General Responses of Cells and Tissues to Injury

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• Oxygen deprivation is a very important and common cause of cell injury and death.
• This may be caused by:

1. Ischaemia: insufficient blood supply reduced the oxygen carried to tissues as well as compromising the availability of metabolic substrates (e.g., glucose);
2. Severe respiratory problems: leads to insufficient gas exchange (e.g., respiratory arrest);
3. Loss of oxygen-carrying capacity of the blood (e.g., carbon monoxide poisoning).

• This includes:

1. Mechanical trauma;
2. Extremes of temperature;
3. Sudden changes in atmospheric pressure;
4. Radiation;
5. And electric shocks.

• This includes:

1. Simple chemicals (e.g., glucose) in hypertonic solutions;
2. Trace amounts of poisons (e.g., cyanide);
3. Alcohol and narcotic drugs;
4. Side effects of therapeutic drugs;
5. As well as background, low-level effects from environmental pollutants (e.g., pesticides).

• These range from tiny viruses to larger and higher form of parasites (e.g., tapeworm).

• This is from hypersensitivity by the immune system (e.g., anaphylactic reaction to a foreign protein or drug).

• Inborn errors of metabolism may cause cell injury.

• There may be deficiencies (e.g., in proteins or specific vitamins), excesses (e.g., in lipids causing atherosclerosis) or lack of an appropriate balance.

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• There are 4 intracellular systems that are particularly vulnerable:

1. Aerobic respiration and the production of ATP;
2. The maintenance of cell membrane integrity;
3. The synthesis of new proteins and enzymes;
4. And the maintenance of the integrity of DNA synthesis and repair.

• There are also several biochemical themes that mediate cellular injury:

1. ATP depletion;
2. Oxygen-derived free radicals;
3. Loss of calcium homeostasis;
4. Defects in membrane permeability;
5. And irreversible mitochondrial damage.

• ATP is required for important processes inside the cells like membrane transport, protein synthesis, and lipogenesis. Thus, its depletion causes significant damage to the cell.
• This is a common consequence of both ischaemic and toxic injury.

• These free radicals may be generated by:

1. Absorption of radiant energy (e.g., UV light);
2. Oxidative metabolic reactions;
3. Enzymatic conversions of exogenous chemicals or drugs;
4. Or as a by-product of mitochondrial respiration.

• These highly reactive unstable species interact with and damage proteins, lipids and carbohydrates.

• Free radicals in the presence of oxygen may cause peroxidation of lipids.
• These lipid peroxides are unstable and reactive causing an autocatalytic chain reaction, which may cause extensive damage to plasma membranes.

• Ischaemia and some toxins cause a net influx of Ca²⁺ into the cell and release Ca²⁺ from the endoplasmic reticulum.
• This results in the activation of various enzymes that degrade the cell:

1. Phospholipases degrade membrane phospolipids;
2. Proteases break down membrane and cytoskeletal proteins;
3. ATPases hasten ATP depletion;
4. And endonucleases are associated with chromatin fragmentation.

• Early loss of selective membrane permeability is a consistent feature of all forms of cell injury.
• The membrane may be damaged directly by toxins, physical and chemical agents or indirectly (e.g., as in loss of calcium homeostasis).

• Mammalian cells are obligately dependent on oxidative metabolism for long-term survival.
• Thus, if its mitochondria are irreparably damaged, the cell will eventually die.

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• When a cell is able to handle "normal physiologic demands".

• New and altered steady states may be achieved with excessive physiologic stress or some pathologic stimuli (e.g., hypertrophy of the myocardium in hypertension).

• However, this altered growth to the stimulus may be pathological (e.g., the development of a neoplasm).
• Whether the change is reversible depends on the tissue (e.g., atrophy involves both reduction in size and loss of cells; for a tissue to be able to recover, it must have the ability to undergo mitosis).

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• This is where the pathologic changes may be reversed when the stimulus is removed.

• This is usually an early and common manifestation of non-lethal hypoxic injury.
• This is caused by the failure of Na⁺, K⁺-ATPase; resulting in sodium entering the cell and potassium leaving, and an isosmotic gain of water.
• The endoplasmic reticulum balloons out as does the mitochondria.

• This increase in water volume is known as "hydropic change" or "vacuolar change" if there is a formation of vacuoles.
• These changes are reversible if oxygenation is restored.

• Various substances (e.g., proteins, lipids, etc.) can accumulate in cells and sometimes result in cell injury.
• They may be:

1. A normal cellular constituent accumulating in excess (e.g., TAG in fatty liver);
2. An abnormal substance, usually a product of abnormal metabolism.
3. A pigment (e.g., lipofuscin).

• This sort of cell injury is usually reversible.
• However, depending on the intensity and duration of the accumulation, it may become irreversible.

• This refers to any alteration within cells or extracellular spaces that gives a homogeneous, glassy-pink appearance in routine H&E sections.
• This includes viral inclusions in the cytoplasm or nucleus, or masses of altered intermediate filaments.

• Amyloid also has a hyaline appearance.
• It is, however, a fibrillar protein with specific biochemical characteristics.
• When it is stained with Congo red, it appears red and shows green bipolar refringence.

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• When the injury to the cell is irreparable, it will eventually lead to cell death.
• There are two important patterns of cell death:

1. Apoptosis;
2. And necrosis.

• The cell itself expends energy to "commit suicide".
• The features of this process include:

1. Marked condensation and fragmentation of the nucleus;
2. Shrinkage of the cell;
3. The formation of cytoplasmic blebs and apoptotic bodies;
4. There are phospholipid changes on the membrane;
5. And the fragments are taken up by surrounding cells and macrophages by phagocytosis with no inflammatory response.

• The pattern of cell death occurs in embryogenesis, cell deletion in proliferating populations (e.g., intestinal epithelium) and certain viral diseases.

• The morphological change is caused by 2 underlying processes:

1. Denaturation of proteins;
2. And enzymatic digestion of organelles and cytoplasm.

• The lysosomal enzymes of a cell digest itself in "autolytic change".
• One of the earliest morphological changes of necrosis is the conspicuous lack of a nucleus (due to autolysis).

Note:
pyknosis = small dark shrunken nuclei
karyorrhexis = nuclear fragmentation
karyolysis = dissolution of nuclear material

• Necrosis with secondary putrefaction is gangrene.

Bibliography

Cotran, R., Kumar, V., Collins, T. (1999) Robbins Pathologic Basis of Disease 6th Ed. W.B. Saunders Company, Philadelphia, Pennsylvania, USA.

Robbins, S., Cotran, R., Kumar, V. (1995) Pocket Companion to Robbins Pathologic Basis of Disease 5th Ed. W.B. Saunders Company, Philadelphia, Pennsylvania, USA.

Kumar, R. University of NSW, Pathology (PATH 3101) Lecture. 3 & 4 March 1999.

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