Influence of oxidative stress on disease development

Abstract

There is ever increasing data indicating the vmast contribution of oxidative stress to the pathogenesis of numerous diseases (atherosclerosis, hypertension, heart failure, diabetes mellitus, stroke, rheumatoid arthritis, and others). Thus, in the pathogenesis of atherosclerosis the primary role is held by reactive oxygen species that are synthetized by endothelial cells of arterial blood vessels, leukocytes and macrophages. Furthermore, native particles of lipoproteins of small density become atherogenic through oxidation caused by reactive oxygen species. The oxidation of small-density lipoproteins stimulates the inflammatory process, and it in turn steps up adhesion and the inflow of monocytes and affects the synthesis and release of numerous proinflammatory cytokines involved in the further course of the process. One of the reasons for the development of arterial hypertension is the simultaneous activation of NAD(P)H oxidase and 12/15-lipoxygenase, since it results in the stepped up production of reactive oxygen species. These stimulate the production of matrix metalloproteinase 2, which lead to vascular remodelling and to increased apoptosis of heart muscle cells. Stepped up apoptosis is linked with myocardial infarction, cardiomyopathies and the development of heart failure. The sensitivity of β-cells of the endocrine part of the pancreas to reactive oxygen species favor the naturally low concentrations of the collectors of free radicals in them, as well as an increase in the concentration of proinflammatory cytokines, glucosis and lipids that induce a reduction in the mass and function of β-cells. Hyperglycemia in diabetes mellitus causes tissue damage through non-enzyme glycosylation of intracellular and extracellular proteins, which results in: reduced enzyme activity, damaged nucleic acid, disrupted natural decomposition of proteins, and activation of cytotoxic pathways. These processes are the basis of the pathogenesis of numerous complications of diabetes mellitus. Since inducible nitrogen-oxide synthesis launches processes that stimulate apoptosis of cerebral endothelial cells, and superoxide-anion radicals, hypochloric acid and hydrogen peroxide damage the parenchyma of an ischemic brain and biomacromolecules (causing lipid peroxidation, oxidation of proteins and deoxyribonucleic acid), brain damage occurs during cerebral ischemia and reperfusion.

Sve više podataka ukazuje na veliki doprinos oksidativnog stresa patogenezi brojnih bolesti (aterosklerozi, hipertenziji, srčanoj insuficijenciji, šećernoj bolesti, moždanom udaru, reumatoidnom artritisu i dr.). Tako, u patogenezi ateroskleroze primarno mesto zauzimaju reaktivne kiseonične vrste koje sintetišu endotelne ćelije arterijskih krvnih sudova, leukociti i makrofagi. Uz to, nativne čestice lipoproteina male gustine postaju aterogene, oksidacijom izazvanom reaktivnim kiseoničnim vrstama. Oksidacija lipoproteina male gustine stimuliše zapaljenjski proces, a on pojačava adheziju i dotok monocita i utiče na sintezu i oslobađanje brojnih proinflamatornih citokina uključenih u dalji tok procesa. Jedan od razloga za razvoj arterijske hipertenzije je istovremena aktivacija NAD(P)H oksidaza i 12/15-lipoksigenaze, jer rezultira pojačanom proizvodnjom reaktivnih kiseoničnih vrsta. One podstiču proizvodnju metaloproteinaza-2 matriksa, koje dovode do vaskularnog remodeliranja i do pojačane apoptoze srčanih mišićnih ćelija. Pojačana apoptoza je povezana sa infarktom miokarda, kardiomiopatijama i razvojem srčane insuficijencije. Osetljivosti β-ćelija endokrinog dela pankreasa na reaktivne kiseonične vrste pogoduju prirodno niske koncentracije skupljača slobodnih radikala u njima, kao i porast koncentracije proinflamatornih citokina, glukoze i lipida koji indukuju smanjenje mase i funkcije β-ćelija. Hiperglikemija kod šećerne bolesti izaziva oštećenja tkiva neenzimskim glikozilovanjem intracelularnih i ekstracelularnih proteina, usled čega se smanjuje enzimska aktivnost, oštećuju nukleinske kiseline, re meti prirodna razgradnja proteina i aktiviraju citotoksični putevi. Ovi procesi su i osnova patogeneze mnogih komplikacija šećerne bolesti. S obzirom na to da inducibilna azot-oksid sintaza pokreće procese koji podstiču apoptozu cerebralnih endotelnih ćelija, a superoksid-anjon radikal, hipohlorna kiselina i vodonik-peroksid oštećuju parenhim ishemičnog mozga i biomakromolekule (izazivaju peroksidaciju lipida, oksidaciju proteina i dezoksiribonukleinske kiseline), tokom cerebralne ishemije i reperfuzije nastaju oštećenja mozga.