includes cell injury,necrosis ,apoptosis

3. CELL INJURY
AND
ADAPTATIONS
PRESENTED BY
DR.LAKSHMI S ANAND
Ist MDS

4. CELL
• The cell (from latin word cella meaning “small room”) is the basic structural
and functional unit of an organ or tissue.
• Cells are active participants in their environment , constantly adjusting
structure and function to accommodate changing demands and extra cellular
stresses.

5. 1) Homeostasis
•cells maintain normal structure & function in
response to physiologic demands.
2) Cellular Adaptation
•as cells encounter stresses they undergo functional or
structural adaptations to maintain
viability / homeostasis.
•respond to some stimuli by increasing or decreasing
specific organelle content.
•adaptive processes: atrophy, hypertrophy, hyperplasia and
metaplasia.

6. 3) Cell Injury
•if limits of the adaptive response are exceeded or if adaptation not possible, a
sequence of events called cell injury occurs.
a)Reversible Cell Injury
•removal of stress results in complete restoration of structural & functional integrity.
b) Irreversible Cell Injury / Cell Death
•if stimulus persists or is severe enough from the start, the cell suffers irreversible
cell injury and death.
•2 main morphologic patterns: necrosis & apoptosis.

8. CELLULAR ADAPTATIONS TO ST RE
SS
Adaptations are reversible changes in the number, size, phenotype,
metabolic activity or functions of cells in response to changes in their
environment.•
Physiologic adaptations are responses of cells to normal stimulation by hormones or
endogenous chemical mediators.
•
Pathologic adaptations are responses to stress that allow cells to modulate their
structure and function and thus escape from injury.

9. The most common morphologically apparent adaptive changes
are
•Atrophy(decrease in cell size)
•Hypertrophy(increase in cell size)
•Hyperplasia(increase in cell number)
•Metaplasia(change in cell type)
•Dysplasia

10. Atrophy
•Reduced size of an organ or tissue resulting from a decrease in cell size
and number
•Results from decreased protein synthesis and increased protein
degradation in cells
•Is accompanied in many situations by increased autophagy with
resulting increase in autophagic vacoules
Causes:
•
Decreased workload
•
Loss of innervation
•
Diminished blood supply
•
Inadequate nutrition
•
Loss of endocrine stimulation
•
Aging (senile atrophy)

11. MECHANISM
•Decreased protein synthesis and increased protein degradation in cells
•Protein synthesis decreases because of reduced metabolic activity.
•The degradation of cellular proteins occurs mainly by the ubiquitin-proteasome
pathway.

12. Physiologic atrophy.
Atrophy is a normal process of aging in some tissues, which could be due to loss of endocrine
stimulation or arteriosclerosis. For example:
i) Atrophy of lymphoid tissue in lymph nodes, appendix and thymus.
ii) Atrophy of brain with aging
Pathologic atrophy.
1.Starvation atrophy
2. Ischaemic atrophy
3. Disuse atrophy
4. Neuropathic atrophy
5. Endocrine atrophy
6. Pressure atrophy
7. Idiopathic atrophy.

14. Testicular atrophy. The seminiferous tubules
show
hyalinisation, peritubular fibrosis and diminished
number and size of spermatogenic elements.
There is prominence of Leydig cells in the
interstitium.

15. Hypertrophy
•is an increase in the size of cells & consequently anincrease in the
size of an organ.
•the enlargement is due to an increased synthesis of structural
proteins & organelles
•Occurs when cells are incapable of dividing
Types:
a)physiologic
b)pathologic

17. MECHANISMS OF HYPERTROPHY:
• Result of increased production of cellular proteins.
• Induced by the linked actions of
a)mechanical sensors (that are triggered by increased work
load)
b)growth factors (including TGF- , insulin-like growth factor-1β
[IGF-1], fibroblast growth factor)
c)vasoactive agents (such as -adrenergic agonists, endothelin-1,α
and angiotensin II).

18. The two main biochemical pathways involved in muscle hypertrophy seem to be the
a)phosphoinositide 3-kinase/Akt pathway
b)signaling downstream of G protein-coupled receptors

19. HEART HYPERTROPHY IN
HYPERTENSION

20. Cardiac hypertrophy. The myocardial muscle fibres are
thick with abundance of eosinophilic cytoplasm. Nuclei are
also enlarged with irregular outlines

21. Hyperplasia
•is an increase in the number of cells in an organ or tissue
•an adaptive response in cells capable of replication
Types:
a) physiologic hyperplasia
1.Hormonal hyperplasia i.e. hyperplasia occurring under the influence of hormonal stimulation
e.g.
i) Hyperplasia of female breast at puberty, during pregnancy and lactation.
ii) Hyperplasia of pregnant uterus.
iii) Proliferative activity of normal endometrium after a normal menstrual cycle.
iv) Prostatic hyperplasia in old age.
2. Compensatory hyperplasia i.e. hyperplasia occurring following removal of part of an organ or
a contralateral organ in paired organ
e.g.
i) Regeneration of the liver following partial hepatectomy
ii) Regeneration of epidermis after skin abrasion
iii) Following nephrectomy on one side, there is hyperplasia of nephrons of the other kidney.

