Cell injury can occur through various causes like ischemia, toxins, infections, radiation, and genetic defects. The cellular response depends on the severity and duration of the injury. Mild or short injuries may result in reversible cell injury through intracellular accumulation of waste products. Strong or persistent injuries can lead to irreversible cell injury and cell death through necrosis. Cells can also undergo programmed cell death through apoptosis. When faced with stress or injury, cells can adapt through processes like atrophy, hypertrophy, hyperplasia, and metaplasia to achieve a new steady state and preserve viability between the normal and injured states.

1. Pathology for Physiotherapy
2nd week
Presented by
Dr Khamis Elessi, BSc,
MD,MSc, DipAcu.
Palestinian Board of PM&R

2. Cell Injury, Adaptation and Death
• Overview of cell injury
• Causes of cell injury
• Mechanisms of cell injury
• Cellular adaptation to injury
• Reversible and irreversible cell injury
• Programmed cell death---- apoptosis
• Cellular aging

3. Overview of cell injury
• Cells in a living, health person participate
actively in their microenvironment.
• They must adjust their structure and function to
fit the dynamic changed demands and stress.
• There must be a homeostasis to keep the
harmonization between cells and extracellular
environment which requires functional
cooperation amongst widely distributed cells.
• If the demands or stress persist a long time, or
they are too strong to exceed the adjusting
range, the cells will be damaged.

4. atrophy,
hypertrophy
hyperplasia
metaplasia
intracellular
accumulations,
degeneration

5. Cell response to injury
• When the stimuli are mild and continuous, the
involved cells, tissue and organ can fit them
through adaptation.
• When the stimuli are strong or persisted, the
cells will be dead (necrosis).
• When the stimuli are intermediate, there is
reversible cell injury: intracellular accumulation
(so called degeneration).
• Note the reversibility of injured cells.

6. Causes of cell injury
• Ischemia/hypoxia (e.g. heart attack)
• Intoxication with Chemical agents & free
radicals (toxins, preservatives, acid, drugs)
• Infectious agents (bacterial, virus, parasite)
• Immunologic reactions (hypersensitivity)
• Genetic defects (Down’s syndrome)
• Nutritional imbalances (protein insufficiency)
• Physical agents (trauma, temperature, Light)
• Aging

7. Hypoxia = deficiency in oxygen at cell Due to :
 Decreased oxygen in air
 Decreased hemoglobin or decreased oxygen
transported to cells
 Diseases of the respiratory and/or cardiovascular
system
Oxygen is important to cell because of oxidative
phosphorylation, which results in the production
of ATP

8. Cellular response to hypoxia
Decreased mitochondrial reactions 
decreased ATP produced 
decreased energy
Ion pumps cease, so can't regulate ions
into/out of cell (ATP needed for this)
Can't pump Na+ and water out of cell, so get
cell swelling  organelle swelling 
cell death

9. Mechanisms of ischemic cell injury
• ATP depletion
• Oxygen deprivation and/or generation of
reactive oxygen species (Free radicals).
• Loss of calcium homeostasis
• Defects in plasma membrane permeability
• Mitochondria damage
• Cell death

10. Mechanism of ischemic and hypoxic injury
Reversible cell
injury . Diminished
oxidative
phosphorylation
and ATP levels
play a central role
in mediating
intracellular effects
(K+ ion, Ca++ ion).
Note: all changes
are potentially
reversible, if the
blood supply
restore in time.
Glycolysis:
anaerobic
glycolysis

11. Free radicals : are chemical species (Unstable atom/s)
with a single unpaired electron on their outer orbital.
Formed by: cell metabolism reactions, radiation,
chemicals (Ex. reduction-oxidation reaction inside
mitochondria which yield small amounts of toxic
intermediate species are generated.
Atom is unstable (needs to gain or lose an electron)
• can alter chemical bonds in proteins, lipids,
carbohydrates and nucleic acids
• can cause chain reaction in cell
Common free radicals: superoxide, hydrogen peroxide
(H2O2) and hydroxyl free (OH•), nitric oxide (NO) .

