This document summarizes key concepts relating to cell injury, adaptation, and death. It discusses how cells respond to stress through reversible or irreversible injury, adaptation, or death. It also describes various types of cellular adaptation like hypertrophy, hyperplasia, atrophy, and metaplasia that cells undergo in response to stress. Additionally, it covers the mechanisms and morphological changes associated with different types of cell injury like necrosis and apoptosis.

1. CELL INJURY,
ADAPTATION, and
DEATH

2. Normal cell is in a steady state
“Homeostasis”
Change in Homeostasis due to stimuli -
Injury
Injury - Reversible / Irreversible
Adaptation / cell death

3. CELLULAR ADAPTATION TO STRESS
Adaptations are reversible changes in the number, size, phenotype, metaboli
Physiologic adaptations are responses of cells to normal stimulation by horm
Pathologic adaptations are responses to stress that allow cells to modulate th

4. Hypertrophy
is an increase in the size of cells & consequently an increase 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
Causes:
a) increased functional demand
b) hormonal stimulation

5. Physiologic Hypertrophy of the Uterus During Pregnancy
Gravid Uterus Normal Uterus

6. Small spindle-shaped uterine Large, plump hypertrophied
smooth muscle cells from a smooth muscle cells from a
normal uterus gravid uterus

7. Heart hypertrophy in hypertens

8. Hyperplasia
is an increase in the number of cells in an organ or tissue
an adaptive response in cells capable of replication
a critical response of connective tissue cells in wound healing
Types:
a) physiologic hyperplasia
1) hormonal
ex. Proliferation of glandular epithelium of the female
breast at puberty & during pregnancy
2) compensatory – hyperplasia that occurs when a portion
of
a tissue is removed or diseased
e.g. partial resection of a liver > mitotic activity 12 hours
later
b) pathologic hyperplasia
Caused by excessive hormonal or growth factor
stimulation

10. HYPERPLASIA OF THE PROSTATE GLAND

11. Atrophy
Shrinkage in the size of the cell by the loss of cell substance
Results from decreased protein synthesis and increased protein degradation
in cells
Is accompanied in many situations by increased autophagy with resulting
Increases in autophagic vacoules
Causes:
Decreased workload
Loss of innervation
Diminished blood supply
Inadequate nutrition
Loss of endocrine stimulation
Aging (senile atrophy)

12. Atrophy of the brain in an Normal brain of a 25-year-old
82-year-old man man

13. ATROPHY IN OSTEOPOROSIS

14. Metaplasia
a reversible change in which one adult cell type ( epithelial or mes
is cellular adaptation whereby cells sensitive to a parti
able to withstand the adverse environment
Epithelial metaplasia
Examples
Squamos change that occurs in the respiratory epithelium in habit
Vitamin A deficiency
Chronic gastric reflux, the normal stratified squamos epithelium of

15. Schematic diagram of columnar to squamos epithelial
B. Metaplastic transformation of esophageal epithelium
Mesenchymal metaplasia Ex. Bone formed in soft
tissue particularly in foci of injury

16. METAPLASIA-ESOPHAGUS

17. METAPLASIA-LUNGS

18. CELLULAR INJURY
Cell Injury- pertains to the sequence of events when cells have no adap
Types of Cell Injury
1. Reversible Injury- injury that persists within certain limits, cells return
2. Irreversible Injury- when the stimulus causing the injury persists and i
a. necrosis
b. apoptosis

19. 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
2. Chemical Agents
a. glucose, salt or oxygen
b. poisons
c. environmental toxins
d. social “stimuli”
e. therapeutic drugs
3. Physical agents- trauma, extremes of temperature, radiation, electric
shock, & sudden changes in atmospheric pressure
4. Infectious agents

20. 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

21. MORPHOLOGY OF CELL AND TISSUE INJURY
All stresses & noxious influences exert their effects first at the molecula
Cellular function is lost far before cell death occurs and the morphologic
Ultrastructural Changes of Reversible Cell injury
Alteration in plasma membrane reflecting disturbance in ion and v
2. Mitochondrial changes
3. Endoplasmic reticulum changes
4. Nuclear alterations

22. PLASMA MEMBRANE ALTERATIONS
Cellular swelling
Formation of cytoplasmic
blebs
Blunting and distortion of
microvilli
Deterioration and loosening
of intercellular attachments

