Causes and Mechanisms of Cell Injury

Question 1

When does cell injury occur?

Answer 1

Cell injury occurs when cells are stressed so severely that they are no longer able to adapt – or when cells are exposed to inherently damaging agents

Question 2

How is tissue damage dependant on cell injury?

Answer 2

Cells may be damaged either reversibly or irreversibly

The effect on the tissue will depend on:

• Duration of injury
• Nature of injurious agent
• Proportion & type of cells affected
• Ability of tissues to regenerate

Question 3

Describe the morphological changes associated with cell injury

Answer 3

The morphological changes associated with cell injury include:

• Decreased generation of ATP
• Loss of cell membrane integrity
• Defects in protein synthesis
• Cytoskeletal damage
• DNA damage

Question 4

What types of cell injury are reversible?

Answer 4

Cell swelling

Fatty changes

Question 5

What types of cell injury are irreversible?

Answer 5

Necrosis

Apoptosis

Question 6

Describe cellular swelling

Answer 6

Occurs whenever cells are incapable of maintaining ionic and fluid homeostasis
This is due to the loss of function of plasma membrane energy dependent ion pumps
Results in:
- Plasma membrane alterations
- Mitochondrial changes
- Dilation of the endoplasmic reticulum
- Nuclear alterations – clumping of nuclear protein

Question 7

Describe fatty change

Answer 7

Also termed “Steatosis”
Occurs in hypoxic injury and various forms of toxic or metabolic injury
Manifested by the appearance of lipid vacuoles in the cytoplasm
- When mild it may have no effect on cellular function
- More severe may impair cellular function
- More severe form may precede to cell death

Question 8

What is necrosis?

Answer 8

Necrosis refers to the spectrum of morphologic changes that follow cell death. Necrosis is the gross and histologic correlate of cell death

Question 9

What causes necrosis?

Answer 9

Largely due to the progressive degradative action of enzymes on lethally damaged cells.

Necrotic cells are unable to maintain membrane integrity, and so their contents leak out usually resulting in an inflammatory response in the surrounding tissue

Question 10

Where are the enzymes involved in necrosis derived from?

Answer 10

The enzymes involved are either derived from the lysosomes of the dead cells = autolysis

or

Lysosomes from immigrant leukocytes during the inflammatory reaction

Question 11

Describe the morphology of necrosis

Answer 11

Necrotic cells show increased eosinophilia which is partly due to loss of basophilia imparted by RNA in cytoplasm & increased binding of eosin to denatured intracytoplasmic proteins

Necrotic cells have a glassy appearance mainly as a result of loss of glycogen particles
As enzymes digest the cytoplasmic organelles, the cytoplasm becomes vacuolated and appear ‘moth-eaten’

Finally, calcification of the dead cells may occur

Question 12

What nuclear changes occur in necrosis?

Answer 12

Nuclear changes appear in the form of one of three patterns – all due to non-specific breakdown of DNA
- Karyolysis: basophilia of chromatin fades
- Karyopyknosis: nuclear shrinkage & basophilia
- Karyorrhexis: nucleus fragmentation
Nucleus in the necrotic cell totally disappears with time

Question 13

What are the different patterns of necrosis?

Answer 13

1. Coagulative necrosis
2. Colliquative /Liquefactive necrosis
3. Fat necrosis
4. Caseous necrosis
5. Gangrenous necrosis

Question 14

Describe coagulative necrosis

Answer 14

The outline of the dead cells are maintained and the tissue is somewhat firm
- e.g. myocardial infarction

Question 15

Describe colliquative/liquefactive necrosis

Answer 15

The dead cells undergo disintegration and affected tissue is liquefied.
- e.g. cerebral infarction

Question 16

Describe fat necrosis

Answer 16

Enzymatic digestion of fat.

- e.g. necrosis of fat by pancreatic enzymes

Question 17

Describe caseous necrosis

Answer 17

Pattern of necrosis where dead tissue lacks structure
Histological staining shows amorphous eosinophilic areas & haematoxyphilic nuclear debris
- e.g. Tuberculosis

Question 18

Describe gangrenous necrosis

Answer 18

Necrosis (secondary to ischemia) usually with superimposed infection.
- e.g. necrosis of distal limbs, usually foot and toes in diabetes

• Wet gangrene : bowel
• Dry gangrene: toes
• Gaseous gangrene: infection

Question 19

How is necrosis resolved?

Answer 19

Ultimately, in the living patient, most necrotic cells and their debris disappear by a combined process of enzymatic digestion and fragmentation

This is followed by phagocytosis of the particulate debris by leucocytes

Question 20

Define apoptosis

Answer 20

“Cell suicide”

Apoptosis is a pathway of cell death induced by a tightly regulated intracellular program.

Cells destined to die activate enzymes that degrade the cell’s’ own nuclear DNA and nuclear cytoplasmic proteins
The dead cell is rapidly cleared before its cell contents have leaked

Cell death by this pathway does not result in an inflammatory reaction in the host

Apoptotic structure is altered in such a way that the apoptotic cell becomes a target for phagocytosis

Question 21

When does apoptosis occur?

Answer 21

It occurs normally in many situations and serves to eliminate unwanted or potentially harmful cells, plus cells which have outlived their usefulness

Question 22

Give examples of physiologic apoptosis

Answer 22

1. During Embryogenesis : Programmed destruction of cells
2. Hormone-dependent tissue
   - eg endometrial cell breakdown during menstrual cycle
3. Cell loss in proliferating cell populations
4. Death of cell which have served their useful purpose
   - e.g. neutrophils in an acute inflammatory response
5. Elimination of potentially harmful self-reactive lymphocytes to prevent reactions against one’s own tissues
6. Cell death induced by cytotoxic T lymphocytes is a defence mechanism against viruses & tumours that serves to kill & eliminate virus-infected and neoplastic cells

Question 23

Give examples of pathologic apoptosis

Answer 23

1. Apoptosis eliminates cells that are genetically altered or injured beyond repair, without a host response, therefore, keeping damage as contained as possible
2. Apoptosis is important in inflammation, neoplasia, AIDS & neurodegenerative disorders
3. DNA damage
   - radiation, cytotoxic anticancer drugs and extremes of temperature
   (Inducing apoptosis of cancer cell is a desired effect of chemotherapeutic agents, many of which work by damaging DNA)
4. Accumulation of mis-folded proteins due to mutations in the responsible genes or damage by free radicals
5. Certain infections (particularly viral)
6. Pathologic atrophy
   - occurs in organs such as pancreas or kidney due to duct obstruction

Question 24

What is the mechanism of apoptosis?

Answer 24

Apoptotic cell loses surface specialisation and shrinks in size

Nuclear chromatin condenses beneath the nuclear membrane

Endonuclease enzymes cleave chromosomes into individual nucleosome fragments

Splitting of cell into several fragments (apoptotic bodies)

Apoptotic fragments are recognised by adjacent cells which ingest them by phagocytosis

Question 25

What is the difference between apoptosis and necrosis?

Answer 25

Apoptosis: Programmed cell-death is the suicide of a cell
In contrast to necrosis, which is a form of cell-death that results from acute tissue injury and provokes an Inflammatory response