12. Neutralization of free radicals
• Normally, there are several enzymic and nonenzymic
systems to inactivate free radicals. Examples.
• Superoxide dismutases (SOD) catalyze the reaction
of 2 superoxide p+ 2 hydrogens (H+) to hydrogen
peroxide (H2O2) plus oxygen (O2).
• Catalase converts hydrogen peroxides to H2O & O2.
• Glutathione peroxidase catalyzes free radical
breakdown. In Fenton reaction 2 molecules of
hydroxyl radical plus 2 molecules of reduced
glutathione (GSH) give 2 molecules of water and one
molecule of oxidized glutathione (GSSH).

13. Neutralization of free radicals

14. Cell mechanisms of injury due to Free Radicals
Free radicals/ reactive chemicals
Normal
metabolisms
O 2
OH•
H2O2
NO
Superoxide dismutases SOD/Catalase
Glutathiole peroxidase/GSSG
Vitamin E, C
Detoxification
Cell membrane
Mitochondria
Endo. Retic.
DNA

15. Effects of Free Radicals
• they attack & destroy the cell membrane,
nuclear acid, mitochondria and endoplasmic
reticulum and lead to cell damage.
• With ischemia, there will be Increased Ca++
concentration inside cells which activates
phospholipases, proteases, ATPases and
endonucleases.
• These activated enzymes lyse the structures of
cells and lead the cell death.

16. Intracellular accumulations/ Intoxication
• Substances that can’t used or disposed off & toxins inhaled or
introduced into cell. Effect on cell depends on toxin and on cell
• Normal body substances (wear & Tear)
• Abnormal products (errors of metabolism) – phenylketonuria
• Substances from outside Fe & Copper deposition
• Lead – CNS toxin – interferes with neurotransmitters causing
hyperactivity. Lead paints cause anemia & toxicity
• CO – binds irreversibly to Hb & deprives body of O2
• Ethanol – CNS toxic – liver toxin- interrupts protein transport –
can cause fetal alcohol syndrome
• Mercury – neurotoxin can cause bone deformities
• Social or street addictive drugs (Marijuana, heroin, hashish,
Tramal).

17. 17
Trauma: Unintentional and Intentional
Injuries
• Blunt force injuries
– Application of mechanical energy to the body
resulting in the tearing, shearing, or crushing of
tissues
– Contusion vs. hematoma – bleeding in skin &
underlying layers
– Abrasion – removal of superficial skin layers
– Laceration or puncture of skin & other layers
– Fractures – broken bones

18. 18
Contusions and Hematomas

19. 19
Unintentional & Intentional Injuries
• Unintentional injuries are harmful acts that occurred without
any intention of causing damage to oneself or others. It occur
in or around the home and many of these injuries occur as a
result of falls, streets, highways, and recreational areas.
• intentional injuries, which are injuries resulting from
purposeful harmful actions upon oneself or others.
• Gunshot wounds
– Entrance wounds (small)
• Close-Contact range entrance wound
• Intermediate range entrance wound (tattooing and
stippling)
– Exit wounds (Large) - Shored exit wound

20. 20
Gunshot Wounds

21. 21
Intentional and Unintentional Injuries

22. 22
Infectious Injury
• Pathogenicity of a microorganism – gram (-) or (+) will
determine which antibiotics to use or anti viral agents
for viral infections
• Virulence: some strains are more dangerous than
others.
• Can affect entire body (fever, pain, increased heart
rate)
• Disease-producing potential
– Invasion and destruction
– Toxin production
– Production of hypersensitivity reactions

