in joints, was found to be safe in a phase I clinical trial in 15 patients with rheumatoid arthritis. This success paved the way for future trials to test the drug’s effectiveness.
For some chronic diseases, scientists are also developing treatments that “inflame” rather than eliminate it. For example, in cancer, macrophages attack tumors. But cancer cells hijack this process and release chemicals that switch macrophages from the M1 (pro-inflammatory) type to the M2 (anti-inflammatory) type. These M2 macrophages suppress inflammation and promote the growth of cancerous tumors.
Based on this fact, Dr. Yara Abd, an assistant professor of oncology at the University of North Carolina in the US, and colleagues wondered if macrophages could be reprogrammed using a virus to better recognize and attack tumor cells in cancer patients, just as M1 macrophages do. were suffering from cancers including breast, ovary and oesophagus. In this trial, treatment with reprogrammed macrophages CT-0508 was found to be safe and results were encouraging.
“During the experiment, we were able to see that CT-0508 has the ability to trigger inflammation in the microenvironment of the cancerous tumor,” Dr. Abdo says, adding that these macrophages also recruit other immune cells and activate them so they can kill the cancer. More data from this trial will be released next year, according to Dr. Abdo. Based on these encouraging results, the team also plans to test an alternative treatment, CT-0525, which uses reprogrammed monocytes instead of macrophages. Its first phase clinical trial has started from 2024.
Next Steps
Dr. Forbes and his team, who have completed a phase II clinical trial, now want to test a new version of their macrophage therapy on patients who have been hospitalized for cirrhosis (severe scarring of the liver). “What Dr. Abdo and other researchers are doing is changing the way we look at inflammation…not just as a flaw, but as an incredible force that can be harnessed and harnessed for the good of humanity.”
