A biochemical compound responsible for falling blood pressure in case of sepsis is discovered

A study by an international group of researchers has reversed the understanding of life-threatening inflammatory diseases, such as sepsis, by highlighting a biochemical agent that could be involved in the rapid decline in advanced blood pressure. of sepsis and which usually causes the death of the patient. This discovery could pave the way for new therapeutic approaches.

Sepsis is the leading cause of death in Brazilian intensive care units, with a mortality rate of about 50%. The disease is triggered by a deregulated response of the body to an infectious agent. For reasons still poorly understood, the immune system begins to fight not only the infectious agent, but also the body itself, resulting in organic dysfunction. The body's biochemical responses to inflammation alter the structure of the blood vessels, resulting in a sudden drop in blood pressure and potentially organ failure and death.

For nearly 10 years, kynurenine – a metabolic product of the amino acid tryptophan – has been suspected to be one of the factors responsible for vasodilation (widening of blood vessels) and the sudden drop in blood pressure. Sepsis case. The new study shows that the problem can also be caused by singlet oxygen, an electronically excited state of oxygen (¹O₂). The singlet oxygen is a highly reactive molecule with two pairs of electrons in the same orbital or different orbitals.

The team that conducted the study included Brazilian researchers from the Research Center on Redox Processes in Biomedicine (Redoxome), one of the centers for research, innovation and dissemination ( INCD) funded by the São Paulo Research Foundation – FAPESP.

According to an article published in Nature, singlet oxygen is involved in the formation of a signaling molecule that regulates vascular tone and blood pressure during inflammation characteristic of sepsis.

On the basis of experiments involving nuclear magnetic resonance and liquid chromatography coupled with mass spectrometry, the researchers demonstrated the formation of a vasodilator different from that previously identified. The compound, which they call cis-WOOH, is formed by the enzyme indoleamine 2,3-dioxygenase 1 (IDO₁) in a reaction involving tryptophan – an essential amino acid contained in the proteins – and singlet oxygen in the presence of high levels of hydrogen peroxide (H₂O₂).

The study was led by Roland Stocker, a researcher at the Victor Chang Cardiac Research Institute in Sydney, Australia. Other Australian researchers have also participated alongside colleagues from Brazil, China, Germany, Japan and the United Kingdom.

"We found that levels of H₂O₂ in the walls of blood vessels increase dramatically during life-threatening inflammatory processes, such as sepsis, reaching extremely high levels. In addition, tryptophan is injected into these arterial endothelial cells, "said Paolo di Mascio, an ordinary professor in the Department of Biochemistry at the Institute of Chemistry of the University of São Paulo (IQ-USP) in Brazil It belongs to Redoxome and co-authored article Fernanda Prado, another Redoxome member, also participated in the study.

The group observed a plentiful expression of the IDO enzyme₁ inside the cells. "This cocktail of H₂O₂, I DO₁ and tryptophan expands the functions of IDO₁, which now tryptophanally treats differently, forming cis-WOOH hydroperoxide. So both the IDO activity₁ and singlet oxygen formation is necessary for tryptophan to cause vasodilation, "said Di Mascio.

In vivo experiments using a mouse model have shown that cis-WOOH acts as a signaling molecule, inducing arterial relaxation and a decrease in blood pressure.

According to the researchers, their findings on the biochemical component responsible for the fall in blood pressure in case of sepsis and on the new biological functions of the enzyme IDO₁ This could serve as a starting point for the discovery of a refined repertoire of redox signaling pathways in which reactive oxygen species, such as singlet oxygen, act as biological messengers.

The article notes that IDO₁ is a potential target for therapy against a range of pathologies as well as sepsis. The results also suggest that singlet oxygen and IDO₁ may be involved in the modulation of the immune response against tumors, thereby promoting tumor escape, so that the inhibition of IDO₁ could be a major target in the development of anticancer drugs.

This is the first time that singlet oxygen plays a pathophysiological signaling role in mammals. The molecule has well-established roles in photosynthetic plants, bacteria and fungi.

& # 39; CSI & # 39; sepsis

The previous study, also conducted by Stocker in collaboration with part of the same group of researchers, revealed that the signaling molecule, cyclic guanosine monophosphate (cGMP), activates protein kinase G1α (PKG1α) when kynurenine dilates blood vessels .

According to the authors of the recent study, however, cis-WOOH-mediated vasodilatation requires significantly less cGMP than kynurenine-mediated vasodilatation, but still requires activation of PKG1α. In contrast to the previous study, researchers have now shown that carefully purified kynurenine does not cause vasodilation in sepsis.

An article published by Nature in its News and Views section compares the search for the real culprit who dilates the blood vessels in sepsis to a classic polar.

"One of the authors of our article published a study in Nature According to Di Mascio, nine years ago, kynurenine was at the origin of the vasodilatation process. After the data was released, however, other researchers attempted to replicate the results. This has greatly troubled the authors. After all, science is reproducibility. "

The search for the real culprit of sepsis vasodilation requires complex logistics and research coordination involving laboratories from six different countries, he added.

"The coordination of the research in all these laboratories was a major operation, our samples came from Australia in liquid nitrogen, and we finally concluded that for the study published nine years ago, the researchers had probably bought kynurenine contaminated with this other product, cis-WOOH "explained Di Mascio.

He recalled that the compound created by the reaction between tryptophan and singlet oxygen had been identified and characterized in a study published in 2008 by Graziella Ronsein, professor at the IQ-USP.

"The important point is that this latest study could lead to new treatments and new approaches," he said. "The mortality due to sepsis is very high in the world, and I think we will see interesting developments that will be positive for society as a result of this study."