23. Mithochondrial Changes
Early it appears condensed as a r
Followed by swelling due to ionic
Amorphous densities which corre
Finally, rupture of membrane follo

24. Endoplasmic Reticulum Changes
Dilation
Detachment of
ribosomes and
dissociation of
polysomes with
decreased protein
synthesis
Progressive
fragmentation and
formation of
intracellular
aggregates of myelin
figures

25. Nuclear Alterations
Disaggregation of
granular and
fibrillar elements

26. Two Patterns of Morphologic Change Correlating to
Reversible Injury that can be recognized under the light
Microscope: cellular swelling and fatty change
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

27. Hydropic degeneration: kidney
Cloudy swelling & hydropic change reflect failure of membrane
ion pumps, due to lack of ATP, allowing cells to accumulate
fluid

28. 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
also reversible

29. Morphologic Alterations in Reversible Cell Injury
Cell swelling
Fatty change
Plasma membrane blebbing and loss of microvilli
Mitochondrial swelling
Dilation of the ER
Eosinophilia (due to decreased cytoplasmic RNA)

30. NECROSIS
Refers to a series of changes that accompany cell
death, largely resulting from the degradative action of
enzymes on lethally injured cells
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

31. 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
2) Pyknosis characterized by nuclear shrinkage and
increased basophila
3) Karyorrhexis – fragmentation and dissolution
Breakdown of plasma membrane and organellar
Membranes
Leakage and enzymatic digestion of cellular contents

32. 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
It is characteristics of infarcts ( areas of ischemic
necrosis) in all solid organs except the brain
A wedge-shaped kidney
Infarct (yellow) with
preserva
tion of the outlines

33. 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
This necrosis is characteristic of hypoxic death of cells
witnin the CNS
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

34. Liquefactive necrosis. An infarct in the brain, showing
dissolution of tissue

35. Caseous Necrosis
Encountered most often infoci of tuberculous infection
Characterized by a cheesy yellow-white appearance of
the area of necrosis
It is often enclosed within a distinctive inflammatory
border
A tuberculous lung with a large
area of caseous necrosis
containing yellow-white and
cheesy debris

36. 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
Fat necrosis in aqcute pancreatitis. The areas of white chalky deposits
represent foci of fat necrosis with calcium soapformation (saponification)
at sites of lipid breakdown in the mesentery

37. Fibrinoid necrosis
A special form of necrosis usually seen in immune
reactions involving blood vessels
This pattern of necrosis is prominent 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 called 'fibrinoid”
Fibrinoid necrosis in an artery
in a patient with Polyarteritis
Nodosa. The wall of the artery
shows a circumferential bright
pink area of necrosis with
protein deposition and
inflammation

38. 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 numerous bacteria
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

40. SUBCELLULAR RESPONSES TO INJURY
Autophagy
Refers to lysosomal digestion of the cell's own
It is thought to be a survival mechanism in times of nutrient
deprivation
Organelles are enclosed in vacoules that fuse with
lysosomes
Heterophagy a cell usually a macrophage ingests
substances from the outside for intracellular destruction

42. Hypertrophy of Smooth Endoplasmic Reticulum
Cells exposed to toxins that are metabolized in the SER show hyp
Mitochondrial Alterations
* alterations in size, number, shape & function
Ex. Mitochondria assume extremely large & abnormal shapes (
Cellular hypertrophy > # of mitochondria in cells
Atrophy < # of mitochondria
Cytoskeletal Abnormalities
some drugs & toxins interfere with the assembly & functions o
accumulations of filaments

43. General Principles Relevant To Most Forms Of Cell Injury
The cellular response to injurious stimuli depends on the type of
injury, its duration, and its severity
The consequences of an injurious stimulus depend on the type ,
status , adaptability , and genetic makeup of the injured cell
Cell injury results from functional & biochemical abnormalities in
one or more of several essential cellular components
The most important target of injurious stimuli are:
1) cell membrane integrity, critical to cellular ionic and osmotic
homeostasis
2) mitochondrial, the site of adenosine triphosphate (ATP)
generation
3) protein synthesis
4) integrity of the genetic apparatus
5) cytoskeleton

