Sepsis is a potentially life-threatening condition, where the body's immune response to an infection goes overdrive and starts to attack healthy cells. This condition leads to tissue damage, organ failure, immune paralysis, and ultimately, death. About 49 million people suffer from sepsis every year, and a fifth of them succumb to it. The death toll from sepsis is much higher than all cancers combined. Despite its high prevalence, the underlying mechanism of how sepsis develops is not well understood, and there is also no treatment.

Building on their previous research, researchers at Tata Memorial Centre (TMC), Mumbai have tried to find out the root cause of sepsis in a recent study. So far, most drugs treat the symptoms of sepsis, such as inflammation, rather than its causes. In this study, the researchers find that broken pieces of chromosomes could trigger sepsis. The results of the study are published in the journal PLoS ONE.

In a healthy individual, billions of cells die each day and release their chromosome particles, called cell-free chromatin. Healthy cells can absorb these particles, leading to cell death and inflammation. In the current study, the researchers hypothesised that these cell-free chromatin trigger sepsis by integrating into and disrupting the DNA of healthy cells. As a result, the healthy cells die, further releasing more chromatin, and a vicious cycle is perpetuated leading to sepsis.

The researchers prepared three different compounds for inactivating the deadly chromatin particles to test their hypothesis. The first was anti-histone antibodies attached to nanoparticles that target the packaging component of chromatin called histones. The second was an enzyme called deoxyribonuclease I, which degrades the DNA of cell-free chromatin. A third, which was a novel combination of resveratrola plant-based antioxidant extracted from the skin of red grapesand copper, which degrades DNA in the chromatin via free radicals.

The drugs were tested in mice injected with a bacterial toxin called lipopolysaccharide. The researchers investigated if the broken chromatin particles would be inactivated, and the sepsis, caused by this toxin, would be cured. They then monitored the levels of cell-free chromatin in different organs and the level of cytokines, which initiates inflammation, in blood and various organs.

The results showed that the use of all three drugs resulted in a downward trend for the parameters of sepsis. Of the three, the combination of resveratrol and small quantities of metallic copper was the most effective.

"Our studies have shown that a combination of the antioxidant resveratrol and small quantities of copper may be of therapeutic effect," says Prof Indraneel Mittra. He is a Professor at the Tata Memorial Centre and the corresponding author of the study.

The findings of the study have broad applications beyond treating sepsis.

"The promise of this study is not limited to the treatment of sepsis. It branches out to improve the side effects of chemotherapy as well", mentions Prof Mittra.

The researchers had previously established that the toxic side effects of chemotherapy are also due to the cell-free chromatin generated by cells that are killed by the drugs. "They then kill other healthy cells," he adds.

The effectiveness of Resveratrol and Copper in treating sepsis may suggest an Ayurvedic angle.

"Ayurveda is replete with plant products related to Resveratrol, like haldi, amla and nimbu. Copper is also a commonly used metal in Ayurveda. With centuries of experience, Ayurveda has observed that plant products and heavy metals are beneficial to health. However, the synergistic effect between two hasn't been scientifically tested. Maybe our discovery of therapeutic effects of Resveratrol and Copper might help to provide clues to the secrets of Ayurveda," signs off Prof. Mittra.

This article has been run past the researchers, whose work is covered, to ensure accuracy.

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Broken chromatin fragments could hold the key in the fight against the deadly sepsis - Research Matters