22. b) pathologic hyperplasia
•
Caused by excessive hormonal or growth factor stimulation
•
Eg:endometrial hyperplasia
•
benign prostate hyperplasia

23. •a reversible change in which one adult celltype ( epithelial or mesenchymal) is replaced by
another adult cell type.
•is cellular adaptation whereby cells sensitive to a particular stress are replaced by other cell types
better able to withstand the adverse environment
EPITHELIAL METAPLASIA
Examples
•Squamous change that occurs in the respiratory epithelium in habitual cigarette smokers ( normal
columnar epithelial cells of trachea & bronchi are replaced by stratified squamous epithelial cells
•Vitamin A deficiency
•Chronic gastric reflux, the normal stratified squamous epithelium of the lower esophagus may
undergo metaplasia to gastric columnar epithelium
METAPLASIA

24. Squamous metaplasia of the uterine cervix. Part
of the endocervical mucosa is lined by normal
columnar epithelium while foci of metaplastic
squamous epithelium are seen at other places.
Columnar metaplasia oesophagus (Barrett’s
oesophagus).
Part of the oesophagus which is normally lined
by squamousepithelium undergoes metaplastic
change to columnar epithelium of
intestinal type.

25. Mesenchymal metaplasia
• Osseous metaplasia. Osseous metaplasia is formation of bone in fibrous tissue, cartilage and
myxoid tissue
• Cartilaginous metaplasia. In healing of fractures cartilaginous metaplasia may occur where there
is undue mobility.
Osseous metaplsia in leiomyoma uterus. The
whorls composed of the smooth muscle cells and
fibroblasts show osseous metaplasia in the centre

26. Dysplasia means ‘disordered cellular development’, often accompanied with metaplasia and
hyperplasia; it is therefore also referred to as atypical hyperplasia. Dysplasia occurs most
often in epithelial cells. Epithelial dysplasia is characterised by cellular proliferation and
cytologic changes. These changes include:
1. Increased number of layers of epithelial cells
2. Disorderly arrangement of cells from basal layer to the surface layer
3. Loss of basal polarity i.e. nuclei lying away from basement membrane
4. Cellular and nuclear pleomorphism
5. Increased nucleocytoplasmic ratio
6. Nuclear hyperchromatism
7. Increased mitotic activity.
•The two most common examples of dysplastic changes are the uterine cervix and
respiratory tract.
•Dysplastic changes often occur due to chronic irritation or prolonged inflammation. On
removal of the inciting stimulus, the changes may disappear.
•Dysplasia progresses into carcinoma in situ(cancer confined to layers superficial to
basement membrane)or invasive cancer.
DYSPLASIA

27. Uterine cervical dysplasia, high grade lesion. It shows
increased number of layers of squamous epithelium having marked
cytologic atypia including mitoses

28. DIFFERENCES BETWEEN METAPLASIA AND DYSPLASIA.
Feature Metaplasia Dysplasia
i) Definition Change of one type of epithelial or mesenchymal
cell to another type of adult epithelial or mesen-
chymal cell
Disordered cellular development, may be
accompanied with hyperplasia or metaplasia
ii) Types Epithelial (squamous, columnar) and
mesenchymal (osseous, cartilaginous
Epithelial only
iii) Tissues affected Most commonly affects bronchial mucosa, uterine
endocervix; others mesenchymal tissues (cartilage,
arteries)
Uterine cervix, bronchial mucosa
iv) Cellular changes Mature cellular development Disordered cellular development
(pleomorphism,
nuclear hyperchromasia, mitosis, loss of
polarity)
v) Natural history Reversible on withdrawal of stimulus May regress on removal of inciting stimulus,
or may progress to higher grades of dysplasia
or carcinoma in situ

29. Cell Injury- pertains to the sequence of events when cells have no adaptive
response or the limits of adaptive capability are exceeded
Types of Cell Injury
1. Reversible Injury- injury that persists within certain limits, cells return to a
stable baseline
2. Irreversible Injury- when the stimulus causing the injury persists and is severe
enough from the beginning that the affected cells die by
a. necrosis
b. apoptosis
CELL INJURY

30. Causes of Cell Injury
1.Hypoxia
Causes:
a. Ischemia
b. Inadequate oxygenation of the blood
c. Reduction in the oxygen-carrying capacity of the blood
1.Chemical Agents
a. glucose, salt or oxygen
b. poisons
c. environmental toxins
d. social agents
e. therapeutic drugs
2.Physical agents- trauma, extremes of temperature, radiation, electric shock,
& sudden changes in atmospheric pressure
3.Infectious agents

31. 5. Immunologic reactions
Example: anaphylactic reaction to a foreign protein or a drug reaction to
self antigens
6. Genetic defects
Examples are genetic malformations associated with Down Syndrome,
sickle cell anemia & inborn errors of metabolism
7. Nutritional Imbalances

33. MECHANISMS OF CELL INJURY
• Depletion of ATP
• Mitochondrial Damage
• Influx of Intracellular Calcium and Loss of Calcium
Homeostasis
• Accumulation of Oxygen-Derived free radical
(Oxidative stress)
• Defects in Membrane Permeability

34. LOSS OF ENERGY (ATP DEPLETION, O2DEPLETION)

35. MITOCHONDRIAL DAMAGE

36. LOSS OF CALCIUM HOMEOSTASIS

37. DEFECTS IN PLASMA MEMBRANE PERMEABILITY

38. FREE RADICALS
• Free radicals have an unpaired electron in their outer
orbit
• Free radicals cause chain reactions
• Generated by:
– Absorption of radiant energy
– Oxidation of endogenous constituents
– Oxidation of exogenous compounds
Reactive oxygen species (ROS) are a type of oxygen-
derived free radical whose role in cell injury is well
established

39. • Free radicals may be generated within cells in several ways.
The reduction-oxidation reactions that occur during normal
metabolic processes.
Absorption of radiant energy (e.g., ultraviolet light, x-rays)
Rapid bursts of ROS are produced in activated leukocytes during
inflammation
Enzymatic metabolism of exogenous chemicals or drugs can
generate free radicals that are not ROS but have similar effects (e.g.,
CCl4 can generate CCl3.

