The investigation of the immunomodulatory, antioxidant and antiapoptotic effects of melatonin during lipopolysaccharide-induced endotoxemia : an experimental study

[D. Sokolović]

150 listova

Biografija autora: list 150. Bibliografija: listovi 125-149.

Immunology

Sepsis is damage to multiple organs, which is caused by an extreme inflammatory response of the host to the infection. The most well-known molecule of microorganisms that cause an inflammatory reaction during sepsis is lipopolysaccharide (LPS), also known as endotoxin, which forms the cell wall of gramnegative bacteria. Through its contact with the Toll-like receptor 4 of immune cells, it causes the activation of intracellular cascades, the translocation of NF-κB into the nucleus, which increases the expression of genes encoding pro-inflammatory cytokines. Melatonin is a hormone synthesized in the pineal gland, it is a regulator of the circadian rhythm and has significant antioxidant and anti-inflammatory effects. The aim of the research within the doctoral dissertation is to examine the immunomodulatory, antioxidant and antiapoptotic effects of melatonin during endotoxemia caused by Escherichia coli lipopolysaccharide. During experimental endotoxemia caused by LPS, there was an increase in the number of neutrophils, a decrease in the number of lymphocytes (due to their massive apoptosis), an increase in the neutrophil-lymphocyte ratio and thrombocytopenia (due to increased consumption of platelets), all of which indicate a state of sepsis. Administering melatonin during endotoxemia normalizes the number of lymphocytes, as well as the ratio of neutrophils and lymphocytes. Endotoxemia in the liver tissue led to an increase in the level of NF-κB and pro-inflammatory cytokines (TNF-α and IL-6), more intense oxidative stress (by increasing lipid peroxidation, decreasing the level of reduced glutathione and decreasing antioxidant defense enzymes), increasing the content of Nrf-2 protein, as well as more intensive apoptosis (by increasing the activity of DNase and caspase-3). Also, during endotoxemia, there was an increase in the level of nitric oxide in the liver (by increasing the activity of iNOS and decreasing the activity of arginase) and increasing the catabolism of polyamines (by increasing the activity of polyamine oxidase).The neurohormone melatonin exerted significant immunomodulatory effects in liver tissue, reducing the activity of myeloperoxidase (which is associated with the inhibition of neutrophil infiltration), lowering the level of proinflammatory cytokines and nitric oxide, which significantly prevented the induced septic condition. In the liver, melatonin reduced the intensity of oxidative damage, showed a significant antiapoptotic effect and redirected Larginine metabolism towards polyamine biosynthesis.The results of this research showed that melatonin has a great hepatoprotective potential during endotoxemia, and can be used as a therapeutic agent in patients with sepsis.

melatonin, lipopolisaharid, NF-κB, TNF-α, interleukin-6, oksidativni stres, apoptoza, azot-monoksid, Nrf-2

melatonin, lipopolysaccharide, NF-κB, TNF-α, interleukin-6, oxidative stress, apoptosis, nitric oxide, Nrf-2

612.017:577.17(043.3)

B500, B740, P004

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