23. 23
Immunologic and Inflammatory Injury
• Phagocytic cells – immune cells that engulf and
destroy invading microbes and toxins
• Immune and inflammatory substances
– Histamine (released by injured or infected cells that
cause local vasodilation), antibodies (endogenous
proteins that combat and identify invading cells and
toxins), lymphokines (chemical produced by imune
cells), complement, and enzymes
• Membrane alterations – leakage of cell contents
due to the presence of antibodies and
histamines

24. 24
Injurious Genetic Factors
• Nuclear alterations: mutations & damage to
DNA
• Alterations in the plasma membrane structure,
shape, receptors, or transport mechanisms
• Examples of genetic diseases
– Down syndrome
– Sickle cell anemia
– muscular dystrophy

25. 25
Injurious Nutritional Imbalances
• Essential nutrients are required for cells to
function normally inadequate proteins,
carbohydrates, fats, vitamins, minerals
• Deficient intake – starvation and improper
diets – protein deficiency “kwashiokor” most
common, Vitamin B 12 deficiency leads to
pernicious anemia, Vit C DEF. --- SCURVY.
• Excessive intake - obesity

26. 26
Temperature Extremes: Cell Injury
• Hypothermic injury
– Slows cellular metabolic processes
– Ice crystal formation and frostbite
• Hyperthermic injury
– Heat cramps
– Heat exhaustion
– Heatstroke
– Protein denaturation

27. 27
Atmospheric Pressure Changes
• Sudden increases or decreases in
atmospheric pressure
–Blast injury
–Nitrogen Narcosis or rapture of the deep
Nitrogen gas has a narcotic effect (laughing
gas)
–Decompression sickness (caisson disease)
• “The bends”

28. 28
Ionizing Radiation
• Any form of radiation capable of removing
orbital electrons from atoms
–X-rays, gamma rays, alpha and beta particles
–Amount of exposure measured in RADS.
People working with X-rays must wear badge
that measures doses of exposure over time
• Mechanism of damage – ionization of
chemicals and breakage of chemical
bonds

29. 29
Effects of ionizing radiation

30. 30
Light & sound cell injury
• Illumination injury
– Eyestrain, obscured vision, and cataract formation
– Caused by light modulation
• Mechanical stresses
– Physical impact or irritation
• Noise – sound can cause tisse and organ
trauma
– Acoustic trauma and noise-induced hearing loss –
tinnitus very common among performing rock band
members

31. Apoptosis
• Cells “fallen apart”
• Regulated cell death during development
• Worn out cells
• Diseased cells (tumor suppressor p53
gene, natural killer or Tc cells)
Cell aging
• Programmed cell change theories
• Developmental Error theories
• Telomerase errors

32. 32
Aging
• Cellular aging: all cells can replicate 40 –
60 times max and may be why clones do
not live as long as parents.
• Tissue and systemic aging: immune
function goes down with age and free
radicals damage cells speeding aging
–Frailty – wasting syndrome of aging due to
decreased protein synthesis and reduced
muscle mass and lowered bone density

33. Summary of cell injury
• Any stimuli and stresses can result in cell
injuries.
• The injurious consequences depend on not only
the type of injury, its duration, its severity, and
also the type, status, adaptability and genetic
makeup of the injured cell.
• Cell injury can be divided into reversible and
irreversible.
• The loss of cell function is far before the cell
death, but the morphological visible changes
appear far behind the cell death.

34. • End of Part 2

35. Cellular adaptation to injury
Adaptation: When cells encounter physiologic
stresses or pathologic stimuli from outside and
inside of body, they can alter themselves to
achieve a new steady state and preserve
viability.
• All kinds of adaptation may be considered as
disorders of growth and/or differentiation
• Cellular adaptation can be considered as a
state between the normal, unstressed cell and
injured, overstressed cell.

