Cellular adaptation and intercellular

1. Dr.S.Kavitha MBBS,MD,
Associate Professor,
Department of pathology
CELL INJURY AND
MECHANISM OF
CELL INJURY

2.  Causes of cell injury
 General mechanisms of cell injury
 Pathogenesis of cell injury
 Free radical induced cell injury
 Examples of reversible cell injury
Learning objectives

3. COMPETENCY PA 2.1,2.2 -Describe the causes,mechanisms,types, effects of cell injur
& their clinical significance
OBJECTIVES:
At the end of the lecture the student should be
able to
 Define cell injury
 Enumerate the Causes /etiology of cell injury
 Describe the salient mechanisms
/pathogenesis of cell injury
 Classify the cellular responses to cell injury &
their clinical significance

4.  Pathology is the study of the structural,
biochemical, and functional changes in cells,
tissues, and organs that underlie disease.
 The four aspects of a disease process that form
the core of pathology are its cause (etiology),
 The biochemical and molecular mechanisms of its
development (pathogenesis),
 The structural alterations induced in the cells and
organs of the body (morphologic
changes), and
 The functional consequences of these changes
(clinical manifestations).

5.  Normal cells have a fairly narrow range of
function or steady state. HOMEOSTASIS.
 Excess physiologic or pathologic stress may
force the cell to a new steady state.
ADAPTATION.
 Too much stress exceeds the cells adaptive
capacity. INJURY.
 Cell injury can be reversible or irreversible.
 Reversiblity depends on the type, severity and
duration of injury.
 Cell death is the result of irreversible injury.
Key concepts

6. STATUS, ADAPTABILITY OF TARGET CELL:
Skeletal muscle can withstand hypoxic injury
for long-time,
Cardiac muscle suffers Irreversible cell injury

8. Adaptation
Reversible Injury
Irreversible injury
Cell Death
Normal cell

9. Hypoxia
 Reduced blood flow(ischemia)
 Inadequate oxygenation of the blood due to
cardiorespiratory failure.
 Decreased oxygen carrying capacity of the
blood as in anaemia and CO poisoning.
 Severe blood loss.
Causes of Cell Injury:

10.  Physical—agents: Mechanical trauma,
radiation, extremes of temperature.
 Chemical—agents: Cyanide, arsenic,
mercury.
 Infectious—agents: Bacteria, fungi,
parasites.
 Immunological—reactions:Auto-immune ds.
 Genetic-Rearrangements: Chromosomal
anomalies, inborn errors of metabolism.
 Nutritional—imbalance: PEM, Vit. Def.
Causes of Cell Injury:

11.  Cell membrane integrity Injury at 1
 Aerobic respiration locus leads to wide
 Protein synthesis ranging
secondary
 Genetic apparatus effects
Depending on : Type
Duration of Injury
Severity
Sites of Damage

12. 5 Mechanisms
 ATP depletion
 Mitochondrial Damage
 Loss of calcium homeostasis
 Defects in membrane
permeability
 Free radical injury
Mechanisms of cell injury

13. ATP Depletion

14.  Reduced oxidative phosphorylation & ATP
depletion,
 Cellular swelling & blebbing of plasma
membrane: due to changes in ion concentrations
and water influx,
 Swelling of ER & Mitochondria,
 Clumping of chromatin.
Reversible Cell Injury:

15. Mitochondrial Damage

16. Mitochondrial Damage
Formation of a high conductance channel
in the mitochondrial membrane, called the
membrane permeability transition pore
Loss of mitochondrial membrane
Failure of normal oxidative phosphorylation
Depletion of ATP

17. Mitochondrial Damage
Abnormal oxidative phosphorylation
Formation of reactive oxygen species(ROS)
Deleterious effects

18. The mitochondria sequester Cytochrome c bet
their outer and inner membranes
Mitochondrial Damage
Increased permeability of the outer
mitochondrial membrane
Leakage of cytochrome C into the cytosol
APOPTOSIS

19.  Intracellular free calcium is very low compared
with extracellular levels.
 Most intracellular calcium is sequestered in
mitochondria and ER.
 Injury cause an increase in cytosolic calcium
due to
1.Increased influx across the plasma membrane.
2.Release of calcium from intracellular stores
(mitochondria and ER)
Calcium Homeostasis

20.  Increased cytosolic calcium activates number
of enzymes
1.Phospholipases(Membrane Damage)
2.Proteases(breakdown both membrane and
cytoskeletal proteins)
3.Endonucleases(DNA fragmentation)
4. ATPases(hastening ATP depletion)

22.  Consequences of membrane damage
 1.Mitochondrial membrane damage.
 2.Plasma membrane
 3.Lysosomal membrane damage
Defects in membrane
permeability

23.  Opening of the mitochondrial permeability
transition pore
 1.Failure of ATP generation
 2.Formation of ROS
 3.Release of cytochrome C -APOPTOSIS
Mitochondrial injury

24. Loss of osmotic balance
Efflux of fluids and ions
Loss of cellular contents
Leak metabolites that are vital for the
reconsititution of ATP
Plasma membrane damage

25.  Lysosomes contain RNases, DNases, proteases,
phosphatases,glucosidases and cathepsins
Lysosomal membrane damage
Leakage of their enzymes into the cytoplasm
Enzymatic digestion of proteins,RNA,DNA,and
glycogen
Necrosis
Lysosomal membrane Damage

28.  Free radicals have single unpaired electron in
its outer orbit.
 Unpaired electrons are highly reactive and
attack and modify -proteins, lipids,
carbohydrates, nucleic acids.
 Generated within mitochondrial inner
membrane.
Free radicals Generation

