Cell Adaptation, cell Injury and

Cell Death

Mahmud Ghaznawie

Dept Pathology
Medical Faculty
Hasanuddin University

Learning Objectives
Cellular adaptation to stress

Hypertrophy
Hyperplasia
Atrophy
Metaplasia

Cell Injury and cell death

Causes of cell injury
Morphology of cell and tissue injury &
death
Mechanisms of cell injury and death

Necrosis and Apoptosis

Intracellular accumulation

Plasma Membrane

Nucleus

Golgi Apparatus

Mitochondria

Lisosome & peroxisome

The rough endoplasmic reticulum

The smooth endoplasmic reticulum

Cytoskeleton

Actin filaments

Microtubules

Intermediate
filaments

Cellular adaptation to stress

Cellular Adaptations of Growth

and Differentiation

Hyperplasia
Hypertrophy
Atrophy
Metaplasia

Hyperplasia
An increase in the number of cells in an
organ or tissue
Physiologic:
Compensatory
Hormonal

Pathologic
Pathologic hyperplasia constitutes a fertile soil in
which cancerous proliferation may eventually arise.

Hypertrophy
an increase in the size of cells, resulting in an
increase in the size of the organ.

Atrophy
a decrease in the size of an organ that
has reached its normal size
Decreased workload (disuse atrophy)
Loss of innervation (denervation atrophy)
Diminished blood supply
Inadequate nutrition
Loss hormonal stimulation
Senile atrophy
Pressure atrophy

Metaplasia
a reversible change in which one adult cell type
(epithelial or mesenchymal) is replaced by
another adult cell type

Cell injury and cell death

Causes of cell injury

Hypoxia
Free radicals
Physical injury
Chemical injury
Infection
Immune reaction

Inflammation
Reperfusion

Hypoxia
Radiation

Ischemia
Aging
Chemical

Ischemic/hypoxic injury
Oxygen
Oxygen
Oxydative phosphorilation
ATP production

Sodium pump

Ribosome detachment
Glycogenolysis

Ischemic/hypoxic injury
Oxygen
Oxygen
Oxydative phosphorilation
ATP production

Sodium pump

Ribosome detachment
Glycogenolysis

Sodium pump

++
Influx Ca ++

Na++ Retension

Cell swollen
Microvilli disappear
Bleb formation
ER swollen
Myelin bodies

Efflux K++

Ischemic/hypoxic injury
Oxygen
Oxygen
Oxydative phosphorilation
ATP production

Sodium pump

Ribosome detachment
Glycogenolysis

Glycogenolysis

Lactic
Lactic acid
acid and
and inorganic
inorganic
phosphate
phosphate

pH

Chromatin
Chromatin clumps
clumps

Ischemic/hypoxic injury
Oxygen
Oxygen
Oxydative phosphorilation
ATP production

Sodium pump

Ribosome detachment
Glycogenolysis

Detachment
Detachment of
of ribosomes
ribosomes

Protein production

Intracellular osmotic pressure

Cell edema

Inflammation

Hypoxia

Reperfusion
Radiation

Iskemia
Aging

Chemical

Injury due to Free Radicals

Free Radicals: atoms or molecules possesing
unpaired electron in an outer orbit
Characteristics of free radicals:
react with any organic / inorganic substance
the results will form a new free radicals new
reaction chain
the reaction will cease by itself or by enzymatic
reaction

 Three important free radicals:

Superoxide anion radical (O2)
Hydrogen peroxide (H2O2)
Hydroxyl ions(OH)

Effects of free radicals on cell membrane:

Membrane lipid peroxidation (especially by OH)
Protein damage: cross-linking of amino acids,
increase protease activation
DNA damage: single helix formation followed by cell
death of even malignant transformation (cancer)

De-activation of free radicals

Spontaneous, because of its instability
Endogenous/exogenous antioxidant
Vitamine E, C and A
Binding to storage & transport proteins (lactoferrin,
ceruloplasmine, dan trasferrin)

Enzymatic
Superoxide dismutase (SOD)
Catalase
Glutathione peroxidase

S.O.D,
Catalase,
and Gluthation peroxidase
are free radical-scavenging
enzymes

Chemical injury
Water soluble
Act directly (by combining with some critical molecular
component or cellular organelle)
E.g: HgCl, cyanide, antibiotics, and chemotherapy
Mercury binds to the sulfhydryl groups of the cell
membrane increased membrane permeability and
inhibit ATPase-dependent transport
Cyanide poisons mitochondrial cytochrome oxidase and
block oxidative phosphorylation

Chemical injury (cont)

Lipid soluble
Indirect effects (converted to reactive toxic
metabolites, which then act on target cells)
E.g: CCl4

Blebs

Myelin figures

Cell swelling
ER swelling
Chromatin
clumps

Autophagy

Ribosomes
detachment

Mitochondrial
swelling

Small
densities

Irreversible

Normal

B
Reversible

Mechanisms membrane damage

(made
(made simple)
simple)
++
Ca++

ATP

Phospolipase
activation
Phospholipid synthesis

Phospholipid
degradation

Membrane damage

Protease
activation
Cytoskeletal
damage

Rupture of
lysosomes

Membrane
defects
Myelin figures

Nucleus
pyknosis
Lysis of ER

Mitochondrial
swelling
Large densities

Cell Death
Could be necrosis or apoptosis
Necrosis
Cell death in association to a living tissue
When due to lisosomal enzymes: autolysis, due to
enzymes of immigrant cells: heterolysis.
Autolysis coagulative necrosis; heterolysis
liquefactive necrosis
Morphological changes occure within hours

The morphology of necrotic cells

Cytoplasm:
Eosinophillic (reaction to denatured proteins)
Glassy appearance (due to loss of glykogen particles)
Vacuolated (due to digestion of organelles)
Calcification

Nucleus: (3 possibilities)
Pyknosis (due to nuclear shrinkage)
Karyorhexis (fragmentation of the pyknotic nucleus)
Karyolisis (basophilia of the chromatine fades)

Normal

Necrosis
The cytoplasm
is more eosinophillic
Nuclei partially lysis

H & E staining
to show edema of the
myocardial fibres

LDH enzyme staining

to area unstained areas

Morphology of necrosis
Coagulative necrosis:
The cell outlines are maintained
Characteristic to hypoxic necrosis exept
on the brain.