44. MECHANISMS OF CELL INJURY
ATP depletion: failure of energy-dependent functions
reversible Injury necrosis
Mitochondrial damage: ATP depletion failure of energy-
dependent cellular functions ultimately necrosis;
under some conditions, leakage of proteins that causes apoptosis
Influx of calcium: activation of enzymes that damage cellular
components and may also trigger apoptosis
Accumulation of reactive oxygen species: covalent modifications of
cellular proteins, lipids, nucleic acids
Increased permeability of cellular membranes: may affect plasma
membrane, lysosomal membranes, mitochondrial membranes;
typically culminates in necrosis
Accumulations of damaged DNA and misfolded proteins triggers
apoptosis

45. Accumulation of Oxygen-Derived Free radicals (Oxidative
Stress)
Free radicals are chemical species with single unpaired electron
in an outer orbital. In such a state the radicals are extremely
unstable & readily react with inorganic or organic chemicals.
Free radicals may be generated within cells by
Reduction-oxidation (redox) reactions
Nitric oxide (NO)
Absorption of radiant energy (e.g. ultraviolet light, x-rays)
Enzymatic metabolism of exogenous chemicals (e.g. carbon
tetrachloride)
Inflammation, because free radicals are produced by leukocytes
that enter tissues

46. Mechanisms that remove Free radicals
Action of superoxide dismutases (SODS)
Glutathione (GSH) peroxidase
Catalase present in perixisomes
Endogenous or exogenous antioxidants (e.g. vitamins E, A
and C, and beta-Carotene may either block the formation of
free radicals or scavenge them once they have formed
Iron and Copper can catalyze the formation of Reactive
Oxygen Species (ROS)

47. 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

48. Causes of Apoptosis
Apoptosis in Physiologic Situations
Death by apoptosis is a normal phenomenon that
serves to eliminate cells that are no longer needed and to
maintain a steady number of various cell populations in tissues
Programmed destruction of cells during embryogenesis,
Including implantation, organogenesis, developmental
involution, and metamorphosis
Involution of hormone- dependent tissues upon hormone
deprivation such as endometrial cell breakdown during the
menstrual cycle and regeression of the lactating breast after
Weaning
Cell loss in proliferating cell populations, such as intestinal
Crypt epithelia

49. Death of cells that have served their useful purpose, such
as neutrophils in an acute inflammatory response and
Lymphocytes at the end of an immune response
Elimination of potentially harmful self-reactive lymphocytes
Either before or after they have completed their maturation
Cell death induced by cytotoxic T lymphocytes, a defense
mechanism against viruses and tumors that serves to kill
eliminate virus-infected and neoplastic cells

50. Apoptosis in Pathologic Situations
Apoptosis eliminates cells that are genetically altered or
Injured beyond repair without eliciting a severe host reaction,
thus keeping the damage as contained as possible
DNA damage
Radiation, cytotoxic anticancer drugs, extremes of
temperature and even hypoxia can damage DNA either
directly or via production of free radicals
Accumulation of misfolded proteins
These may arise because of mutations in the genes
encoding these proteins or because of extrinsic factors
such as free radicals
Excessive accumulation of these proteins in the ER leads
to a condition called ER stress

51. Cell injury in certain infections particularly viral infections
Pathologic atrophy in parenchymal organs after duct
obstruction such as in pancreas, parotid gland and kidney
Morphologic Alterations in Apoptosis
Nuclear chromatin condensation
Formation of apoptotic bodies ( fragments of nuclei and
cytoplasm)
The fundamental event in apoptosis is the activation of enzyme
called caspases

52. 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

53. INTRACELLULAR ACCUMULATIONS
THREE MAIN PATHWAYS OF ABNORMAL INTRACELLULAR
ACCUMULATIONS
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
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
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

54. 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

55. Fatty Liver

56. 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

57. Proteins
Less common than lipid accumulations
Occur because excess are presented to the cells or
because the cells synthesize excessive amounts
Examples:
1) Nephrotic syndrome there is heavy protein leakage
across the glomerular filter due to a much larger
reabsorption of albumin
2) accumulation of newly synthesized imunoglobulins
in RER of some plasma cells forming rounded,
eosinophilic Russell bodies
3) Mallory body or “ alcoholic hyalin” is an eosinophilic
cytoplasmic inclusion in liver cells highly characteristic
of alcoholic liver disease
4) Neurofibrillary tangle found in the brain in Alzheimer
disease