29. ◦ Partially reduced, unavoidable byproducts of
mitochondrial respiration.
◦ E.g., OH-, O2-,H2O2,
 Have single unpaired electron in outer orbit;
highly unstable configuration.
 Capable of damaging lipids, proteins & nucleic
acids.
Oxygen Free Radicals:

30.  Imbalance between free O2 radical generating
system & radical scavenging system results in
OXIDATIVE STRESS.
 During initiate autocatalytic reactions:
molecules with which they react are themselves
convert into free radicals propagating the chain
of reaction.
Oxygen Free Radicals:

31.  Absorption of radiant energy: ionizing radiation,
UV rays, X-rays.
 Enzymatic metabolism of exogenous chemicals
or drugs
 The reduction-oxidation Rn that occur during
normal metabolic process.
Production of free radicals:

32.  Transition metals :Copper & Iron ; donate or
accept free electrons and catalyze free radical
formation: Fenton Reaction.
 Nitric oxide: an imp. Chemical mediator, that
can act as free radical.
 Free radicals include
 Superoxide anion
 Hydrogen peroxide
 Hydroxyl radicals
 The most reactive free radical is hydroxyl free
radical.
Production of free radicals:

35.  Lipid peroxidation of membranes
 Oxidative modification of proteins
 Single stranded breaks in DNA
Effects of Free Radicals:

36.  Membrane lipids are attacked(plasma and
organelle membrane)
 Free radicals and lipids combination releases
formation of unstable peroxides
 In turn activates autocatalytic reaction
 Leads to extensive tissue damage.
Lipid peroxidation

37.  Most of the enzymes are made up of
aminoacids and proteins.
 Free radicals cause oxidation of these
aminoacids.
 Results in damage to active site of enzymes.
 Structural proteins are damaged.
 Extensive destruction of protein machinery
 DNA DAMAGE
 Free radicals breaks the DNA and results in
cross linking.
Protein oxidation

38.  Enzymatic:: Super oxide Dismutase
Glutathione peroxidase
Catalase
 Non Enzymatic:: Vit-E, Vit- A, Vit-C,
Ferritin,
Ceruloplasmin.
Anti-Oxidants

39. Progression of
Cell Injury and
Death
Minutes to hours:
•Molecular and
Biochemical changes
•Detection:
Ultrastructural or
histochemical
methods
Hours to days
•Detection: Light
microscopy or naked
eye

40. Reversible Cell Injury:
 Reduced oxidative phosphorylation & ATP
depletion,
 Cellular swelling & blebbing of plasma
membrane: due to changes in ion concentrations
and water influx,
 Swelling of ER & Mitochondria,
 Clumping of chromatin.

41. Reversible Cell
Injury
Functional and
Structural alterations
Early stages (Mild)
Correctable
2 features:
1. Cell Swelling –
ATP dependent
Na-K pump
failure
2. Fatty Change –
disruption of
metabolic
pathways

42. Reversible Injury (Ultra structurally)
• Blebbing , blunting,
loss of microvilli
• Mitochondrial
swelling and
amorphous
densities
• Myelin figures
• ER dilatation
• Nucleus:
Disaggregation of
granular and
fibrillar elements

43. Irreversible Cell Injury:
 Point of No return: Lethal Hit– structural
changes like amorphous densities in mitochondria,
loss of membrane permeability.
 Swelling of mitochondria, lysosome
rupture,nuclear condensation, Myelin figure
formation.
 Final result- cell adaptation /death
 Cell death : 2 types
1. Necrosis
2. Apoptosis

44. Normal cell and the
Changes in Reversible
And Irreversible
Cell injury

45.  Most common type of cell injury
 Diminished blood flow to the tissue
 Aerobic glycolysis Anaerobic glycolysis
Cessation of glycolysis.
 1st
 Reduced oxidative phosphorylation in
Mitochondria
 2nd
 Depletion of ATP
 3rd
 Reduced activity of Na pump
ISCHEMIC & HYPOXIC INJURY

46.  4th
 Increased glycolysis—decreased Ph
 5th
 Detachment of ribosomes, reduced
protein synthesis, lipid deposition
 6th
 Cellular swelling, Increased K efflux
ISCHEMIC & HYPOXIC INJURY

48.  Reversible injury– flow restored– may recover
 Golden Period of ischemia
 Can save many lives
 Concept of emergency angiography in cath lab
 Rarely the restoration may adversely damage
the tissue This is Reperfusion Injury
ISCHEMIA & REPURFUSION
INJURY

49.  Restored blood brings in high concentration of
calcium,calcium overload drives mitochondrial
permeability transition pore opening and
subsequent ATP depletion.
 Ischemic injury recruits circulating inflammatory
cells,causes additional tissue injury.
 By restoring blood flow, reperfusion may actually
increase local inflammatory cell infiltration.
 Damaged mitochondria Increased ROS
ISCHEMIA & REPURFUSION
INJURY

50. INJURIOUS STIMULUS
Decreased
ATP
LOSS OF
ENERGY
DEPENDENT
CELULAR
FUNCTIONS
MEMBRANE DAMAGE
MITOCHONDRIA
DAMAGE
LYSOSOME
RUPTURE
PLASMA
MEMBRANE
RUPTURE
INCREASED
intracellular Ca++
REACTIVE
OXYGEN
SPECIES
PROTEIN
BREAK
DOWN
DNA
DAMAGE
ENZYMATIC DIGESTION OF
CELL COMPONENTS
LOSS OF
CELL
CONTENTS
CELL
DEATH