This is the brief overview on the topic CELL INJURY. After reading this you will get to know about adaptations, types, etiology, pathogenesis of cell injury.

1. CELL INJURY
BY,
DR. KAAVIYA THARSINI P.S
Ist YEAR PG

2. CELL
• A cell is defined as the smallest, basic
fundamental units of life that are
responsible for all life's process.
• It is the structural, functional and the
biological units of all living beings.
• It can replicate itself independently, hence
known as the 'BUILDING BLOCKS OF LIFE"

3. •CELLULAR
COMPONENTS

4. CELLS
Cells are active participants in their environment, constantly adjusting
their structure and function to accommodate changing demands and
extracellular stresses.
Cells normally maintain a steady state called homeostasis in which the
intracellular milieu is kept within a fairly narrow range of physiologic
parameter.
As cells encounter physiologic stresses or pathologic stimuli, they can
undergo adaptation, achieving a new steady state and preserving
viability and function.
If the adaptive capability is exceeded or if the external stress is
inherently harmful, cell injury develops

5. CELL INJURY
• If the limits of adaptive responses are exceeded or if
cells are exposed to injurious agents or stress, deprived of
essential nutrients, or become compromised by mutations
that affect essential cellular constituents, a sequence of
events follows that is termed CELL INJURY

6. ETIOLOGY OF CELL INJURY:
The causes of cell injury range from the gross physical trauma to the single
gene defect.
Most injurious stimuli can be grouped into the following categories
• Oxygen deprivation
• Physical agents
• Chemical agents
• Infectious agents
• Immunologic factors
• Genetic factors
• Nutritional factors
• Aging

7. NATURE OF INJURIOUS STIMULUS CELLULAR RESPONSE
• Altered physiologic stimuli; some nonlethal injurious stimuli
• Increased demand, increased stimulation (e.g., by growth factors,
hormones)
• Decreased nutrients, decreased stimulation
• Chronic irritation (physical or chemical)
Cellular adaptations
Hyperplasia, hypertrophy
Atrophy
Metaplasia
• Reduced oxygen supply; chemical injury; microbial infection
• Acute and transient
• Progressive and severe
Cell injury
Acute reversible injury
Irreversible injury → cell death
• Cumulative sublethal injury over long life span Cellular aging

8. OVERVIEW OF CELL
INJURY:

9. CELLULAR ADAPTATIONS:
The principal adaptive responses are
1. Hypertrophy
2.Hyperplasia
3.Atropy
4.Metaplasia

10. •HYPERTROPHY:
Hypertrophy is an increase in the size of
parenchymal cells resulting in enlargement of
the organ or tissue, without any change in the
number of cells.
CAUSES:
It is caused by increased functional demand or
by hormonal stimulation.
In non-dividing cells , hypertrophy occurs.

11. • Hypertrophy may be physiologic or pathologic.
• A. Physiologic hypertrophy
• Enlarged size of the uterus in pregnancy is an example of
physiologic hypertrophy as well as hyperplasia.​
• Hypertrophy of skeletal muscle e.g. hypertrophied muscles in
athletes and manual labourers.​
• B. Pathologic hypertrophy
• Examples of certain diseases associated with hypertrophy
are as under:​
• Hypertrophy of cardiac muscle may occur in a number of
cardiovascular diseases.
• Compensatory hypertrophy may occur in an organ when the
contralateral organ is removed e.g. i) Following nephrectomy on
one side in a young patient, there is compensatory hypertrophy as
well as hyperplasia of the nephrons of the other kidney.​

12. HYPERPLASIA:
Hyperplasia is an increase in the number of parenchymal cells resulting in
enlargement of the organ or tissue
CAUSES
As with other adaptive disorders of growth, hyperplasia may also be physiologic
and pathologic.
A. Physiologic hyperplasia
1. Hormonal hyperplasia
Hyperplasia of female breast at puberty, during pregnancy and
lactation.
2. Compensatory hyperplasia
Regeneration of the liver following partial hepatectomy.
Regeneration of epidermis after skin abrasion.
B. Pathologic hyperplasia
In wound healing, there is formation of granulation tissue due to proliferation
of fibroblasts and endothelial cells.
Formation of skin warts from hyperplasia of epidermis due to human
papilloma virus.