40. Transition metals such as iron and copper donate or accept free
electrons during intracellular reactions and catalyze free radical
formation, as in the Fenton reaction
Nitric oxide (NO), an important chemical mediator generated by
endothelial cells, macrophages, neurons, and other cell types , can
act as a free radical and can also be converted to highly reactive
peroxynitrite anion (ONOO-
) as well as NO2 and NO3
-
.

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42. MECHANISM OF FREE RADICAL
INJURY
• Lipid peroxidation  damage to cellular and
organellar membranes
• Protein cross-linking and fragmentation due to
oxidative modification of amino acids and proteins
• DNA damage due to reactions of free radicals with
thymine

43. REVERSIBLE INJURY -- MORPHOLOGY
• Light microscopic changes
– Cell swelling
– Fatty change

44. • The ultrastructural changes of reversible cell injury include:
Plasma membrane alterations, such as blebbing, blunting, and loss
of microvilli
Mitochondrial changes including swelling and the appearance of
small amorphous densities
 Dilation of the ER, with detachment of polysomes;
intracytoplasmic myelin figures may be present
Nuclear alterations, with disaggregation of granular and fibrillar
elements

45. Cellular Swelling
•Is the result of failure of energy-dependent ion pumps in the plasma membrane
leading to an inability to maintain ionic & fluid homeostasis
•first manifestation of almost all forms of injury to cells microscopically small,
clear vacoules may be seen within the cytoplasm sometimes called hydropic
change or vacoular degeneration
•swelling of cells is reversible
Hydropic change kidney. The tubular epithelial cells are
distended with cytoplasmic vacuoles while the interstitial
vasculature iscompressed. The nuclei of affected tubules
are pale

46. Fatty Change
* occurs in hypoxic injury & various forms of toxic( alcohol & halogenated hydrocarbons like
chloroform) or metabolic injury like diabetes mellitus & obesity manifested by the appearance of lipid
vacoules in the cytoplasm
principally encountered in cells participating in and involved in fat metabolism e.g. hepatocytes &
myocardial cells
It is also reversible
Fatty liver. Many of the hepatocytes are distended with
large fat vacuoles pushing the nuclei to the periphery
(macrovesicles),while others show multiple small
vacuoles in the cytoplasm (microvesicles).

47. SUBCELLULAR RESPONSES TO CELL INJURY
•Autophagic vacuoles
•Induction/hypertrophy of SER
•Abnormal mitochondria
•Cytoskeletal abnormalities

49. AUTOLYSIS
Autolysis (i.e. self-digestion) is disintegration of the cell by its own hydrolytic
enzymes liberated from lysosomes. Autolysis is rapid in some tissues rich in
hydrolytic enzymes such as in the pancreas, and gastric mucosa; intermediate in
tissues like the heart, liver and kidney; and slow in fibrous tissue.Morphologically,
autolysis is identified by homogeneous and eosinophilic cytoplasm with loss of
cellular details and remains of cell as debris

50. 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.
•The enzymes responsible for digestion of the cell are derived either from
the:
1) Lysosomes of the dying cells themselves or from
2) lysosomes of leukocytes that are recruited as part of the
inflammatory reaction to the dead cells

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52. Morphologic alterations in Necrosis
•Increased eosinophilia (pink staining from eosin dye)
• Myelin figures ( whorled phospholipid masses)
•Nuclear changes assume one of three patterns all due to breakdown of DNA
& chromatin:
1)Karyolysis: The basophilia of the chromatin may fade a change that
presumably reflects loss of DNA because of enzymatic degradation by
endonucleases
2)Pyknosis characterized by nuclear shrinkage and increased basophila
3)Karyorrhexis – fragmentation and dissolution of the pyknotic nuclei
•Breakdown of plasma membrane and organellar Membranes
•Leakage and enzymatic digestion of cellular contents

53. PATTERNS OF TISSUE NECROSIS
Coagulative Necrosis
A form of tissue necrosis in which the component cells are dead but the basic
tissue architecture is preserved for at least several days
A wedge-shaped kidney Infarct
(yellow) with preservation of the
outlines

54. • the injury denatures not only structural proteins but also enzymes and so blocks the proteolysis
of the dead cells; as a result, eosinophilic, anucleate cells may persist for days or weeks.
• Ultimately the necrotic cells are removed by phagocytosis by infiltrating leukocytes and by
digestion of the dead cells by the action of lysosomal enzymes of the leukocytes.
• Ischemia caused by obstruction in a vessel may lead to coagulative necrosis of the supplied
tissue in all organs except the brain. A localized area of coagulative necrosis is called an
infarct.
Coagulative necrosis in infarct kidney. The affected
area on right shows cells with intensely eosinophilic
cytoplasm of tubular cells but the outlines of tubules
are still maintained. The nuclei show granular debris.
The interface between viable and non-viable area
shows nonspecific chronic inflammation and
proliferating vessels.

55. Liquefactive Necrosis
•Seen in focal bacterial or occassionally fungal infections because microbes
stimulate the accumulation of Inflammatory cells and the enzymes of leukocytes
digest ( “liquefy”) the tissue
•Associated with suppurative inflammation (accumulation of pus)
•The areas undergoing necrosis are transformed into a Semi-solid consistency or
state (liquid viscuous mass) Example: abcess
•The necrotic material is frequently creamy yellow because of the presence of
dead leukocytes and is called pus.
•Hypoxic death of cells within the central nervous system often manifests as
liquefactive necrosis

56. LIQUEFACTIVE NECROSIS. AN INFARCT IN THE BRAIN,
SHOWING DISSOLUTION OF TISSUE

57. Liquefactive necrosis brain. The necrosed area on right
side of the field shows a cystic space containing cell
debris, while the surrounding zone shows granulation
tissue and gliosis

58. Caseous necrosis
• is encountered most often in foci of tuberculous infection. The
term “caseous” (cheeselike) is derived from the friable white
appearance of the area of necrosis.
• On microscopic examination, the necrotic area appears as a
collection of fragmented or lysed cells and amorphous granular
debris enclosed within a distinctive inflammatory border; this
appearance is characteristic of a focus of inflammation known as a
granuloma.

