Page 49 - Textbook of Pathology, 6th Edition

2. Hydrogen peroxide (H O ): H O is reduced to water peroxides. This reaction is termed lipid peroxidation. The 33
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enzymatically by catalase (in the peroxisomes) and lipid peroxides are decomposed by transition metals such
glutathione peroxidase GSH (both in the cytosol and as iron. Lipid peroxidation is propagated to other sites
mitochondria). causing widespread membrane damage and destruction of
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3. Hydroxyl radical (OH ): OH radical is formed by 2 ways organelles.
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in biologic processes—by radiolysis of water and by reaction ii) Oxidation of proteins. Oxygen-derived free radicals cause CHAPTER 3
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of H O with ferrous (Fe ) ions; the latter process is termed cell injury by oxidation of protein macromolecules of the cells,
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as Fenton reaction. crosslinkages of labile amino acids as well as by fragmen-
tation of polypeptides directly. The end-result is degradation
Other oxygen free radicals. In addition to superoxide, H O 2 of cytosolic neutral proteases and cell destruction.
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and hydroxyl radicals generated during of O to H O
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reaction, a few other more active oxygen free radicals which iii) DNA damage. Free radicals cause breaks in the single
formed in the body are as follows: strands of the nuclear and mitochondrial DNA. This results
i) Release of superoxide free radical in Fenton reaction (see in cell injury; it may also cause malignant transformation of
below). cells.
ii) Nitric oxide (NO), a chemical mediator generated by iv) Cytoskeletal damage. Reactive oxygen species are also
various body cells (endothelial cells, neurons, macrophages known to interact with cytoskeletal elements and interfere
etc), combines with superoxide and forms peroxynitrate in mitochondrial aerobic phosphorylation and thus cause
(ONOO) which is a potent free radical. ATP depletion. Cell Injury and Cellular Adaptations
iii) Halide reagent (chlorine or chloride) released in the Conditions with free radical injury. Currently, oxygen-
leucocytes reacts with superoxide and forms hypochlorous acid derived free radicals have been known to play an important
(HOCl) which is a cytotoxic free radical. role in many forms of cell injury:
iv) Exogenous sources of free radicals include some environ- i) Ischaemic reperfusion injury
mental agents such as tobacco and industrial pollutants. ii) Ionising radiation by causing radiolysis of water
iii) Chemical toxicity
Cytotoxicity of oxygen free radicals. Free radicals are formed iv) Chemical carcinogenesis
in physiologic as well as pathologic processes. Basically, v) Hyperoxia (toxicity due to oxygen therapy)
oxygen radicals are unstable and are destroyed spon- vi) Cellular aging
taneously. The rate of spontaneous destruction is determined vii) Killing of microbial agents
by catalytic action of certain enzymes such as superoxide viii) Inflammatory damage
dismutase (SOD), catalase and glutathione peroxidase. The ix) Destruction of tumour cells
net effect of free radical injury in physiologic and disease x) Atherosclerosis.
states, therefore, depends upon the rate of free radical
formation and rate of their elimination. Antioxidants. Antioxidants are endogenous or exogenous
However, if not degraded, then free radicals are highly substances which inactivate the free radicals. These
destructive to the cell since they have electron-free residue substances include the following:
and thus bind to all molecules of the cell; this is termed Vitamins E, A and C (ascorbic acid)
oxidative stress. Out of various free radicals, hydroxyl radical Sulfhydryl-containing compounds e.g. cysteine and
is the most reactive species. Free radicals may produce glutathione.
membrane damage by the following mechanisms (Fig. 3.9): Serum proteins e.g. ceruloplasmin and transferrin.
i) Lipid peroxidation. Polyunsaturated fatty acids (PUFA) of 3. SUBSEQUENT INFLAMMATORY EACTION.
membrane are attacked repeatedly and severely by oxygen- Ischaemia-reperfusion event is followed by inflammatory
derived free radicals to yield highly destructive PUFA reaction. Incoming activated neutrophils utilise oxygen
radicals—lipid hydroperoxy radicals and lipid hypo- quickly (oxygen burst) and release a lot of oxygen free radicals.
Ischaemia is also associated with accumulation of precursors
of ATP, namely ADP and pyruvate, which further build-up
generation of free radicals.

Pathogenesis of Chemical Injury
Chemicals induce cell injury by one of the two mechanisms:
by direct cytotoxicity, or by conversion of chemical into
reactive metabolites.

DIRECT CYTOTOXIC EFFECTS. Some chemicals combine
with components of the cell and produce direct cytotoxicity
without requiring metabolic activation. The cytotoxic damage
Figure 3.9 Mechanism of cell death by hydroxyl radical, the most is usually greatest to cells which are involved in the
reactive oxygen species. metabolism of such chemicals e.g. in mercuric chloride