Apoptosis and Necrosis Concepts

Cell Injury and Cell Death

• Cell injury occurs due to biochemical and morphologic changes
• It is caused by exogenous factors (like trauma, heat, cold, radiation, chemicals, bacterial toxins and drugs) or endogenous factors (like inborn errors of metabolism, sickle cell disease, intestinal malabsorption, obesity and malnutrition)
• Cell injury results in reversible damage or irreversible disruption of normal cell function
• Hypoxia is a decrease in the supply of oxygen, caused by a complete block in the oxygen supply
• Anoxia is a condition where there is a lower concentration of oxygen in the air; examples include high altitude or drowning and lung disease. Other examples of this are anemia, Ischemia, thrombosis, embolism, rupture of an aneurysm, and cyanide poisoning.

Learning Objectives

• List causes of cell injury
• Describe effects of cell injury
• Define reversible and irreversible cell injury
• Compare reversible and irreversible cell injury
• Define necrosis and apoptosis and list main differences
• List characteristic cellular changes observed in necrosis
• List characteristic cellular changes observed in apoptosis
• Compare/contrast healthy and necrotic cells based on morphology in H&E stained and electron micrograph images
• Describe mechanisms of apoptosis and its regulation
• Diagram intrinsic and extrinsic pathways of apoptosis induction, emphasizing proteins activating caspases
• Differentiate between necrosis and apoptosis based on cellular morphology in microscopic images
• Define anoikis and correlate it with tumor metastasis

Cell and Tissue Injury

• Cell injury is a consequence of biochemical and morphologic changes

• Causes include exogenous (e.g. trauma, heat/cold, radiation, chemicals) and endogenous factors (e.g., metabolic errors, nutritional deficiencies).

• Reversible cell injury may involve swelling of endoplasmic reticulum and mitochondria, membrane blebs and myelin figures. Recovery is possible.

• Irreversible injury results in necrosis or apoptosis

Exogenous Causes of Cell Injury

• Physical injury: Trauma, heat or cold; ultraviolet light or ionizing radiation
• Chemical injury: Alcohol or corrosive substances
• Bacterial toxicity: Cholera toxin inducing watery diarrhea, mercury toxicity to the kidneys
• Drug toxicity: Mercury toxicity to the kidneys

Endogenous Causes of Cell Injury

• Genetic defects: Inborn errors of metabolism, sickle cell disease
• Nutritional deficiency: Intestinal malabsorption resulting from celiac disease, obesity, malnutrition

What Happens to Injured Cells?

• ATP depletion: Detachment of ribosomes; increased anaerobic glycolysis; lactic acid accumulation; decreased activity of enzymes; reduced activity of plasma membrane ATP-dependent sodium pumps; lysosomal membrane damage.
• Mitochondrial damage: Swelling of the inner mitochondrial membrane; altered membrane permeability; affecting transmembrane potential and opening of pores
• Calcium changes: Loss of calcium homeostasis; effects within the cell; activation of ATPases, proteases, phosphatases and endonucleases.
• Free radical formation: Reactions with inorganic and organic material; production and removal rates of free radicals; lipid peroxidation leading to membrane damage; protein modifications leading to mis-folding; DNA damage leading to mutations

Types of Cell Injury

• Two types: Reversible and irreversible
• Reversible causes: Exposure to toxins in low concentration, brief hypoxia or anoxia
• Irreversible causes: Heavy doses of toxins, anoxia, severe and prolonged hypoxia, or injury that is unable to recover from

Reversible Cell Injury

• A form of cell injury in which the cell can recover to its original steady state
• The changes produced are called reversible cell injury
• If adverse environmental influences evoke a cellular response that remains within the range of homeostasis then responses remain within the range of homeostasis and cells return to original state after cessation of injury
• Recognized by: Mild injury that happens in the body, short-lived, like a cold or virus, induced by low concentration of toxins, hypoxia, or brief period of anoxia during anaerobic respiration, disruption of Na+/K+ ATPase pump going back to normal
• Leading to: Cell swelling, impaired cellular regulation; mitochondria and endoplasmic reticulum swelling with detachment of ribosomes; surface blebs due to increased calcium, leading to changes in the microfilaments of the cytoskeleton; loss of microvilli structure

Irreversible Cell Injury

• Permanent damage; cannot come back to original function; may lead to cell death
• Occurs when cells are exposed to causes of cell injury and cannot recover; this is a 'point of no return'
• Cell death happens in two ways: necrosis and apoptosis
• Depending on the cause of injury, either necrosis or apoptosis will be the outcome

Necrosis

• The following nuclear changes occur:
• Pyknosis: irreversible condensation of chromatin
• Karyorrhexis: destructive fragment of the nucleus or nucleus burst
• Karyolysis: complete dissolution of the chromatin by endonucleases; basophilia of the nucleus fades
• The following cytoplasmic changes occur: swelling of the organelles (especially mitochondria) and rough ER; rupture of the plasma membrane leading to spillage of all cytoplasmic contents

Types of Necrosis

• Coagulative necrosis: The most common; tissue remains firm; architecture is preserved; cell shape and organ structure are preserved for few days; caused by ischemia or infarction
• Liquefactive necrosis: Tissue becomes liquefied through enzymatic action; maintains cheese-like appearance
• Caseous necrosis: Dead tissue appears soft and white; frequently associated with TB
• Gangrene: Dry gangrene is coagulative necrosis resembling mummified tissue; wet gangrene is superimposed infection and then liquefactive necrosis
• Fat necrosis: Involves adipose tissue; restricted to smooth muscle wall of small arteries, arterioles, and renal glomeruli
• Fibrinoid necrosis: Necrotic tissue and debris disappear by a combined process, or if not destroyed, they attract calcium salts and other minerals resulting in calcification

Apoptosis

• A type of programmed cell death

• Two types: Intrinsic (or Mitochondrial) pathway and Extrinsic (or Death Receptor) pathway

• Intrinsic pathway: When mitochondria experience damage or an altered cell cycle, they secrete factors (e.g., cytochrome C) and activate procaspase 8

• Extrinsic pathway: Cell surface death receptors (e.g., Fas receptor) are triggered.

• When mitochondrial membranes become permeable, cytochrome C leaks to the cytoplasm; triggers procaspase 9 activation, leading to apoptotic death

• AIF (Apoptosis-inducing factor): Moves to the nucleus, binds to DNA and leads to cell death without caspase participation

• Granzyme B and Perforin: Cytotoxic T cells secrete granzyme B and perforin. Granzyme B enters the infected cell and perforin forms pores on the cell membrane.

• Causes of apoptosis include growth factor withdrawal, DNA damage, and protein misfolding.

Anoikis

• A special form of apoptotic process occurring in cells in response to loss of adhesion to the ECM
• Critical for maintaining tissue homeostasis
• Some cancer cells develop mechanisms to escape anoikis, which can lead to seeding in inappropriate sites

Other Forms of Programmed Cell Death

• Autophagy, paraptosis, pyroptosis, mitotic catastrophe, and entosis are other types of programmed cell death, including the uncontrolled mechanism of necrosis.

Apoptosis vs Necrosis

• Necrosis is a pathological response to cell injury and Apoptosis is a normal cell response for elimination, following specific signals.
• Chromatin clumping and mitochondrial swelling/rupture are characteristics of necrosis. Cytoplasmic shrinkage is a feature of apoptosis.

Note: Please refer to the provided images for detailed illustrations of the cellular changes. This summary provides an overview and does not replace detailed study using the images.

Test your understanding of apoptosis and necrosis with this quiz. Explore key differences, features of cell death, and the role of energy in these processes. Perfect for students studying cell biology or related fields.