59. Caseous necrosis lymph node. There is
eosinophilic, amorphous, granular material,
while the periphery shows granulomatous
inflammation.

60. FAT NECROSIS
refers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases
into the substance of the pancreas and the peritoneal cavity
Occurs in acute pancreatitis
In this disorder pancreatic enzymes leak out of acinar cells and liquefy the
membranes of fat cells in the peritoneum. The released lipases split the
triglyceride esters contained within fat cells. . The fatty acids, so derived,
combine with calcium to produce grossly visible chalky-white areas (fat
saponification)

61. Fat necrosis. The areas of white chalky deposits represent foci of
fat necrosis with calcium soap formation (saponification) at sites
of lipid breakdown in the mesentery.

62. Fat necrosis in acute pancreatitis. There is cloudy
appearance of adipocytes, coarse basophilic granular
debris while the periphery shows a few mixed
inflammatory cells.

63. Fibrinoid necrosis
• is a special form of necrosis usually seen in immune reactions
involving blood vessels. This pattern of necrosis typically occurs
when complexes of antigens and antibodies are deposited in the
walls of arteries.
• Deposits of these “immune complexes,” together with fibrin that
has leaked out of vessels, result in a bright pink and amorphous
appearance in H&E stains, called “fibrinoid” (fibrin-like) . eg
immunologically mediated vasculitis syndromes

64. Fibrinoid necrosis in autoimmune vasculitis. The vessel
wall shows brightly pink amorphous material and nuclear
fragments of necrosed neutrophils

65. Gangrenous Necrosis
This is not a distinctive pattern of cell death
It is usually applied to a limb, generally the lower leg, that has lost its blood
supply involving multiple tissue layers
Types:
•Wet gangrene
Occurs in naturally moist areas like mouth, bowels,lungs
Characterized by bacterial growth
•Dry gangrene
begins at the distal part of the limb due to ischemia and often
occurs in the toes and feet of elderly patients due to arteriosclerosis
This is mainly due to arterial occlusion
There is limited putrefaction and bacteria fail to survive

66. APOPTOSIS (“FALLING OFF”)
Is a pathway of cell death that is induced by a tightly regulated suicide
program in which cells destined to die activate enzymes capable of degrading
the cells own nuclear DNA and nuclear and cytoplasmic proteins
It differs from necrosis in the following characteristics
1)Plasma membrane of the apoptotic cell remains intact
2)Has no leakage of cellular contents
3)Does not elicit an inflammatory reaction in the host
Sometimes coexist with necrosis
Apoptosis induced by some pathologic stimuli may progress to necrosis

67. Physiologic Processes:
1. Organised cell destruction in sculpting of tissues during development of embryo.
2. Physiologic involution of cells in hormone-dependent tissues
e.g. endometrial shedding, regression of lactating breast after withdrawal of breast-feeding.
3. Normal cell destruction followed by replacement proliferation such as in intestinal epithelium.
4. Involution of the thymus in early age.
Pathologic Processes:
1. Cell death in tumours exposed to chemotherapeutic agents.
2. Cell death by cytotoxic T cells in immune mechanisms such as in graft-versus-host disease and rejection
reactions.
3. Progressive depletion of CD4+T cells in the pathogenesis of AIDS.
4. Cell death in viral infections e.g. formation of Councilman bodies in viral hepatitis.
5. Pathologic atrophy of organs and tissues on withdrawal of stimuli e.g. prostatic atrophy after
orchiectomy, atrophy of kidney or salivary gland on obstruction of ureter or ducts, respectively.
6. Cell death in response to injurious agents involved in causation of necrosis e.g. radiation, hypoxia and
mild thermal injury.
7. In degenerative diseases of CNS e.g. in Alzheimer’s disease, Parkinson’s disease, and chronic infective
dementias.
8. Heart diseases e.g. heart failure, acute myocardial infarction(20% necrosis and 80% apoptosis).

68. MORPHOLOGIC CHANGES IN
APOPTOSIS• Cell shrinkage. The cell is smaller in size; the cytoplasm is dense
and the organelles, though relatively normal, are more tightly
packed .
• Chromatin condensation. This is the most characteristic
feature of apoptosis. The chromatin aggregates peripherally, under
the nuclear membrane, into dense masses of various shapes and
sizes .The nucleus itself may break up, producing two or more
fragments.

69. • Formation of cytoplasmic blebs and apoptotic bodies. The
apoptotic cell first shows extensive surface blebbing, then
undergoes fragmentation into membrane-bound apoptotic bodies
composed of cytoplasm and tightly packed organelles, with or
without nuclear fragments .
• Phagocytosis of apoptotic cells or cell bodies, usually by
macrophages. The apoptotic bodies are rapidly ingested by
phagocytes and degraded by the phagocyte's lysosomal enzymes

72. Two Major Pathways in the Initiation of Apopotosis
1)Mitochondrial ( intrinsic) pathway
Triggered by loss of survival signals, DNA damage and accumulation of
misfolded proteins (ER stress)
2)Death receptor (extrinsic) pathway
Responsible for the elimination of self-reactive lymphocytes and damage by
cytotoxic T lymphocytes

75. EXECUTION
After the appropriate stimulus has been received by the cell and the necessary
controls exerted, a cell will undergo the organized degradation of cellular organelles
by activated proteolytic caspases.
A cell undergoing apoptosis shows a characteristic morphology that can be
observed with a microscope:
• Cell shrinkage and rounding due to the breakdown of the proteinaceous
cytoskeleton by caspases.