13. METAPLASIA:
Metaplasia is defined as a reversible change of one type of epithelial
or mesenchymal adult cells to another type of adult epithelial or
mesenchymal cells, usually in response to abnormal stimuli, and often
reverts back to normal on removal of stimulus.
Metaplasia is broadly divided into 2 types: epithelial and mesenchymal
EPITHELIAL METAPLASIA :
This is the more common type. The metaplastic change may be
patchy or diff use and usually results in replacement of epithelium
Depending upon the type of epithelium transformed, two types of epithelial
metaplasia are seen: squamous and columnar.
1. Squamous metaplasia
2. Columnar metaplasia

14. ATROPHY
Reduction of the number and size of
parenchymal cells of an organ or its parts which was
once normal is called atrophy .
CAUSES
Atrophy may occur from physiologic or
pathologic causes:
A. Physiologic atrophy
Atrophy of thymus in adult life.
B. Pathologic atrophy
Starvation atrophy
Ischaemic atrophy
Disuse atrophy

15. MESENCHYMAL METAPLASIA
Less often, there is transformation of one adult type of mesenchymal tissue to
another. The examples are as under:
1. Osseous metaplasia
Osseous metaplasia is formation of bone in fibrous tissue, cartilage and
myxoid tissue.
i) In arterial wall in old age
ii) In soft tissues in myositis ossificans
2. Cartilaginous metaplasia; In healing of fractures, cartilaginous metaplasia may
occur where there is undue mobility.

16. • Depletion of ATP
• Mitochondrial damage and dysfunction
• Influx of calcium
• Accumulation of Oxygen derived free radicals
• Defects in membrane permeability
• Damage to DNA and Proteins
VARIOUS MECHANISMS OF CELL INJURY:

17. • DEPLETION OF ATP:
Effects:
• 1.Decreased activity of ATP dependent
sodium pumps
• 2.Increased lactic acid accumulation
• 3.Failure of ATP dependent Calcium
pumps
• 4.Structural disruption of Protein
synthetic apparatus

18. • MITOCHONDRIAL
DAMAGE AND
DYSFUNCTION
• Abnormal oxidative phosphorylation -
formation of reactive oxygen species - Necrosis
• Damage to mitochondria - formation of
mitochondrial permeability transition pore -
loss of mitochondrial membrane potential
and pH changes – compromising oxidative
phosphorylation.
• several proteins (cytochrome C and
caspases) - when released into the cytoplasm -
activate a pathway of apoptosis.
•

19. Increased intracellular Ca2+ causes cell
injury by several mechanisms:
• activates a number of enzymes with
potentially deleterious effects on cells.
These include phospholipases ,proteases
,endonucleases and ATPases.
• results in the induction of apoptosis,
by direct activation of caspases and by
increasing mitochondrial permeability.

20. ACCUMULATION
OF OXYGEN
DERIVED FREE
MOLECULES:
Reactive oxygen species (ROS) are a type of oxygen derived
free radical whose role in cell injury is well established.
ROS are produced normally in cells during mitochondrial
respiration and energy generation, but they are degraded
and removed by cellular defense systems.
Thus, cells are able to maintain a steady state in which free
radicals may be present transiently at low concentrations but
do not cause damage.
Increased production or decreased scavenging of ROS may
lead to an excess of these free radicals, a condition called
oxidative stress.
Oxidative stress has been implicated in a wide variety of
pathologic processes, including cell injury, cancer, aging, and
some degenerative diseases such as Alzheimer disease.

