Mechanism of Hypoxia Induced Cell Injury | What Is Hypoxia?

Hypoxia is caused by inadequate oxygenation to the cell because of the lack of blood supply to a tissue due to thrombosis. Haemorrhage can cause hypoxia by interrupting the blood supply or blood is not getting oxygenated properly, as it occurs in cardiorespiratory failure, and the oxygen carrying capacity of blood is diminished in carbon monoxide poisoning hypoxia will occur. The first point of attack of hypoxia is on the cell’s aerobic respiration, in other words, oxidative phosphorylation. Lack of ATP generation leads to an inability of the cell to maintain its ion-transport systems and the cell begins to swell. If the hypoxia continues, extensive damage to the cell membrane and cell death will ensue.

Signs And Symptoms Of Hypoxia

Free Radical Induced Injury

Most agents acting this way cause cell damage by affecting directly cell membranes and trigger a lethal sequence of events. Free radicals are chemical species that have a single unpaired electron in outer orbit, it initiate autocatalytic reaction which mainly occur in reperfusion of the ischemic cell. Activated oxygen radicals are now known to be the common mechanism to cell in injury in many conditions, i.e. aging, chemical and radiation injury, bacterial infections, inflammation, tumor necrosis etc.

Free radicals like superoxide radicals, hydroxyl ions and peroxide ions are very destructive to cells which cause lipid peroxidation, oxidation of protein, DNA damage, and cytoskeleton damage etc. They are initiated within cells by enzymatic reactions and non-enzymatic systems.

The system have a series of protective mechanisms to protect the cells from these free radicals like antioxidant enzymes such as catalase, glutathione peroxidase and superoxide dismutase. Vitamin E and selenium also help for protection from free radical induced cellular damage. The deficiency of all these protective mechanism may lead to free radical reactive cellular damage, especially in muscle. Different causes for initiation of free
radical:

• Ionizing Radiation: Exposure of Ionizing Radiation causes the generation of a variety of free radical species. This occurs following radiation-induced splitting of molecules which often generates free radical products.
• Enzymatic metabolism of chemicals or drugs. For e.g, carbon tetrachloride can generate [CCl3]* which cause autooxidation of the polyenic fatty acid present within membrane
  phospholipids.
• Cellular Respiration: Regulated transfer of free radicals is the basis of the Electron Transport Chain that powers Cellular Respiration. Although the free radicals generated during electron transport are tightly controlled, a small amount can escape and cause damage. Escape of free radicals is substantially enhanced when mitochondria are injured which occurs frequently following metabolic cell injury.
• Chemical Cell Injury: Metabolism of several exogenous chemicals can result in the generation of free radicals. Some metals which accept or donate electron (e–). For e.g. Cu and Fe (Fenton reaction). Nitric oxide (NO) can act as a free radical and converted into highly reactive peroxynitrate anion (ONOO–) as well as NO2* and NO–

Normally, NO can be produced by endothelial, neurons, macrophages etc. The redox reactions occur during normal metabolism. For e.g, in respiration, molecular oxygen is reduced to water by accepting 4 electrons. During this process, small amount of toxic intermediates are formed. Free radical reaction can be studied as follows:

• 1. Lipid Peroxidation: Polyunsaturated fatty acid of membrane is attackedrepeatedly by free radicals to form highly destructive polyunsaturated fatty acid (PUFA) radicals like lipid hydroperoxy radicals and lipid hypoperoxides. This is termed as lipid peroxidation. These lipids are widely spreaded to other part of membrane that is lipid peroxidation takes
  place at adjoining part of membrane causing damage to entire cell membrane.
• 2. Oxidation of protein: Free radical causes cleavage by oxidation of protein macromolecules of cell causing cross linkage in the amino acid sequences of protein and fragmentation of polypeptides.
• 3. Effect on DNA damage: Free radical breaks DNA fragments to single strand, so there will be formation of DNA which is defective. Replication of this DNA is not possible and thereby cell death may occur.
• 4. Cytoskeleton Damage: Free radicals interfere with mitochondrial aerobic phosphorylation and decreases synthesis of ATP leading to cytoskeleton damage. There are certain anti-oxidants present endogenously to fight against these oxidative free radicals like Vitamin-E, sulphahydral containing substances like cystine, SOD, catalase, GTH & serum
  proteins.
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