36. 36
Cellular Adaptation
Physiologic vs. pathogenic
Atrophy
Hypertrophy
Hyperplasia
Metaplasia
Dysplasia

37. Cells Adaptive responses to injuries & Inflammation
• Atrophy, Aplasia, Agenesis
– a = without
– nourishment, form, begining
• Hypertrophy
– hyper = above, more
– trophe = nourishment, food
• Hyperplasia
– plastein = (v.) to form, to shape;
(n.) growth, development
• Hypoplasia
– hypo = below, less
• Metaplasia
– meta = change or beyond
• Dysplasia
– dys = bad or disordered
• Factors behind these
changes
• Altered demand (muscle
activity)
• Altered stimulation
(growth factors,
hormones)
• Altered nutrition &
Substances use
(including gas exchange)

38. Atrophy
• Definition: (briefly, decrease in cell size)
Shrinkage in the size of the parenchymal cells by
loss of cell substances in a well developed organ or
tissue is known as atrophy. Or acquired shrinkage of
cells, tissues or organs.
• Simple atrophy (loss of cell size only)
• Numerous atrophy (loss of cell size and number
through apoptosis)
• Differentiation: aplasia, hypoplasia

39. Testis:
Right: Atrophied Left: Normal

40. kidneys & ureters of a one-year-old boy. The Rt Kidney is
hypoplastic and the LT one with a three-ureters abnormality.

41. The reasons of atrophy
 Decreased workload ------disuse atrophy
 Loss of innervation ------neuropathic atrophy
 Diminished blood supply --ischemic atrophy
 Absence of nutrition -----undernourished atrophy
 Loss of hormone stimuli -- endocrine atrophy
 Aging process --- senile atrophy

42. Brain atrophy in an old patient with arteriosclerosis. Note the
widened sulci and narrow convolutions.

43. Brain atrophy in a patient with Alzheimer’s disease. The gyri
are narrowed and the sulci widened toward to frontal pole.

44. some skeletal muscle fibers. The number of cells is the same as
before atrophy occurred, but the size of some fibers is reduced.
In this case, innervation of the small fibers in the center was lost.
This is a trichrome stain.
Muscle Atrophy

45. Atrophy
• The atrophied cells, tissue and organ have
the following caracteristics:
– Reduction of physiologic functions
– Decreased synthesis
– Increased catabolism—increased protein
degradation through
Lysosomes digest the senescent organelles
(autolysis)
– If the number of cells decrease, there is
apoptosis (cell suicide), or programmed cell
death

46. Hypertrophy
• Definition: (briefly: increase in cell size)
• an increase in the size of parenchymal cells
and consequently an increase in the size of
the organ.
No increase of cell
number in a purified
hypertrophy!

47. Hypertrophy
• Compensatory hypertrophy
– Mechanical stimuli---skeletal
muscle of a sportsman
– Increased workload---left
ventricle hypertrophy of
systemic hypertension
– Decompensation---heart failure
• Endocrine hypertrophy
– Hormonal stimuli---pregnant
uterus
--Cushing’s syndrome

48. Physiologic hypertrophy of the uterus during pregnancy.
Left: gross appearance of a normal uterus and a gravid uterus.
Middle: small spindle-shaped uterine smooth muscle cells from
A normal uterus.
Right: large, plump hypertrophied smooth muscle cells from
a gravid uterus.

49. Cushing’s syndrome resulted from adenoma of adrenal cortex

50. Hypertrophy of left ventricle (centripetal hypertrophy) in
a patient with essential hypertension. Note the marked
thickened wall of ventricle.

51. a. Hypertrophy of the left ventricle
b. Normal myocardial fibers
c. Hypertrophic myocardial fibers

52. Hypertrophy
Hypertrophic cells & organ are characterized with:
• Increased function
• Increased synthesis of structural protein
• Induced by two types of signals
– Mechanical triggers:-stretch
– Trophic triggers:-activation of alpha-adrenergic
receptors
Different from hyperplasia & pseudohypertrophy (a
pathologic situation . Ex.in myasthenia gravis, a type
of myopathy caused by hyperplastic thymus or
thymoma. In this condition the muscles in lower limbs
are atrophied and replaced by fat, so the legs of
patient look enlarged. It is actually real atrophy.