22. • DEFECTS IN MEMBRANE
PERMEABILITY:
• Decreased phospholipid synthesis
• Increased phospholipid breakdown
• Cytoskeletal abnormalities
• Lipid break down products

23. • REVERSIBLE CELL INJURY :
Reversible cell injury is where
the functional and morphologic
changes are reversible if the
damaging stimulus is removed.
At this stage, although there
may be significant structural and
functional abnormalities, the
injury has typically not
progressed to severe membrane
damage and nuclear dissolution.

24. INTRACELLULAR CHANGES:

25. MORPHOLOGY OF REVERSIBLE
CELL INJURY:
Various morphological forms of
reversible cell injury are
# Hydropic change
# Fatty change

26. • HYDROPIC CHANGE:
• Hydropic change means accumulation of
water within the cytoplasm of the cell.
Microscopically, it is characterized by the
following features :
• i) The cells are swollen and the
microvasculature compressed.
• ii) Small clear vacuoles are seen in the cells
and hence the term vacuolar degeneration. These
vacuoles represent distended cisternae of the
endoplasmic reticulum.
• iii) Small cytoplasmic blebs may be seen.
• iv) The nucleus may appear pale.

27. • FATTY CHANGE:
• Fatty change is manifested by the appearance
of triglyceride containing lipid vacuoles in the
cytoplasm.
• It is principally encountered in organs that are
involved in lipid metabolism, such as the liver

29. IRREVERSIBLE CELL INJURY :
Persistence of etiology results in irreversible damage to the structure and function of the
the cell.
The stage at which this point of no return or irreversibility is reached from reversible
cell injury is unclear but the sequence of events is a continuation of reversibly injured cell.
Two essential phenomena always distinguish irreversible from reversible cell injury
Inability of the cell to reverse mitochondrial dysfunction on reperfusion or reoxygenation.
Profound disturbance in cell membrane function .

30. • NECROSIS:
Necrosis is defined as a localised area of death of tissue followed by
degradation of tissue by hydrolytic enzymes liberated from dead cells; it is invariably
accompanied by inflammatory reaction.
Necrosis is characterized by changes in the cytoplasm and nuclei of the injured
cells
CYTOPLASMIC CHANGES:
Necrotic cells show increased eosinophilia.
Compared with viable cells the cell may have a more glassy, homogeneous
appearance, mostly because of the loss of glycogen particles.
Myelin figures are more prominent in necrotic cells than during reversible
injury.
When enzymes have digested cytoplasmic organelles, the cytoplasm
becomes vacuolated and appears "moth-eaten.
By electron microscopy. necrotic cells are characterized by
discontinuities in plasma and organelle membranes,
marked dilation of mitochondria with the appearance of large amorphous
densities,
disruption of lysosomes

31. • NUCLEAR CHANGES.
• Nuclear changes assume one of three patterns, all due to breakdown of DNA and chromatin.
• The basophilia of the chromatin may fade (karyolysis), presumably secondary to
deoxyribonuclease (DNase) activity.
• A second pattern is pyknosis, characterized by nuclear shrinkage and increased basophilia; the
DNA condenses into a solid shrunken mass.
• In the third pattern, karyorrhexis, the pyknotic nucleus undergoes fragmentation.
• Electron microscopy reveal profound nuclear changes culminating in nuclear dissolution.

32. • Coagulative necrosis:
• # It is a form of necrosis in which the underlying tissue architecture is preserved for atleast several
days.
• # The affected tissues take on a firm texture. Presumably the injury denatures not only structural
proteins but also enzymes, thereby blocking the proteolysis of the dead cells; as a result, eosinophilic, anucleate
cells may persist for days or weeks.
• # Leukocytes are recruited to the site of necrosis, and the dead cells are digested by the action of
lysosomal enzymes of the leukocytes. The cellular debris is then removed by phagocytosis.
• # Coagulative necrosis is characteristic of infarcts (areas of ischemic necrosis) in all of the solid organs
except the brain

33. • Liquefactive necrosis:
• 1) It is seen in focal bacterial or occasionally, fungal
infections, because microbes stimulate the accumulation of
inflammatory cells and the enzymes of leukocytes digest
("liquefy") the tissue.
• 2) For obscure reasons, hypoxic death of cells
within the central nervous system often evokes liquefactive
necrosis.
• 3) Whatever the pathogenesis, the dead cells are
completely digested, transforming the tissue into a liquid
viscous mass. Eventually, the digested tissue is removed by
phagocytes.
• 4) If the process was initiated by acute
inflammation, as in a bacterial infection, the material is
frequently creamy yellow and is called pus.