76. • The cell breaks apart into several vesicles called apoptotic bodies, which are then
phagocytosed.
• Apoptosis progresses quickly and its products are quickly removed, making it difficult
to detect or visualize.
• During karyorrhexis, endonuclease activation leaves short DNA fragments, regularly
spaced in size. These give a characteristic "laddered" appearance on agar gel after
electrophoresis

77. REMOVAL OF DEAD CELLS
• Dying cells that undergo the final stages of apoptosis display phagocytotic
molecules, such as phosphatidylserine, on their cell surface.
• Phosphatidylserine is normally found on the cytosolic surface of the plasma
membrane, but is redistributed during apoptosis to the extracellular surface by
a hypothetical protein known as scramblase

78. • These molecules mark the cell for phagocytosis by cells possessing the
appropriate receptors, such as macrophages. Upon recognition, the phagocyte
reorganizes its cytoskeleton for engulfment of the cell.
• The removal of dying cells by phagocytes occurs in an orderly manner
without eliciting an inflammatory response.

80. DIFFERENCE BETWEEN APOPTOSIS & NECROSIS
FEATURE APOPTOSIS NECROSIS
Definition Programmed and coordinated cell death Cell death along with degradation of tissue
by hydrolytic enzymes
Causative agents Physiologic and pathologic processes Hypoxia, toxins
Morphology i)No Inflammatory reaction
ii)Death of single cells
iii) Cell shrinkage
iv) Cytoplasmic blebs on membrane
v) Apoptotic bodies
vi) Chromatin condensation
vii) Phagocytosis of apoptotic bodies by
macrophages
i)Inflammatory reaction always present
ii) Death of many adjacent cells
iii) Cell swelling initially
iv) Membrane disruption
v) Damaged organelles
vi) Nuclear disruption
vii) Phagocytosis of cell debris by macrophages
Molecular changes i)Lysosomes and other organelles intact
ii) Genetic activation by proto-oncogenes
and oncosuppressor genes, and cytotoxicT
cell-mediated target cell killing
iii) Initiation of apoptosis by intra- and
extracellularstimuli, followed by activation of
caspase pathway
(FAS-R, BCL-2, p53
i)Lysosomal breakdown with liberation of
hydrolytic enzymes
ii) Cell death by ATP depletion, membrane
damage, free radical injury

81. Anoikis is a specific type of apoptosis resulting solely from loss of survival signals derived from
attachment to extracellular matrix (ECM) and/or neighbouring cells
Anoikis is a common form of cellular murder whereby neighbouring cells squeeze a cell out by the
process of extrusion
ANOIKIS

82. MECHANISM
Bioactive lipid sphingosine-1-phosphate (S1P)
binds the G protein–coupled receptor sphingosine- 1-phosphate receptor 2 (S1P2) in their
neighbouring cells
activate Rho-mediated contraction of an actomyosin ring
Actomyosin contraction squeezes cells apically out of the
epithelial monolayer, while neighboring cells move in to prevent
a gap from forming, thus preserving epithelial
barrier function

83. OTHER CELL DEATH
MODALITIES

84. AUTOPHAGIC CELL DEATH
Autophagy is a conserved catabolic process that degrades cellular contents and recycles damaged
organelles
During autophagy, cells form autophagosomes that capture cellular contents and target them for
degradation
initiation, nucleation, and elongation
STEPS
INITIATION: phagophore
ULK1 complex
NUCLEATION: class III phosphatidylinositol kinase (PI3K)-Beclin1 complex
ELONGATION:two ubiquitin-like conjugation systems

85. The Atg12-Atg5-Atg16 complex promotes lipidation of the microtubule-associated protein 1
light chain 3 (LC3) with phosphatidylethanolamine (PE) to form the LC3-II complex, which
elongates the membranes of the forming autophagosome. The LC3-II complex remains
covalently bound to the mature autophagosome until it fuses with the lysosome to form an
autolysosome. Lysosomal hydrolases degrade the contents of the autolysosome, including
internalized LC3, so that molecules, particularly amino acids, can be released into the cytosol to
serve as building blocks to conserve energy and rebuild organelles
autosis represents a distinct cell death mechanism that is similar to ACD. Autosis is morphologically
characterized by the disappearance of the endoplasmic reticulum and by convolution
and swelling of the perinuclear space
AUTOSIS

86. SECONDARY NECROSIS
Necrosis can also result when apoptotic cells are not phagocytosed after undergoing apoptosis, in a
process termed secondary necrosis
CASPASE 3
Cleave DFNA5
Convert to DFNA5-N fragment
Insert into plasmamembrane
Pore created
Realease inflammatory molcules

87. OTHER FORMS OF NECROSIS
PYROPTOSIS
Pyroptosis is an essential antimicrobial response that triggers a cell-autonomous inflammatory
form of regulated cell death in response to bacteria, viral, fungal, and protozoan infections

88. NECROPTOSIS
The best-characterized form of regulated necrotic cell death is necroptosis, a pathway important in
inflammation and viral infection

89. FERROPTOSIS
Ferroptosis, an iron-dependent form of regulated cell death

90. PHAGOPTOSIS
Phagoptosis is a form of cell murder that occurs when a phagocyte consumes an otherwise viable
cell

91. ENTOSIS
entosis occurs when a live cell drives itself inside another cell, rather than passively being eaten

92. PARTHANATOS
Parthanatos is a form of regulated necrosis caused by PARP-1 overactivation during traumatic
brain injury, excitotoxicity, and ischemia and in many neurodegenerative disorders

