Regulation of hepcidin in chronic inflammation induced by inhalation anaesthetics and iron dextran in rats

U radu je istražen učinak inhalacijskih anestetika u nazočnosti željeza na prooksidacijske/antioksidacijske učinke perifernih tkiva i organa u kroničnoj upali. Cilj rada je spoznaja kako prekomjerni unos željeza mijenja fiziološke, funkcionalne značajke perifernih tkiva i kako različiti anestetici mijenjaju metabolizam stanica s obzirom na prijelazne metale kao inicijatore nastanka reaktivnih vrsta kisika (ROS) i upale kroz regulaciju hepcidina, transferina i makrofagne polarizacije. Štakori soja Y59 su intraperitonelno (ip) injicirani otopinom željezo dekstrana u dozi od 50 mg/kg ili su izloženi inhalacijskim anesteticima sevofluranu (2,4%) i izofluranu (1,3%) te kombinaciji tijekom 28 dana svaki drugi dan. Rezultati pokazuju da primjena anestetika smanjuje tjelesnu težinu štakora, povećava oksidacijski stres (OS) u perifernim tkivima vodeći M1 makrofagnoj polarizaciji. Prekomjerni unos željeza vodi nakupljanju željeza u perifernim tkivima, povećanju OS i upale te povećanju odnosa IL-12/IL-10 citokina prema M1 makrofagnom fenotipu. Kombinacija sevoflurana i željeza akumulira željezo u tkivima pokazujući protektivni učinak željeza i M2 fenotip makrofaga. Kombinacija željezo dekstrana i izoflurana kod štakora vodi hipoksiji, pojačanom otpuštanju željeza iz makrofaga retikulo-endotelnog sustava te pojačanoj eritropoezi. Razina hepcidina u jetri regulirana je složenom međureakcijom upale, oksidacijskog stresa, razine slobodnog željeza, eritropoezom i hipoksijom.The thesis investigates the effect of inhaled anaesthetics in the presence of iron on the prooxidative/antioxidant effects of peripheral tissues and organs in chronic inflammation. It intends to understand how excessive iron intake alters physiological, functional characteristics of peripheral tissues and whether different anaesthetics can alter cell metabolism regarding transition metals as initiators of reactive oxygen species (ROS) and inflammation through regulation of hepcidin, transferrin, and macrophage polarization. Y59 rats were injected intraperitoneally (ip) a solution of iron dextran at a dose of 50 mg/kg or were exposed to inhaled anaesthetics sevoflurane (2.4%) and isoflurane (1.3%) and the combination for 28 days every other day. The results show that anaesthetics reduce the rat's body weight and increase oxidative stress (OS) in peripheral tissues, leading to M1 macrophage polarization. Excessive iron intake leads to iron accumulation in peripheral tissues, an increase in OS and inflammation, and an increase in the ratio of IL-12/IL-10 cytokines to the M1 macrophage phenotype. The combination of sevoflurane and iron accumulates iron in tissues, showing iron's protective effect and the M2 phenotype of macrophages. The combination of iron dextran and isoflurane in rats leads to hypoxia, increased iron release from macrophages of the reticuloendothelial system and increased erythropoiesis. Hepcidin levels in the liver are regulated by a complex interreaction of inflammation, oxidative stress, free iron levels, erythropoiesis and hypoxia