Occur because the

lysosomal enzymes we
also damaged

Liquefactive necrosis:
Due to autolysis or heterolysis
Characteristic to bacterial
infection (pus) and hypoxic
necrosis to the brain

Gangrenous necrosis:
infected coagulative necrosis
(may then turns to liquefactive
necrosis)

Caseous necrosis
Special form of coagulative necrosis,
spesific to tbc
Macroscopically looks like cheese
Microscopic:
amorphous mass,
granular, surrounded by
inflammatory cells

Enzymic fat
necrosis

Destruction of fat due to pancreatic lipase

Fatty acid formed will bind to calcium
Microscopic: necrotic area, calcium
deposition (blue), and inflammation of the
surrounding tissue

Fibrinoid necrosis

Apoptosis
Could be physiological or pathological
Programmed cell death in embryogenesis, involusion of
hormon dependent organs, cell death in cancer, etc)

Morphology:
Shrinkage
Chromatin condensation
Formation of blebs and apoptotic bodies
Phagocytosis of apoptotic bodies

APOPTOSIS

NECROSIS

Mechanisms of apoptosis. The two pathways of apoptosis differ in their induction and regulation, and both
culminate in the activation of "executioner" caspases. The induction of apoptosis by the mitochondrial
pathway involves the action of sensors and effectors of the Bcl-2 family, which induce leakage of
mitochondrial proteins. Also shown are some of the anti-apoptotic proteins ("regulators") that inhibit
mitochondrial leakiness and cytochrome c-dependent caspase activation in the mitochondrial pathway. In
the death receptor pathway engagement of death receptors leads directly to caspase activation. The
regulators of death receptor-mediated caspase activation are not shown.

The intrinsic (mitochondrial) pathway of apoptosis. A, Cell viability is maintained by the induction
of anti-apoptotic proteins such as Bcl-2 by survival signals. These proteins maintain the integrity
of mitochondrial membranes and prevent leakage of mitochondrial proteins. B, Loss of survival
signals, DNA damage, and other insults activate sensors that antagonize the anti-apoptotic
proteins and activate the pro-apoptotic proteins Bax and Bak, which form channels in the
mitochondrial membrane. The subsequent leakage of cytochrome c (and other proteins) leads to
caspase activation and apoptosis.

Apoptotic bodies

Mechanisms of protein folding and the unfolded protein response. A, Chaperones, such
as heat shock proteins (Hsp), protect unfolded or partially folded proteins from
degradation and guide proteins into organelles. B, Misfolded proteins trigger a protective
unfolded protein response (UPR). If this response is inadequate to cope with the level of
misfolded proteins, it induces apoptosis.

Subcellular changes
Lisosome
Autophagy dan
heterophagy

Autophagy

Smooth endoplasmic reticulum

Massively enlarged

Mitochondria
Enlarged

Intracellular accumulation

Fatty liver. A, Schematic diagram of the possible mechanisms leading

to accumulation of triglycerides in fatty liver. Defects in any of the
steps of uptake, catabolism, or secretion can result in lipid
accumulation.

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Fatty change of the liver. In most cells the well-preserved nucleus is

squeezed into the displaced rim of cytoplasm about the fat vacuole.
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2005 Elsevier

Cholesterolosis. Cholesterol-laden macrophages (foam cells,

arrow) in a focus of gallbladder cholesterolosis.
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2005 Elsevier

Protein reabsorption droplets in the renal tubular epithelium.

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2005 Elsevier

Lipofuscin granules in a cardiac myocyte shown by light

microscopy

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2005 Elsevier

Lipofuscin granules in a cardiac myocyte shown by electron

microscopy (note the perinuclear, intralysosomal location).
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2005 Elsevier

Hemosiderin granules in liver cells. H+E stain

showing golden-brown, finely granular pigment.

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2005 Elsevier

Hemosiderin granules in liver cells. Prussian blue stain, specific for iron (seen
as blue granules). Downloaded from: StudentConsult (on 19 February 2012 10:23 PM)
2005 Elsevier

Dystrophic calcification of the aortic valve. View looking down onto the
unopened aortic valve in a heart with calcific aortic stenosis. It is markedly
narrowed (stenosis). The semilunar cusps are thickened and fibrotic, and
behind each cusp are irregular masses of piled-up dystrophic calcification.
2005 Elsevier

Conclusion
Cell injury in the basis of any
pathologic processes
It could be reversible or irreversible
(ended with cell death)
The morphological changes are so
characteristic
The mechanism of cell injury should
be beared in mind in your further
study of BMD and medicine

LEARN THIS

Exam Questions on cell injury

http://peir2.path.uab.edu/bmp/article_6.shtml

Thank you

Mahmud Ghaznawie