93. NETosis
NETosis is a form of proinflamatory response of neutrophils to immobilize and kill the extracellular
pathogen, which causes release of NETs (neutrophil extracellular traps) made of DNA following cell lysis

94. RECOVERY FROM THE BRINK OF DEATH

95. Anastasis refers to cellular recovery from the brink of apoptotic death. Anastasis is a process by
which cells survive executioner caspase activation following transient exposure to a lethal dose of an
apoptotic stimulus.
ANASTASIS

96. 1.A number of heat-shock proteins can suppress MOMP and caspase activation.
2.Fragmented mitochondria glue themselves back together, while a subset of
mitochondria remain intact or partially functional to supply energy to help cells recover.
3.Messenger RNAs that accumulate before the cells die from apoptosis could support a
quick recovery.
4.Damaged proteins, mitochondria, and other cellular components are removed,
possibly via autophagy and other mechanisms.
5.Cells lose the phosphatidylserine “eat me” signal from their surfaces.
6. Anastasis can induce angiogenesis and cell migration, which could enhance nutrient
absorption and remove waste resulting from apoptosis. It can also arrest the cell cycle to
give the cell time to repair.

98. RESUSCITATION
Necroptosis is a programmed version of necrosis, a form of cell death linked with uncontrolled
reactions to injuries or stress. The process involves the protein MLKL poking holes in the plasma
membrane, which causes the cells to rupture. However, the cell can blunt this process through the
ESCRT-III protein complex, which isolates these holes onto bubbles in the plasma membrane.
Shedding these bubbles then repairs the cells, a process called “resuscitation.”

99. Hijacking entosis
In entosis, one cell engulfs another living cell, which is then killed and digested by lysosomes.
Sometimes engulfed cells survive, even proliferating within their cellular captor or escaping
altogether

100. FERROPTOSIS
Ferroptosis is a regulated form of cell death that is dependent on iron. Cells initiate this pathway
when normal uptake and metabolism of the amino acid cysteine (cystine is the oxidized dimer form
of cysteine) is disturbed. Once triggered, ferroptosis will result in cell death in a few hours. However,
researchers administer lipophilic antioxidants or iron chelators to completely protect cells from
succumbing to this form of cell death

101. DYSTEGULATION OF CELL DEATH AND SURVIVAL IN
CANCER
1. Autophagy
Tumor cells can have high metabolic needs and experience oxygen and nutrient deficiencies
as they enter new microenvironments, so enhancing autophagy can enable their survival
• hypoxia can stimulate adaptive autophagy through hypoxia-inducible factor 1 alpha (HIF1-
α)-dependent activation of proapoptotic proteins that induce autophagy without triggering
cell death
Similarly, under nutrient deprivation conditions,AMPkinase activates catabolic autophagy,
which provides nutrients required for tumor survival
• Ras-driven cancers are notably addicted to autophagy, a process that likely promotes
growth of the primary tumor, as well as survival after invasion, essential for metastasis

102. 2.Entosis
Entosis appears frequently in cancer, with a third of the cells in breast cancers showing internalized
live cells
Entosis may act as a tumor suppressor by internalizing and killing abnormally dividing cells
However, entosis can also promote tumor formation, as entosed cells can interfere with
cytokinesis of the host cell, leading to aneuploidy
Entosed cancer cells may be able to survive and proliferate inside another cell during metabolic
stress and starvation—conditions commonly seen in tumors.

103. 3.RESISTING ANOIKIS
Anoikis is an indispensable mechanism for maintaining tissue homeostasis by preventing cells
from surviving at sites where they do not belong. Thus, resistance to anoikis is a critical step for
tumor cell invasion and metastasis
upregulation of epidermal growth factor receptor (EGFR) families plays an important role in
overriding anoikis

104. INTRACELLULAR ACCUMULATIONS
THREE MAIN PATHWAYS OF ABNORMAL INTRACELLULAR
ACCUMULATIONS
1.A normal substance is produced at abnormal or an increased rate, but
metabolic rate is inadequate to remove it
Example. Fatty change in the liver

105. 2. A normal or abnormal endogenous substance accumulates because of genetic or
acquired defects in its folding, packaging, transport or secretion
Example. Accumulation of of proteins in anti-trypsin deficiency
3. An abnormal exogenous substance is deposited and accumulates because the cell has
neither the enzymatic machinery to degrade the substance nor the ability to transport It to
other sites.
Example. Accumulation of carbon or silica particles

106. FATTY CHANGE (STEATOSIS)
Refers to any abnormal accumulation of triglycerides within parenchymal cells
Most often seen in the liver but may also occur in the heart, Skeletal muscle,
kidney and other organs
May be caused by toxins, protein malnutrition, diabetes mellitus, obesity and
anoxia
Alcohol abuse and diabetes associated with obesity are the most common
causes of fatty liver

107. Cholesterol and Cholesteryl Esters
Result of defective catabolism and excessive intake
Present in lipid vacoules of smooth muscle cells and macrophages in
atherosclerosis (hardening of the aorta)
Give atherosclerotic plaques their characteristic yellow color and contibute to the
pathogenesis of the lesion
Xanthomas are hypercholesterolemic tumurous masses found in the connective
tissue of the skin or tendons

