A study provides new data on the genetic mechanisms involved in sepsis, the leading cause of death in ICUs
Researchers from the Biosanitary Research Institute of Granada (ibs.GRANADA) have provided new data on the genetic mechanisms related to sepsis, an exaggerated inflammatory response of the body to an infection that is the first cause of death in Intensive Care Units (ICUs). ) of any hospital in the world.
The intracellular communication research group at ibs.GRANADA, whose main researcher is Darío Acuña-Castroviejo, has recently published an article in the prestigious journal shock, in which they study the changes in the expression of the so-called "clock genes" (those responsible for regulating the function of each cell in the body) of septic patients, relating these changes to the degree of inflammatory response, oxidative damage, and levels of 6 -sulphatoxymelatonin, the main metabolite of melatonin in urine and mediator of clock genes.
Sepsis in a patient leads to the formation of numerous pro-inflammatory molecules, such as inducible nitric oxide synthase, which produces large amounts of nitric oxide, a very powerful vasodilator that, together with other molecules, will reduce blood pressure and decrease blood intake. blood to tissues. These two responses are the basis for the hypovolemic shock and multi-organ failure that septic patients develop, culminating in their death.
In Spain there are about 180.000 cases of sepsis per year, and mortality reaches 25% of patients in the ICU. Treatment consists of antibiotics to slow the infection, as well as interventions to slow the systemic inflammatory response and restore blood pressure. However, there are currently no specific treatments for sepsis to control this inflammatory response and multi-organ failure.
The "clock genes" are part of a centralized system called the biological clock, which regulates the rhythmic functions of the organism. From the sleep/wake rhythm to the rhythm of brain neurotransmitters, through hormonal and metabolic rhythms, all circadian rhythms are under the control of said clock.
The activity of the immune system is another rhythmic function controlled by the clock genes, in such a way that they act as a brake to limit its activity. But when there is an alteration in the expression of the clock genes, innate immunity can be triggered and, in turn, some of the pro-inflammatory cytokines produced as a result of this inflammatory activation alter the clock genes themselves, establishing a vicious circle that enhances a increased inflammatory response.
Clock gene expression in septic patients
This hypothesis is the one that has been analyzed in this study. To do this, the researchers determined the expression of clock genes in the blood of septic patients, comparing it with non-septic patients, both hospitalized in the same ICU and, therefore, under the same environmental conditions.
The results indicated that the degree of alteration in the expression of the clock genes is directly related to the severity of the inflammatory response. When septic patients recovered and inflammation was reduced, the expression of clock genes also recovered. The alteration of the clock genes was also related to the degree of oxidative stress produced by the inflammatory response, as well as to the biochemical markers of sepsis, such as procalcitonin.
In addition, melatonin production increased directly with inflammation, being higher in septic patients than in non-septic patients. This melatonin was negatively associated with oxidative stress indexes and inflammation markers, indicating that its production was due to a compensatory response of the organism to fight against the inflammatory process.
The results of this work demonstrate the participation of the alteration of the clock genes in the inflammatory response of sepsis, and that melatonin is associated with an improvement in the evolution of said response and improvement in patients.
Bibliographic reference:
Carlos Acuna-Fernandez; Jorge Marin; Maria Diaz Married; Iryna Rusanova; Beneharo Darias-Delbey; Luis Perez-Guillama; Javier Florido-Ruiz; Dario Acuna-Castroviejo.
Daily Changes in The Expression of Clock Genes in Sepsis and Their Relation with Sepsis Outcome and Urinary Excretion of 6-Sulfatoxymelatonin. Shock 2019; DOI: 10.1097 / SHK.000000000000143.