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
 Intermediate
Actin filaments Microtubules 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 Hypoxia
Reperfusion
Radiation

Ischemia
Aging
Chemical
 Ischemic/hypoxic injury

Oxygen 

Oxydative phosphorilation 

ATP production 

Sodium pump  Ribosome detachment

Glycogenolysis
 Ischemic/hypoxic injury

Oxygen 

Oxydative phosphorilation 

ATP production 

Sodium pump  Ribosome detachment

Glycogenolysis
 Sodium pump 

Influx Ca ++ Na+ Retension Efflux K+

• Cell swollen
• Microvilli disappear
• Bleb formation
• ER swollen
• Myelin bodies
 Ischemic/hypoxic injury

Oxygen 

Oxydative phosphorilation 

ATP production 

Sodium pump  Ribosome detachment

Glycogenolysis
 Glycogenolysis 

Lactic acid and inorganic

phosphate

pH 

Chromatin clumps
 Ischemic/hypoxic injury

Oxygen 

Oxydative phosphorilation 

ATP production 

Sodium pump  Ribosome detachment

Glycogenolysis
 Detachment of 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 Ribosomes
clumps detachment

Mitochondrial
Autophagy swelling

Small
densities
 C
A
Irreversible
Normal

B
Reversible
 Mechanisms membrane damage
(made simple)
ATP  Ca++ 

Phospolipase Protease
activation activation

Phospholipid synthesis  Phospholipid Cytoskeletal

degradation damage

Membrane damage
 Rupture of Membrane
lysosomes
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 lysosomal enzymes: autolysis, due to
enzymes of immigrant cells: heterolysis.
– Autolysis  coagulative necrosis; heterolysis 
liquefactive necrosis
– Morphological changes occur 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
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.
 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. Downloaded from: StudentConsult (on 19 February 2012 10:23 PM)
Fatty change of the liver. In most cells the well-preserved nucleus is
squeezed into the displaced rim of cytoplasm about the fat vacuole.
Downloaded from: StudentConsult (on 19 February 2012 10:23 PM)
© 2005 Elsevier
Cholesterolosis. Cholesterol-laden macrophages (foam cells,
arrow) in a focus of gallbladder cholesterolosis.
Downloaded from: StudentConsult (on 19 February 2012 10:23 PM)
© 2005 Elsevier
Protein reabsorption droplets in the renal tubular epithelium.
Downloaded from: StudentConsult (on 19 February 2012 10:23 PM)
© 2005 Elsevier
Lipofuscin granules in a cardiac myocyte shown by light
microscopy Downloaded from: StudentConsult (on 19 February 2012 10:23 PM)
© 2005 Elsevier
Lipofuscin granules in a cardiac myocyte shown by electron
microscopy (note the perinuclear, intralysosomal location).
Downloaded from: StudentConsult (on 19 February 2012 10:23 PM)
© 2005 Elsevier
 Hemosiderin granules in liver cells. H+E stain
showing golden-brown, finely granular pigment.
Downloaded from: StudentConsult (on 19 February 2012 10:23 PM)
© 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
– Exam Questions on cell injury
– http://peir2.path.uab.edu/bmp/article_6.shtml
Mahmud Ghaznawie