108. Proteins
Intracellular accumulations of proteins usually appear as rounded, eosinophilic
droplets, vacuoles, or aggregates in the cytoplasm.
By electron microscopy they can be amorphous, fibrillar, or crystalline in
appearance
Pathologic accumulation of proteins in the cytoplasm of cells may occur in the following conditions
1.In proteinuria, there is excessive renal tubular reabsorption of proteins by the proximal tubular
epithelial cells which show pink hyaline droplets in their cytoplasm. The change is reversible so that
with control of proteinuria the protein droplets disappear.
2. The cytoplasm of actively functioning plasma cells shows pink hyaline inclusions called Russell’s
bodies representing synthesised immunoglobulins.
3. In α1-antitrypsin deficiency, the cytoplasm of hepatocytes shows eosinophilic globular deposits of a
mutant protein.
4. Mallory’s body or alcoholic hyalin in the hepatocytes is intracellular accumulation of intermediate
filaments of cytokeratin and appear as amorphous pink masses

110. Glycogen
Accumulations of these are associated with abnormalities in the metabolism of
either glucose or glycogen
Ex.
1)In poorly controlled diabetes mellitus, glycogen accumulates in renal tubular
epithelium, cardiac myocytes, and β cells of Islets of langerhans
2)Glycogen storage diseases or glycogeneses are Genetic disorders
where glycogen accumulates in macrophages of patients with defects in
lysosomal enzymes

111. Hepatic glycogenosis

112. Pigments
Pigments are coloured substances present in most living
beings including humans. There are 2 broad categories of
pigments: endogenous and exogenous
Exogenous – Exogenous pigments are the pigments introduced into the body
from outside such as by inhalation, ingestion or inoculation
1)Inhaled pigments
Aggregates of the pigment eg: carbon, blacken the draining lymph nodes and
pulmonary parenchyma (Anthracosis)
Heavy accumulations may induce emphysema or a fibroblastic reaction that
can result in a serious lung disease called coal workers pneumoconiosis

113. Anthracosis lung. There is presence of abundant coarse black carbon
pigment in the septal walls and around the bronchiole.

114. Ingested Pigments
Chronic ingestion of certain metals may produce pigmentation. The examples are as under:
i)Argyria is chronic ingestion of silver compounds and results in brownish pigmentation in the skin,
bowel, and kidney.
ii) Chronic lead poisoning may produce the characteristic blue lines on teeth at the gumline.
iii) Melanosis coli results from prolonged ingestion of certain cathartics.
iv) Carotenaemia is yellowish-red colouration of the skin caused by excessive ingestion of carrots
which contain carotene.
Injected Pigments (Tattooing)
Pigments like India ink, cinnabar and carbon are introduced into the dermis in the process of
tattooing where the pigment is taken up by macrophages and lies permanently in the
connective tissue.

115. Endogenous – synthesized within the body itself
1)Lipofuscin or “wear-and -tear pigment or lipochrome
An insoluble brownish-yellow granular intracellular material that accumulates in
the heart, liver, & brain as a function of age or atrophy represents complexes of
lipid & protein that derive from the free radical-catalyzed peroxidation of
polyunsaturated lipids
It is not injurious to the cell but is important as a marker of past free-radical
Injury
The brown pigment when present in large amounts, imparts an appearance
to the tissue that is called brown atrophy
Brown atrophy of the heart. The lipofuscin pigment
granules are seen in the cytoplasm of the myocardial
fibres, especially around the nuclei.

116. 2) Melanin
Melanin, derived from the Greek (melas, black), is an endogenous, non-
hemoglobin-derived, brown-black pigment formed when the enzyme
tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine in
melanocytes.
Compound naevus showing clusters of benign naevus
cells in the dermis as well as in lower epidermis. These
cells contain coarse, granular, brown-black melanin
pigment

117. 3) Hemosiderin
A hemoglobin-derived granular pigment that is golden yellow to brown
and accumulates in tissues when there is a local or systemic excess of
iron
Iron can be identified by the Prussian blue reaction
Haemosiderin pigment in the cytoplasm of
hepatocytes seen as Prussian blue granules

118. 4)Homogentisic acid, a black pigment that occurs in patients with
alkaptonuria, a rare metabolic disease. Here the pigment is
deposited in the skin, connective tissue, and cartilage, and the
pigmentation is known as ochronosis

119. Deposition of calcium salts in tissues other than osteoid or
enamel is called pathologic or heterotopic calcification. Two
distinct types of pathologic calcification are recognised:
Dystrophic calcification, which is characterised by deposition
of calcium salts in dead or degenerated tissues with normal
calcium metabolism and normal serum calcium
levels.
Metastatic calcification, on the other hand, occurs in
apparently normal tissues and is associated with deranged
calcium metabolism and hypercalcaemia
PATHOLOGIC CALCIFICATION

120. DYSTROPHICCALCIFICATION.
dystrophic calcification may occur due to 2 types of causes:
Calcification in dead tissue
Calcification of degenerated tissue.
Calcification in dead tissue
1. Caseous necrosis in tuberculosis is the most common site for dystrophic calcification.
2. Liquefaction necrosis in chronic abscesses may get calcified.
3. Fat necrosis following acute pancreatitis or traumatic fat necrosis in the breast results in
deposition of calcium soaps.
4. Gamna-Gandy bodies in chronic venous congestion (CVC) of the spleen is characterised by
calcific deposits admixed with haemosiderin on fibrous tissue.
5. Infarcts may sometimes undergo dystrophic calcification.
6. Thrombi, especially in the veins, may produce phleboliths.
7. Haematomas in the vicinity of bones may undergo dystrophic calcification.
8. Dead parasites like in hydatid cyst, Schistosoma eggs, and cysticercosis are some of the
examples showing dystrophic calcification.

