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Abstract

Ischemia-reperfusion damage causes high morbidity and mortality for patients who have clinical conditions such as myocardial infarction, organ transplantations, cerebrovascular infarction, cardiopulmonary resuscitation, thrombolytic therapy and hemorrhagic shock. Ischemic tissue damage starting with decreasing blood supply and oxygen deficiency in affected tissues increases through reoxygenation when reperfusion provided. Decreasing mitochondrial ATP production causes shift from aerobic to anaerobic intracellular metabolism and leads to acidosis. Decelerating of ATP dependent Na-K pumps leads to increased intracellular hydrogen load. This increase in hydrogen ions is balanced with increased intracellular calcium levels via Na-Ca pumps. Increased calcium ions also activate many cytosolic proteases. Tissue reoxygenation with reperfusion accelerates several critical biochemical pathways for the production of reactive oxygen species (ROS) such as hydroxyl radicals (OH•), superoxide radicals (O2•-) and hydrogen peroxides H2O2 and reactive nitrogen species (RNS) such as peroxynitrides (ONOO-). However, increased reactive radicals can lead to collection of inflammatory cells to the inflammatory region. Cytokines released through the interaction between inflammatory (especially polymorphonuclear leukocytes) and endothelial cells cause expanding of damage due to reperfusion. Xanthine oxidase, nitric oxide synthase, NADPH oxidase, which is responsible for respiratory burst in phagocytes, and electron transport chain in mitochondria are the main mechanisms responsible for the production of ROS and RNS. These free radicals attack important macromolecules such as lipid structures of cell membranes, intracellular proteins and genetic material and can cause cell damage and death. Since ischemiareperfusion injury is a quite complex process, the relationship between ischemia-reperfusion and oxidative stress mainly discussed in this review

Keywords

• Ischemia-reperfusion damage, Oxidative stress, Reactive oxygene species

İSKEMİ-REPERFÜZYON HASARI VE OKSİDATİF STRES İLİŞKİSİNE BİYOKİMYASAL BAKIŞ

Abstract

İskemi-reperfüzyon hasarı; miyokard infarktüsü, serebrovasküler infarkt, organ transplantasyonları, kardiyopulmoner resusitasyon, trombolitik tedavi ve hemorajik şok gibi birçok klinik durumda halen hastalar için yüksek morbidite ve mortalite nedenidir. Dokuya giden kan akımının azalması ve oksijen yetersizliği ile başlayan iskemik doku hasarı, reperfüzyon sağlandığında hasarlanmış dokuların yeniden oksijenasyonu ile artarak devam eder. Hücrelerdeki mitokondriyel ATP üretiminin azalması hücre içi metabolizmanın anaerobik yöne kaymasına ve hücre içi asidoza sebep olur. ATP bağımlı Na-K iyon pompalarının yavaşlaması, hücre içi hidrojen artışına yol açar. Artmış hidrojen yükünü dengelemek için ATP bağımlı olmayan Na-Ca pompası intraselüler kalsiyum miktarını artırır. Artmış kalsiyum yükü ise birçok sitozolik proteazı aktive eder. Hücre içi proteaz aktivasyonu ve reperfüzyonla dokuların yeniden oksijenasyonu ise sonuçta hidroksil radikali (OH•), süperoksit radikali (O2•−) ve hidrojen peroksit H2O2 gibi reaktif oksijen türleri (ROS) ile peroksinitrit (ONOO-) gibi reaktif nitrojen türlerinin (RNS) üretimine yol açan kritik biyokimyasal yolakları hızlandırır. Ayrıca artmış serbest radikallerin neden olduğu inflamasyon, bölgeye inflamatuvar hücrelerin toplanmasını tetikler. Endotelyal hücrelerle başta polimorf çekirdekli lökositler olmak üzere inflamatuvar hücreler arasındaki etkileşimler, birçok sitokinin salınmasına ve iskeminin yol açtığı hasarın reperfüzyonla genişlemesine yol açar. Ksantin oksidaz, nitrik oksit sentaz, mitokondrilerde bulunan elektron transport zinciri ve fagositlerdeki solunumsal patlamadan sorumlu NADPH oksidaz, ROS ve RNS üretiminden sorumlu başlıca mekanizmalardır. Sonuçta oluşan serbest radikaller hücre membranlarındaki lipit yapılar, hücre içi yapısal ve fonksiyonel proteinler ve genetik materyal gibi önemli makromoleküllere zarar vererek hücre hasarı veya ölümüne yol açarlar. İskemi-reperfüzyonda hasar oluşumu oldukça kompleks bir süreç olup, bu derlemede başlıca oksidatif stres ile ilişkisi ele alınmıştır.

Keywords

• İskemi-reperfüzyon hasarı, oksidatif stres, reaktif oksijen türleri

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