58. Protein reabsorption droplets in the renal tubular epithelium

59. 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

60. Pigments
colored substances that are either exogenous or
endogenous
Exogenous – coming from outside the body
1) Carbon ( ex. Coal dust)
Most common air pollutant
Aggregates of the pigment 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

61. 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

62. The pale golden brown finely granular pigment seen here in nearly
all hepatocytes is lipochrome (lipofuscin).

63. 2) Melanin
An endogenous, brown-black pigment synthesized
exclusively by melanocytes when the enzyme tyrosinase
catalyzes tyrosine to (DOPA) dihydroxyphenylalanine
located in the epidermis
Acts as a screen against harmful ultraviolet radiation
Basal keratinocytes in the skin can accumulate the
pigment (e.g. in freckles)

64. Melanin pigment in melanoma

65. 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 is normally stored within cells in association with the
protein apoferritin, forming ferritin micelles
Iron can be identified by the Prussian blue reaction

66. Local excess of iron & consequently of hemosiderin result
from hemorrhage
Ex. Bruise
The original red-blue color of hemoglobin is
transformed to varying shades of green-blue by the
local formation of biliverdin (green bile) and bilirubin
(red bile) from the heme moiety
The iron of hemoglobin accumulate as golden- yellow
hemosiderin

67. Hemosiderosis
a condition where hemosiderin is deposited in many
organs and tissues whenever there is systemic overload
of iron
It occurs in the following settings
Increased absorption of dietary iron
Impaired utilization of iron
Hemolytic anemias
Transfusions
Hereditary Hemochromatosis
A condition where there is extensive accumulations of iron
with tissue injury like liver fibrosis, heart failure and
diabetes mellitus
Characterized principally by
1) the deposition of hemosiderin in the following organs (in
decreasing order of severity):liver, pancreas,
myocardium, pituitary, adrenal, thyroid, joints & skin
2) cirrhosis and 3) pancreatic fibrosis

68. PATHOLOGIC CALCIFICATION
implies the abnormal deposition of calcium salts, together
with small amounts of iron, magnesium, and other minerals
TYPES
A. Dystrophic calcification
deposition of calcium in dead or dying tissues
occurs in the absence of calcium metabolic
derangements ( with normal serum levels of calcium)
Local deposits of calcium may occur in
1) necrotic tissue which is not absorbed
old infarcts
tuberculous foci
old collection of pus
dead parasites
acute pancreatic necrosis

69. 2) Tissue undergoing slow degeneration
Hyaline areas in benign tumors
Fibroids
In arteries due to atheromatous degeneration or old age
Old thrombi
Diseased or abnormal heart valves
Pathogenesis
Initiation ( or nucleation)
Propagation
Both may be intracellular or extracellular with calcium
phosphate as the end product

70. B. Metastatic Calcification
deposition of calcium salts in normal tissues
almost always reflects some derangement in calcium
metabolism ( hypercalcemia)
Four major causes of hypercalcemia
1) Increased secretion of parathyroid hormone, due to either
parathyroid tumors or production of parathyroid hormone-
Related protein by other malignant tumors
2) Destruction of bone due to the effects of accelerated
turnover (e.g. Paget disease),immobilization, or tumors
(increased bone catabolism associated with multiple
myeloma, leukemia or diffuse skeletal metastases)
3) Vitamin D-related disorders like vitamin D intoxication and
sarcoidosis ( in which macrophages activate a vitamin D
precursor
4) Renal failure, in which phosphate retention leads to
secondary hyperparathyroidism

71. 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
Cellular senescence
Aging of a person is intimately related to cellular aging
Mechanisms known or suspected to be responsible for cellular
aging
DNA damage
defective DNA repair mechanisms
DNA repair may be activated by calorie restriction (known
to prolong aging in model organisms)

72. Replicative senescence
Reduced capacity of cells to divide because of decreasing
amounts of telomerase and progressive shortening of
chromosomal ends (telomeres)
Telomeres
are short repeated sequences of DNA present at the
linear ends of chromosomes
Importance
* for ensuring the complete replication of chromosome
ends
* and for protecting the ends from fusion & degradation
Progressive accumulation of metabolic damage
Repeated environmental exposure to radiation
Progressive reduction of antioxidant defense mechanism
Like Vit. E & glutathione peroxidase
Possible roles of growth factors

73. Telomerase in Ageing:
Germ
cells
Somatic
cells

74. WERNER SYNDROME
A rare disease characterized by premature aging