34. • Caseous necrosis:
# Caseous means "cheese-like" referring to the friable yellow-
white appearance of the area of necrosis.
# On microscopic examination, the necrotic focus appears as a
collection of fragmented or lysed cells with an amorphous granular pink
appearance in the usual H&E-stained tissue.
# Unlike with coagulative necrosis, the tissue architecture is
completely obliterated and cellular outlines cannot be discerned. The
area of caseous necrosis is often enclosed within a distinctive
inflammatory border; this appearance is characteristic of a focus of
inflammation known as a granuloma.
# It is encountered most often in foci of tuberculous infection

35. Fat necrosis:
• It refers to focal areas of fat destruction.
• In acute pancreatitis, pancreatic
enzymes liquefy the membranes of fat cells in the
peritoneum, and lipases split the triglyceride
esters contained within fat cells.
• The released fatty acids combine with
calcium to produce grossly visible chalky white
areas which enable the surgeon and the
pathologist to identify the lesions .
• On histologic examination, the foci of
necrosis contain shadowy outlines of necrotic fat
cells with basophilic calcium deposits, surrounded
by an inflammatory reaction.

36. • Fibrinoid necrosis:
• It is a special form of necrosis, visible by light
microscopy, usually in immune reactions in which
complexes of antigens and antibodies are
deposited in the walls of arteries.
• The deposited immune complexes, together
with fibrin that has leaked out of vessels, produce a
bright pink and amorphous appearance on H&E
preparations called fibrinoid (fibrin-like) by
pathologists
• The immunologically mediated diseases
(e.g., poly- arteritis nodosa) in which this type of
necrosis is seen

37. APOPTOSIS (programmed cell death)
Apoptosis is a pathway of cell death in
which cells activate enzymes that degrade the cell’s
own nuclear DNA and cytoplasmic fragments of the
apoptotic cells then break off, giving the appearance
that is responsible for the name (apoptosis, "falling off").

38. Apoptosis in
Physiologic
Situations:

39. Apoptosis in
Physiologic
Situations:

40. Apoptosis in Pathologic Conditions :
Death by apoptosis is responsible for loss of
cells in a variety of pathologic states:
1)DNA damage.
2) Accumulation of misfolded proteins
3 )Pathological atrophy in parenchymal organs
after duct obstruction

41. • MECHANISMS:
Apoptosis results from the activation of enzymes
called caspases.
The activation of caspases depends on a finely tuned
balance between production of pro- and anti-
apoptotic proteins.
Two distinct converge on caspase activation:
1. The Mitochondrial (Intrinsic)pathway
2.The Death receptor (Extrinsic) pathway

42. ■ Mitochondrial (intrinsic) pathway:
Damage
Sensors activated BH3 proteins – BCL receptor
Activate Bax and Bak (Proapoptotic proteins)
Channels in mitochondria
Leakage of mitochondrial proteins and cytochrome C
Cytochrome C activates Caspase 9
Caspase cascade activation

43. ■ Death receptor (extrinsic) pathway:
expression of death receptors (TNF receptor 1 and fas receptor)
Fas ligand expressed on activated T lymphocytes attaches to the cells
expressing fas receptor
FADD domain binds to inactive form of caspase 8
Multiple pro caspase 8 comes to its proximity and cleaves them to
become active caspase 8
Caspase 8 cleaves and activates Bid ( Proapoptotic proteins)
feeding into mitochondrial pathway
Combined activation leads to lethal blow to the cell

44. EXECUTION PHASE APOPTOSIS:
activation of the initiator caspase-9 ( in mitochondrial pathway)
initiator caspases-8 and -10 (in death receptor pathway)
initiator caspase cleaved to become active form, which thereby activates the executioner caspases.
Executioner caspases (caspase-3 and -6) act on many cellular components. For instance, these once activated, cleave an
inhibitor of a cytoplasmic DNase and thus make the DNase enzymatically active; this enzyme induces cleavage of DNA.
Caspases also degrade structural components of the nuclear matrix and thus promote fragmentation of nuclei.

