Irreversible cellular injury can occur through two main types of cell death: necrosis and apoptosis. Necrosis is premature, unprogrammed cell death that is always pathological, occurring due to external factors like ischemia, toxins, or infections. It is characterized by loss of membrane integrity and inflammatory changes. Apoptosis is a normal, programmed form of cell death important for development, hormone regulation, and removing damaged cells. It occurs through an active enzymatic process and does not cause inflammation. Both pathways ultimately lead to cellular demise but differ significantly in their mechanisms and morphological appearance.

1. Irreversible cellular injury.
Necrosis – types. Apoptosis.

2. Synopsis
 Irreversible cellular injury – cellular
death.
 Clinical - anatomical forms of
necrosis.
 Apoptosis- programmed cell death.

3. Morphology of cellular injury
 Subcellular alterations
 Related to biochemical changes
 Reversible cell injury
 2 groups
 Irreversible cell injury
 =cell death
 2 types

Necrosis

Apoptosis
 The concequences of an pathologic
factor depend on the cell type, status
and adaptability of the injured cell

4. Irreversible cell injury
 Two types of cell death, which differ in
their morphology, mechanisms, and
roles in disease and physiology
 necrosis

“premature” or “untimely” death due to
“causes”

always pathologic
 ischemia, toxins, various infections, trauma.
 apoptosis

“normal” death
 When a cell is deprived of growth factors
or the cell's DNA or proteins are damaged
beyond repair, the cell kills

physiologic and pathologic

5. Necrosis
 A local death of cells, tissues, part of an organ,
and sometimes an entire organ.
 This term included the series of changes that
accompany cell death, largely resulting from the
degradative action of enzymes on lethally injured
cells.

Necrotic cells are unable to maintain membrane integrity,
and their contents often leak out.

The enzymes responsible for digestion of the cell are derived
either from the lysosomes of the dying cells themselves or
from the lysosomes of leukocytes that are recruited as part of
the inflammatory reaction to the dead cells.

6. Causes of necrosis
 Hypoxia
 Ischemia
 Hypoxemia
 Loss of oxygen carrying capacity
 Free radical damage
 Chemicals, drugs, toxins
 Infections
 Physical agents
 Immunologic reactions
 Genetic abnormalities
 Nutritional imbalance

7. Necrosis
 Development
 Immediately
 Slowly - necrobiosis
 Responses of the heart to
different types of stress:

Ischemia
 incomplete occluded coronary artery –
hypoxia, reversible cell injury
 complete or prolonged occlusion – cell
death

8. Necrosis
 Electron microscopy
 breakdown of plasma membrane and organellar membranes,
 marked dilation of mitochondria with the appearance of large
amorphous densities
 disruption of lysosomes,
 intracytoplasmic myelin figures
 Nuclear changes, culminating in nuclear dissolution.

Pyknosis (nuclear shrinkage)

Karyorrhexis (nuclear memmbrane ruptured)

Karyolysis (complete dissolution of of nucleus, loss of chromatin)

9. Clinical - anatomical forms of necrosis
 Several morphologically distinct patterns of
tissue necrosis, which may provide clues about
the underlying cause
 Coagulative (parenchymal organs)
 Liquefactive (brain)
 Gangrenous (Extremities, Bowel, non-specific)

wet

dry
 Caseous (cheese) (Tuberculosis)
 Fat necrosis (pancreas, breast)
 Fibrinoid (Rheumatoid, non-specific)
 Decubitus ulcer
 Sequestrum

10. Coagulative necrosis
 It is a form of tissue necrosis in which the component cells
are dead but the basic tissue architecture is preserved for
at least several days
 Dry necrosis - tissues rich in proteins, less water

Denaturation and coagulations of proteins due to inactivation of
enzymes
 Characteristic of infarcts
(areas of ischemic necrosis)
in all solid organs except the brain
 Heart
 Ren
 spleen

11. Coagulative necrosis
 Macroscopy
 Necrotic areas –whitish,
firm, protruding above
surrounding tissue
 Microscopy
 The necrotic cells - ↑
eosinophilia
 Shadows of structures

Ren -glomerules, tubules
 Nuclear fragments

12. Coagulative necrosis (heart)
 the cellular appearance looks “cooked” and cell
structures and delineation is lost
Necrosis myocardii

13. Coagulative necrosis (ren)
 the cellular appearance looks “cooked” and cell structures and
delineation is lost
Necrosis renis

14. Caseous necrosis
 Variant of coagulation
necrosis associated with
acellular, cheese-like
(caseous) material
 Tuberculosis
 Lues
 brucelosis
 Microscopic features
 The acellular material in the
center of a granuloma -
multinucleated giant cells

No shadows

15. Necrosis pulmonis
(Bronchopneumonia tbc caseosa)

16. Necrosis lymphonodi
(Tuberculosis lymphonodi)

17. Liquefactive necrosis
 = Necrotic degradation of tissue
that softens and becomes liquified
 Mechanisms
 Lysosomal enzymes released by
necrotic cells or neutrophils cause
liquefaction of tissue

Pseudocysts, containing liquid.
 Brain
 CNS infarction

Autocatalytic effect of hydrolytic
enzymes generated by neuroglial cells
produces a cystic space
 Abscess in a bacterial infection

Hydrolytic enzymes generated by
neutrophils liquefy dead tissue.

