Pathology (CELL INJURY, CELL DEATH, and CELLULAR ADAPTATION)

Reversible Cell Injury

→ Stage of cell injury at which the deranged function and morphology of the injured cells can return to normal if the damaging stimulus is removed

Irreversible Cell Injury

→ Occurs when when the damage is so severe that the cell cannot recover, even after the removal of the injurious stimulus

→ Leads to cell death

Necrosis

→ “Accidental cell death”

→ Occurs as a result of acute injury, infection, or other harmful condition

1. Initial Injury

2. ATP Depletion

3. Increased Intracellular Calcium

4. Cell Swelling and Membrane Damage

5. Loss of Organelles and Nuclear

6. Leakage of Cellular Contents

7. Inflammation and Tissue Damage

Stages of Necrosis

Initial Injury

→ Triggers: trauma, infections, toxins, ischemia

→ Impact:

• Loss of cell membrane integrity and disrupt cellular homeostasis

• Leads to influx of calcium ions and water, resulting in cell swelling

ATP Depletion

→ Mitochondrial Dysfunction

• Injury leads to mitochondrial damage

• Sharp decline to ATP production

  → Failure of Ion Pumps

  • ATP-dependent ions pumps fail

  • Accumulation of sodium inside the cell

  • Leads to osmotic swelling

 Mitochondrial Dysfunction

• Injury leads to mitochondrial damage

• Sharp decline to ATP production

→ Failure of Ion Pumps

• ATP-dependent ions pumps fail

• Accumulation of sodium inside the cell

• Leads to osmotic swelling

Increased Intracellular Calcium

→ Calcium Influx

• Loss of membrane integrity allows calcium to flood into the cell from the extracellular space

           → Enzyme Activation

• Elevated calcium levels activate destructive enzymes

• Protease: breaks down protein

• Lipase: degrades lipids

• Endonuclease: cleaves to DNA

Calcium Influx

• Loss of membrane integrity allows calcium to flood into the cell from the extracellular space

Enzyme Activation

• Elevated calcium levels activate destructive enzymes

breaks down protein

Protease

 degrades lipids

Lipase

Endonuclease

 cleaves to DNA

Cell Swelling and Membrane Damage

→ Oncotic Swelling

• Cell continues to swell as water enters due to osmotic imbalance

→ Membrane Rupture

• As the cell swells, the plasma membrane and organelles begin to rupture\

• → Lysosomal Enzyme Release

  • Lysosomal enzymes are released into the cytoplasm, leading to further degradation

Oncotic Swelling

• Cell continues to swell as water enters due to osmotic imbalance

Membrane Rupture

• As the cell swells, the plasma membrane and organelles begin to rupture

 Lysosomal Enzyme Release

Lysosomal enzymes are released into the cytoplasm, leading to further degradation

Loss of Organelles and Nuclear

1. Breakdown

• Mitochondrial Rupture

• Karyolysis

• Nucleus dissolves as the chromatin is degraded by endonucleases

Leakage of Cellular Contents

-Membrane Disruption

• The final breakdown of the cell membrane causes the release of cellular contents into the extracellular space

-Inflammatory Response

• The released cellular components act as danger signals, which trigger an inflammatory response by attracting immune cells to the site of injury

Membrane Disruption

• The final breakdown of the cell membrane causes the release of cellular contents into the extracellular space

Inflammatory Response

• The released cellular components act as danger signals, which trigger an inflammatory response by attracting immune cells to the site of injury

Inflammation and Tissue Damage

- Inflammation

• The inflammation caused by necrosis can lead to further tissue damage, exacerbating the injury to surrounding cells

  • Tissue Scarring

• If extensive, necrosis can result in scar tissue formation or fibrosis, which can impair the function of the affected organ

Inflammation

The inflammation caused by necrosis can lead to further tissue damage, exacerbating the injury to surrounding cells

Tissue Scarring

If extensive, necrosis can result in scar tissue formation or fibrosis, which can impair the function of the affected organ

Coagulative Necrosis

Liquefactice Necrosis

Caseous Necrosis

Fat Necrosis

Fribrinoid Necrosis

Gangrenous Necrosis

Types of Necrosis

Coagulative Necrosis

• The affected cells die, but the tissue architecture remains preserved for a few days, The dead cells’ proteins denature and coagulate, forming a firm and opaque tissue

Liquefactice Necrosis

• Microbes stimulate rapid accumulation of inflammatory cells, and the enzymes of leukocytes digest (“liquefy”) the tissue