45. Apoptotic bodies makes it edible for phagocytes by
Flipping of
phosphotidylserine to outside
of plasma membrane
Coated by
thrombospondin
Secreting soluble
factors
coated with natural
antibodies and proteins of
the complement system,
notably C1q
recognized by phagocytes
dead cells disappear, often within minutes, and without leaving a trace.

46. Feature Necrosis Apoptosis
Cell size Enlarged (swelling) Reduced (shrinkage
Nucleus Pyknosis
Karyohexsis
Karyolysis
Fragmentation
Plasma membrane Distrupted Intact,altered structure
Cellular contents Enzymatic digestion, may
leakout of cell
Intact, released in
apoptotic bodies
Inflammation Frequent No
Physiologic or
pathologic role
Invariably pathologic Often physiologic but may
be pathologic at times
DIFFERENCES:

47. AUTOPHAGY / AUTOLYSIS:
• Autophagy is a process in which a cell eats its own contents (Greek: auto, self; phagy,
eating).
• Autophagy is an adaptive response that is enhanced during nutrient deprivation, allowing
the cell to cannibalize itself to survive.
• Autophagy is implicated in many physiologic states (e.g., aging and exercise) and pathologic
states including cancers, inflammatory bowel diseases, and neurodegenerative disorders.

48. It proceeds through several steps
• Formation of an isolation membrane, also called phagophore, believed to be derived from the ER
• Elongation of the vesicle
• Maturation of the autophagosome, its fusion with lysosomes, and eventual degradation of the
contents

49. NECROPTOSIS:
■ Necroptosis resembles necrosis
morphologically and apoptosis
mechanistically as a form of programmed
cell death.
It is also programmed cell death but
without caspase activation

50. MECHANISM;
■ Necroptosis is triggered by ligation of TNFR1, and viral
proteins of RNA and DNA viruses.
■ Necroptosis is caspase-independent but dependent on
signaling by the RIP1 and RIP3 complex.
■ RIP1-RIP3 signaling reduces mitochondrial ATP generation,
causes production of ROS, and permeabilizes lysosomal
membranes, thereby causing cellular swelling and membrane
damage as occurs in necrosis.
■ Release of cellular contents evokes an inflammatory
reaction as in necrosis

51. ABNORMAL INTRACELLULAR DEPOSITIONS
Abnormal deposits of materials in cells and tissues are the result of
excessive intake or defective transport or catabolism.
■ Deposition of lipids
■ Fatty change: Accumulation of free triglycerides
in cells, resulting from excessive intake or defective transport (often
because of defects in synthesis of transport proteins); manifestation of
reversible cell injury
■ Cholesterol deposition: Result of defective
catabolism and excessive intake; in macrophages and smooth muscle cells
of vessel walls in atherosclerosis
■ Deposition of proteins: Reabsorbed proteins in kidney
tubules; immunoglobulins in plasma cells

52. ■ PATHOLOGIC CALCIFICATIONS
■ Dystrophic calcification: Deposition of calcium at sites of cell injury
and necrosis
■ Metastatic calcification: Deposition of calcium in normal tissues,
caused by hypercalcemia (usually a consequence of parathyroid hormone
excess
■ Deposition of glycogen: In macrophages of
patients with defects in lysosomal enzymes that break down
glycogen (glycogen storage diseases)
■ Deposition of pigments: Typically
indigestible pigments, such as carbon, lipofuscin (breakdown
product of lipid peroxidation), or iron (usually due to overload,
as in hemosiderosis

53. THANK YOU