53. Hyperplasia
• Definition: (briefly, increase in cell number)
• An increase in the number of parenchymal
cells in an organ or tissue.
• Hyperplasia can occur with hypertrophy in
various tissue except muscles.
• Hyperplasia can be divided into
– Physiologic hyperplasia
• Hormonal: breast glandular epithelium at
pregnancy
– Pathologic hyperplasia
• Compensatory: liver after partial resection

54. Hyperplasia of endometrium in an adult woman with menorrhagia
(too much bleeding of menses in an adult woman )

55. Examples of hyperplasia: Red bone marrow
of blood donor

56. Examples of hyperplasia: Hyperadrenalism

57. Examples of hyperplasia: Goiter (absence of iodine)

58. Hyperplasia of
prostatic gland - The
reason of hyperplasia is
exceeding androgen
secretion which leads
hyperplasia of prostatic
gland and stroma cells
Note the prostate is
nodular enlarged

59. Hyperplasia
• Hyperplasia is induced by
stimulation of hormonal or growth
factors, cytokines and chemokines
through the signal transduction
pathway.
• Hyperplasia can turn off when the
organ restores or the stimulus
stops
• Continuous pathologic hyperplasia
constitutes a fertile soil for
cancerous proliferation

60. Metaplasia
• Definition: (briefly: change in cell type)
• A reversible change in which one adult cell type
is replaced by another adult cell type.
• This replacement is through hyperplasia of
“stem cell” or “undifferentiated cell”, so
metaplasia is actually an abnormal hyperplasia.
• The significances of metaplasia are
– To be able to withstand the stress better
– To be able to transform into a cancerous
proliferation

62. Squamous metaplasia in bronchus in a heavy smoker

63. Squamous metaplasia of laryngeal respiratory epithelium in a
heavy smoker

64. Columnar to squamous metaplasia: Barrett metaplasia in
lower part of esophagus

65. Intestinal metaplasia
in a patient with
chronic atrophic
Gastritis
(Note the goblet Cells)

66. Dysplasia
• Dysplasia is considered as an abnormal
epithelial hyperplasia with the loss of the normal
cell architectural orientation and uniformity of
the individual cells.
• change in cell resulting in abnormal cell size,
shape or organization (Seen In mature cells only,
in respiratory tract, cervix w/ pathology)
– Immature cells are normally expected to
change in size, shape as they grow and
mature
• Considered a reversible change

67. Skin dysplasia—actinic keratosis

68. Neoplasia
• Neoplasia (from Ancient Greek neo- "new" and plasma
"formation creation"), is an abnormal growth of tissue,
and when also forming a mass called tumor or tumour,
• The World Health Organization (WHO) classifies
neoplasms into four main groups: benign neoplasms, in
situ neoplasms, malignant neoplasms, and neoplasms of
uncertain or unknown behavior. Malignant neoplasms are
also simply known as cancers.
• Prior to the abnormal growth of tissue, as neoplasia, cells
often undergo an abnormal pattern of growth, such as
metaplasia or dysplasia. However, metaplasia or
dysplasia do not always progress to neoplasia.

70. Summary of adaptation
• Shrinkage of an organ can result from
– Atrophy
– Aplasia and hypoplasia
• Hyperplasia persists only for so long as the
stimulus is applied. When it is removed, the
hyperplastic tissue tends to revert to its normal
size.
• Hyperplasia must be distinguished from
dysplasia and neoplastic proliferation.

71. Summary of adaptation
• Metaplasia is an abnormal hyperplasia.
• It can become a malignant neoplasm.
• All kind of adaptation can be considered as
abnormal growth and/or differentiation
• Adaptation is the result of long time persisted,
but mild stimuli
• Most adaptations are reversible when the
stimulus is removed

72. • End of Part 3

73. Thank you for your attention!