• Hypoxic death of cells in CNS

Caseous Necrosis

• The necrotic tissue is fragmented or lysed into amorphous debris, which is then surrounded by a granulomatous inflammatory reaction

Fat Necrosis

• Lipases released from injured cells break down triglycerides into fatty acids, which can combine with calcium to form chalky white deposits (saponification)

Fribrinoid Necrosis

• Complexes of antigens and antibodies are deposited in the walls of blood vessels

Wet gangrene

Coagulative necrosis due to ischemia

Dry gangrene

Superimposed bacterial infection, leading to liquefactive necrosis

Wet gangrene

• Swollen, moist, and foul-smelling due to infection

Dry gangrene

• Dry, shriveled, and blackened

Apoptosis

→ “Programmed cell death”

→ Highly regulated and controlled process of cell death

→ Essential for normal development, immune function, and cell turnover

Effector Caspases

• Both  pathways converge on the activation of effector caspases, particularly caspase-3, caspase-6, and caspase-7, which are responsible for the execution phase of apoptosis

Caspase Cascade

The activation of effector caspases creates a cascade that rapidly dismantles the cell

Chromatin Condensation (Pyknosis)

• Caspases cleave key structural proteins in the nucleus, leading to chromatin condensation and nuclear shrinkage

 DNA Fragmentation

• Caspases activate DNAse enzymes, which cleave DNA into characteristic fragments

Cell Shrinkage

• The cell shrinks and detaches from neighboring cells, a process mediated by the breakdown of the cytoskeleton

Membrane Blebbing

• The plasma membrane form bubble-like protrusions called blebs, as the cell prepares to fragment

Apoptotic Bodies

• The cell fragments into the smaller, membrane-bound apoptotic bodies, which contain portions of the cytoplasm and organelles

Phosphatidylserine Exposure

Phosphatidylserine, a phospholipid normally found in the inner leaflet of the plasma membrane, flips to the outer leaflet acting as an “eat me” signal for phagocyte

Recognition by Phagocytes

• Apoptotic bodies are recognized and engulfed by phagocytes such as macrophages without triggering an inflammatory response

Clearance

The apoptotic bodies are degraded within the phagocytes, ensuring that cellular contents do not leak into the surrounding tissue

Hypertrophy

• Increased cell and organ size.

• Often in response to increased workload.

Hyperplasia

• Increased cell numbers.

• In response to hormones and other growth factors.

Atrophy

• Decreased cell and organ size.

• As a result of decreased nutrient supply or disuse.

Metaplasia

• Change in phenotype of differentiated cells.

• Often in response to chronic irritation, that makes cells better able to withstand the stress.

• May result in reduced functions or increased propensity for malignant transformation.

Dysplasia

• Abnormal development of cells within tissues or organs.

INFLAMMATION

→ A protective response to eliminate harmful stimuli (e.g., microbes, damaged cells).

Acute Inflammation

→ The initial, rapid response to infections and tissue damage.

Infections

 Tissue Necrosis

Foreign Bodies

Immune Reactions (Hypersensitivity)

Causes of Inflammation

Infections

 Products of microbes are recognized by the host and elicit different types of inflammatory reactions.

 Tissue Necrosis

• Caused by ischemia (reduced blood flow), infarction (in heart, brain, other tissues), trauma, thermal injury, irradiation, and chemical injury.

• Molecules released from necrotic cells trigger inflammation even in the absence of infection (so-called "sterile inflammation").

Foreign Bodies

•  Sutures and tissue implants also elicit sterile inflammation.

Immune Reactions (Hypersensitivity)

• Reactions in which the normally protective immune system damages the individual's own tissues.

• Allergies and autoimmune diseases are caused by immune responses.

• Inflammation is a major contributor to tissue injury.

→ Heat (calor in Latin)

→ Redness (rubor)

→ Swelling (tumor)

→ Pain (dolor)

→ Loss of Function (functio laesa)

Cardinal Signs of Inflammation

Calor

Cardinal Signs of Inflammation in Latin

Heat

Rubor

Cardinal Signs of Inflammation in Latin

Redness

Tumor

Cardinal Signs of Inflammation in Latin

Swelling

Dolor

Cardinal Signs of Inflammation in Latin

Pain

Functio laesa

Cardinal Signs of Inflammation in Latin

Loss of function

Chronic Inflammation

→ Is of longer duration and is associated with continuing tissue destruction and fibrosis (the deposition of connective tissue).