18. Liquefactive necrosis (brain)

19. Gangrenous necrosis
 Necrosis of tissues in contact with
outside environment
 It is not a distinctive pattern of cell
death, but the term is still commonly
used in clinical practice
 generally the lower leg - ishemia
 Dry gangrene

Macroscopy – grey -black colour
 Wet gangrene

When bacterial infection is
superimposed - liquefactive action of
the bacteria and the attracted
leukocytes

Durty green colour, smell
 Noma
 wet gangrene of lips and cheeks in
exhausted children

20. Fat necrosis
 Pancreas - in acute pancreatitis
 Activation of pancreatic lipase causing
hydrolysis of triglyceride in fat cells
 And conversion of fatty acids into
soap (saponification)

Combination of fatty acids and
calcium
 Gross appearance
 Chalky yellow-white deposits in
peripancreatic and omental adipose
tissue
 Microscopy
 Pale outlines of fat cells filled with
basophilic-staining calcified areas
 Traumatic fat necrosis
 Occurs in fatty tissue (e.g., female
breast tissue) as a result of trauma
 Not enzyme-mediated

21. Fibrinoid necrosis
 It is a special form of
necrosis limited to small
muscular arteries,
arterioles, venules, and
glomerular capillaries
 In connective tissue
diseases
 Immune vasculitis (e.g.,
polyarteritis nodosa )
 malignant hypertension

22. Decubitus ulcer
 =pressure sore
 Decumbere means "to lie down"
 Results from the prolong pressure,
that cuts off the blood supply to the
skin, causing the skin and other
tissue to die
 Older people -70 y, hea
 Severe illness (people who cannot
move themselves)

Back, knees, elbows, ankles

23. Sequestrum
 A fragment of dead
tissue, that has separated
from healthy tissue as a
result of injury or disease
 Bone – osteomyelitis
 lung

24. Outcome of necrosis
 Irreversible injury
 Inflammation – line of demarcation
 Phagocytosis – neutrophils (enzymes)
 Organisation

Granulation tissue⇒ cicatrix (connective tissue),
calcification

liquefactive necrosis (brain) – pseudocyst (glial
capsule)

25. Enzyme markers of cell death
 Tissues release certain enzymes that indicate
the type of tissue involved and extent of injury.
 Aspartate aminotransferase (AST), Alanine
aminotransferase (ALT)- – markers of diffuse liver
cell necrosis (e.g., viral hepatitis)
 Creatine kinase MB (CK-MB) - isoenzyme increased
in acute myocardial infarction or myocarditis
 Amylase and lipase - marker enzymes for acute
pancreatitis

26. APOPTOSIS
 A cell death that is induced by a tightly regulated suicide
program
 When a cell is deprived of growth factors
 or the cell's DNA or proteins are damaged beyond repair
 Kerr and Wyllie, 1972
 "falling off“ (fragments of the apoptotic cells break off)
 Apoptosis is an active enzymatic process in which
nucleoproteins are broken down and then the cell is
fragmented
 caspases

mitochondrial pathway - most often

the death receptor pathway - cytotoxic T lymphocytes

27. Microscopic appearance of
apoptosis
 Cell detachment from
neighboring cells
 Deeply eosinophilic-staining
cytoplasm
 Pyknotic, fragmented, or
absent nucleus-apoptotic
bodies
 No inflammatory infiltrate
surrounding the cell

28. Features of Necrosis and Apoptosis
Feature Necrosis Apoptosis
Cell size Enlarged
(swelling)
Reduced (shrinkage)
Nucleus Pyknosis →
karyorrhexis →
karyolysis
Fragmentation into
nucleosome-size fragments
Plasma
membrane
Disrupted Intact; altered structure
Cellular
contents
Enzymatic
digestion; may
leak out of cell
Intact; may be released
in apoptotic bodies
Adjacent
inflammation
Frequent No
Physiologic/
Pathologic
role
Invariably
pathologic
Often physiologic,
may be pathologic after some
forms of cell injury (DNA damage)

29. APOPTOSIS
 Normal (preprogrammed)
 serves to eliminate potentially harmful cells
and cells that have outlived their
usefulness
 Pathologic (associated with necrosis)
 when cells are damaged beyond repair,
especially when the damage affects the
cell's DNA or proteins

30. “NORMAL” APOPTOSIS
 Embryogenesis
 implantation, organogenesis, developmental involution, metamorphosis
 Hormonal “Involution”
 such as endometrial cell breakdown during the menstrual cycle, and
regression of the lactating breast
 Cell loss in proliferating cell populations
 such as intestinal crypt epithelia, -to maintain a constant number
 Post Inflammatory “Clean-up”
 neutrophils in an acute inflammatory response, and lymphocytes at the
end of an immune response
 Elimination of potentially harmful self-reactive lymphocytes

in order to prevent reactions against one's own tissues
 Cytotoxic T-Cells cleaning up


31. “PATHOLOGIC” APOPTOSIS
 “Toxic” effect on cells, e.g., chemicals, pathogens
 Radiation, cytotoxic anticancer drugs, extremes of
temperature, and even hypoxia

damage DNA - directly or via production of free radicals.
 After duct obstruction
 Pathologic atrophy - in the pancreas, parotid gland, and
kidney
 Cell injury in certain infections
 particularly viral infections, in which loss of infected cells is
largely due to apoptotic death
 Tumors – delayed apoptosis, slow cell death
 Anti-tumor therapy