Cell injury and necrosis

When the nature of injury is such that the cell can no longer adapt, the cell undergoes reversible and/or irreversible changes which may lead to cell necrosis, apoptosis and death.

Reversible cell injury

• Reduced oxidative phosphorylation and ATP formation
• Generalized swelling of the cell and organelles
• Formation of plasma membrane blebs
• Detachment of ribosomes from the RER
• Clumping of nuclear chromatin
• Myelin figures appear

Irreversible cell injury

• Mitochondrial damage with swelling and amorphous deposits
• Necrosis
• Apoptosis
• Lysosomal enzymes digest cytosolic structures
• Increased cellular swelling
• Swelling and disruption of the lysosomes
• Disruption of cellular membranes
• Nuclear pyknosis, karyorrhexis and karyolysis
• Prominent myelin figures

Causes of cell injury

Cell injury may result from various causes acting on a gross and microscopic level.

1. Hypoxia: It is inadequate oxygenation of tissue. In hypoxia, tissues either cannot utilize oxygen or they do not get enough oxygen. Hypoxia may be due to hypoxemia (reduced PaO2 from low inspired oxygen concentration, hypoventilation, V/Q defects, shunts, diffusion defects and circulatory shock),anemia, CO poisoning, methemoglobinemia, cyanide poisoning and shock. It results in reduced ATP formation by the mitochondria.

2. Physical injury: Physical trauma, extremes of temperatures, electric shock, barometric pressure changes etc. can all cause cellular injury e.g. frostbite in extreme cold weather.

3. Chemical injury: Adverse and toxic effects of drugs, poisons like carbon tetrachloride, strong acids and alkalis etc., heavy metals like lead, arsenic, mercury etc. are included in a long and ever increasing list of chemical agents that cause cell injury and cell death.

4. Infectious agents: All types of pathogenic microbes including viruses, bacteria, fungi, rickettsia, parasites and prions can cause cell injury.

5. Immune reactions: Failure of immune regulation may result in host tissue damage as a result of immune reactions. Injury may also occur from autoimmunity and complement mediated damage e.g. Grave’s disease, Goodpasture’s syndrome, paroxysmal nocturnal hemoglobinuria etc.

6. Nutritional imbalances: Both nutritional deficiencies and nutritional excess cause cell injury ranging in spectrum from kwashiorkor, marasmus, anemia to obesity and metabolic syndrome.

7. Genetic defects: Genetic mutations lead to various disorders such as cystic fibrosis, sickle cell anemia, Marfan’s syndrome. Most of them are inherited.

Mechanisms of cell injury

Multiple defects are seen in cellular function as a manifestation of cell injury.

1. Depletion of ATP: It is seen in hypoxic and chemical cell injuries. Injuries may affect oxidative phosphorylation in the mitochondria and glycolysis leading to reduced ATP production. Depletion of ATP causes dysfunction of the Na+K+ATPase pump leading to increased intracellular Na+ concentration, which causes osmosis and water flows into the cell leading to cellular swelling. Hypoxia also results in increased anaerobic glycolysis and lactic acid formation which decreases the intracellular pH, due to which some enzymes may get inactivated. ATP depletion also affects the function of the Ca++ pump leading to an influx of Ca++ into the cells. Increased intracellular Ca++, in turn, activates various enzymes such as ATPases, phospholipases, proteases and endonucleases and increases mitochondrial membrane permeability leading to apoptosis. ATP depletion also interferes with ribosomal protein synthesis, causing detachment of ribosomes from RER and dissociation of polysomes. Protein misfolding occurs.

2. Mitochondrial damage: Damage to the mitochondrial membrane is reversible in the early stages but becomes irreversible if the injury persists or is severe. Membrane damage causes mitochondrial swelling and loss of mitochondrial proton motive force and ATP production by oxidative phosphorylation stops. Cyt c is released from the mitochondria initiating apoptosis.

3. Influx of Ca++ into the cell: Most intracellular Ca++ is sequestered in the endoplasmic reticulum and mitochondria. Ischemia and toxins can cause the release of Ca++ from its intracellular stores leading to activation of lytic enzymes.

4. Free radical injury: Free radicals are reactive oxygen species. Free radicals have a single unpaired electron in their outer orbit. Cell injury by free radicals is seen in radiation and chemical induced injury, ischemia-reperfusion injury and aging. Free radicals are created on exposure to ionizing radiation (OH and H free radicals); all living cells and immune cells from normal metabolism (O2- or superoxide anion, H2O2 and OH), nitric oxide and nitrites, metals like iron and copper and during metabolism or detoxification of drugs and toxins like paracetamol. Free radicals cause damage to the cell by multiple mechanisms. They cause peroxidation of lipids in the cell and organelle membrane, forming peroxides that kickstart an autocatalytic reaction leading to more severe cellular damage. Free radicals also cause oxidative modification of proteins leading to protein breakdown. Free radicals cause single stranded breaks in both nuclear and mitochondrial DNA.

Stepwise reduction of O2 to H2O

The body uses several mechanisms to counteract the action of free radicals and to actively neutralize them. Catalase breaks down H2O2 into O2 and H2O. Superoxide dismutase converts superoxide to H2O2. Reduced glutathione in the enzyme glutathione peroxidase scavenges free radicals like H2O2 and OH- converting them to H2O. Reduced glutathione is converted to oxidized glutathione in the process. The enzyme glutathione reductase uses NADPH from the pentose phosphate pathway, to keep glutathione in the reduced state. The body keeps metals like iron and copper bound to storage and transport proteins as ferritin, transferrin, ceruloplasmin etc. to prevent the formation of OH free radicals from free iron and copper. Vitamins A,E,C and glutathione are naturally occurring antioxidants.

1. Membrane damage: Membrane phospholipids are affected in cell injuries. Phospholipases cleave the cell membrane phospholipids. Cytoskeletal filaments are broken down causing the cell membrane to detach from the cytoskeleton and promoting cellular swelling and rupture. There is an influx of fluid and ions into the cells. Rupture of lysosomes releases enzymes such as proteases, DNSases, RNAases, cathepsins etc. leading to the dissolution of cellular components.