121. Dystrophic calcification in caseous necrosis in
tuberculous lymph node. In H & E, the deposits are
basophilic granular while the periphery shows healed
granulomas

122. Calcification in degenerated tissues
1. Dense old scars may undergo hyaline degeneration and subsequent calcification.
2. Atheromas in the aorta and coronaries frequently undergo calcification.
3. Mönckeberg’s sclerosis shows calcification in the tunica
media of muscular arteries in elderly people
4. Stroma of tumours such as uterine fibroids, breast cancer, thyroid adenoma, goitre etc show
calcification.
5. Some tumours show characteristic spherules of calcification called psammoma bodies or
calcospherites such as in meningioma, papillary serous cystadenocarcinoma of the
ovary and papillary carcinoma of the thyroid.
6. Cysts which have been present for a long time may show calcification of their walls e.g.
epidermal and pilar cysts.
7. Calcinosis cutis is a condition of unknown cause in which there are irregular nodular deposits
of calcium salts in the skin and subcutaneous tissue.
8. Senile degenerative changes may be accompanied by dystrophic calcification such as in costal
cartilages, tracheal or bronchial cartilages, and pineal gland in the brain etc.

123. Pathogenesis of dystrophic calcification.
Since serum calcium levels are within normal limits, the denatured proteins in
necrotic or degenerated tissue bind phosphate ions, which react with calcium
ions to form precipitates of calcium phosphate.
The process of dystrophic calcification has been likened to the formation of
normal hydroxyapatite in the bone involving 2 phases: initiation and
propagation.
Initiation is the phase in which precipitates of calcium phosphate begin to
accumulate intracellularly in the mitochondria, or extracellularly in membrane-
bound vesicles.
Propagation is the phase in which minerals deposited in the initiation phase are
propagated to form mineral crystals

124. METASTATIC CALCIFICATION.
Since metastatic calcification occurs in normal tissues due to hypercalcaemia, its
causes would include one of the following two conditions:
Excessive mobilisation of calcium from the bone.
Excessive absorption of calcium from the gut.
Excessive mobilisation of calcium from the bone.
1. Hyperparathyroidism which may be primary such as due to parathyroid adenoma, or secondary
such as from parathyroid hyperplasia, chronic renal failure etc.
2. Bony destructive lesions such as multiple myeloma, metastatic carcinoma.
3. Prolonged immobilisation of a patient results in disuse atrophy of the bones and hypercalcaemia
Excessive absorption of calcium from the gut.
excess calcium may be absorbed from the gut causing
hypercalcaemia and metastatic calcification. These causes are as under:
1. Hypervitaminosis D results in increased calcium absorption.
2. Milk-alkali syndrome caused by excessive oral intake of calcium in the form of milk and
administration of calcium carbonate in the treatment of peptic ulcer.
3. Hypercalcaemia of infancy is another condition in which metastatic calcification may occur.

125. Pathogenesis of metastatic calcification.
Metasatic calcification occurs due to excessive binding of inorganic phosphate ions with calcium
ions, which are elevated due to underlying metabolic derangement. This leads to formation of
precipitates of calcium phosphate at the preferential sites. Metastatic calcification is reversible
upon correction of underlying metabolic disorder.
Metastatic calcification in tubular basement
membrane
in nephrocalcinosis due to hypercalcaemia.

126. CELLULAR AGING
results from combination of accumulating cellular damage (e.g., by free
radicals), reduced capacity to divide (replicative senescence), and reduced
ability to repair damaged DNA
Mechanisms known or suspected to be responsible for cellular aging
Decreased cellular replication
Accumulation of metabolic and genetic damage

128. • Decreased cellular replication: After a fixed number of
divisions all somatic cells become arrested in a terminally
nondividing state, known as senescence.
• One probable mechanism in human cells is that with each cell
division there is incomplete replication of chromosome ends
(telomere shortening), which ultimately results in cell cycle arrest.
• Telomeres are short repeated sequences of DNA (TTAGGG)
present at the linear ends of chromosomes that are important for
ensuring the complete replication of chromosomal ends and for
protecting chromosomal termini from fusion and degradation.

129. • Telomere length is normally maintained by nucleotide addition
mediated by an enzyme called telomerase.
• Telomerase is a specialized RNA-protein complex that uses its own
RNA as a template for adding nucleotides to the ends of
chromosomes.
• Telomerase activity is highest in germ cells and present at lower
levels in stem cells, but it is usually undetectable in most somatic
tissues Therefore, as somatic cells divide, their telomeres become
shorter, and they exit the cell cycle, resulting in an inability to
generate new cells to replace damaged ones.

131. • Accumulation of metabolic and genetic damage: Increased
oxidative damage could result from repeated environmental
exposure to such influences as ionizing radiation, mitochondrial
dysfunction, or reduction of antioxidant defense mechanisms with
age (e.g., vitamin E, glutathione peroxidase).
• The amount of oxidative damage, which increases as an organism
ages, may be an important cause of senescence.

132. MOLECULAR MECHANISM

134. CONCLUSION
• Cells are the basic structural units of tissues ,which form organs
and systems in the human body. In health, the cells remain in
accord with each other.
• In general, cells of the body have inbuilt mechanism to deal with
changes in environment to an extent.
• The cellular response to stress may vary and depends upon many
variables.
• Study of abnormalities in structure and function of cells in disease
has remained the focus of attention in understanding of diseases.

135. • Most forms of diseases begin with cell injury followed by
consequent loss of cellular function.
• In order to learn the fundamentals of disease processes at cellular
level, it is essential to have an understanding of the causes and
mechanisms of cell injury and cellular adaptations.

136. REFERENCES
• Textbook of pathology- Robbin’s 8th
edn.
• Unconventional Ways to Live and Die: Cell Death and Survival in Development,Homeostasis,
and Disease: Annual Review of Cell and Developmental Biology
• The scientist magazine february 2019 edition