source-robbins

1. CELLULAR ADAPTATION
AND
RESPONSE TO INJURY
Speaker: Surg Lt Cdr Sangeeta Prasad
Moderator: Surg Cdr Ritu Mehta

2. SCOPE
 Homeostasis
 Adaptation
 Cell injury and cell death
 Apoptosis
 Necroptosis

3. HOMEOSTASIS
Normal cells is confined to a fairly narrow range
of function and structure due to its:
Differentiation and specialization
State of metabolism
constraints of neighboring cells
Availability of Metabolic substrate

4. What happens when a cell in homeostasis is
subjected to stress or injury

5. ADAPTATION
Reversible functional and structural response
to changes in physiological states and some
pathological stimuli, during which new but
altered steady states are achieved
• Physiologic: in response to normal
stimulation by hormones or endogenous
chemical mediators, need for compensatory
increase after damage or resection.
• Pathologic: in response to stress that
allow cells to modulate their structure and
function and thus escape injury.

7. HYPERTROPHY
Increase in size of the cell.
Increased size is due to synthesis and
assembly of additional intracellular structural
components.
Occurs when cells are incapable of dividing

8. TYPES OF HYPERTROPHY
 Physiologic: ↑ functional demand,
↑hormones, ↑growth factors
Eg: muscles in body builders, uterus in
pregnancy
 Pathologic: cardiac hypertrophy

10. HYPERPLASIA
Increase in number of cells.
Takes place in cells capable of dividing.
It’s the result of growth factor driven
proliferation of mature cells and in some
cases, by increased output of new cells from
tissue stem cells

11. TYPES OF HYPERPLASIA
1. Physiologic:
Breast during menstruation/pregnancy
Liver after resection
Bone marrow when there is deficiency of
terminally differentiated blood cells
2. Pathologic:
Endometrial hyperplasia
Benign prostratic hyperplasia
Papilloma virus-skin warts

12. ATROPHY
Drecrease in cell size and number
Types
1. Physiologic: During fetal
development(notochord and thyroglossal
duct) and ↓ size of uterus post partum
2. Pathologic: atrophy of disuse, loss of
innervation, ↓blood supply, inadequate
nutrition, loss of endocrine stimulation,
pressure

13. MECHANISM OF ATROPHY
• ↓PROTEIN SYNTHESIS – as a result of
↓metabolic activity
• ↑PROTEIN DEGRADATION- occurs by
ubiquitin proteasome pathway

14. UBIQUITIN-PROTEASOME PATHWAY

15. METAPLASIA
• It is a reversible change in which one
differentiated cell type (epithelial or
mesenchymal) is replaced by another cell
type.
• It is the result of reprogramming of stem cell
into a different lineage or of undifferentiated
cells into a new lineage.
• Not a change in phenotype of already
differentiated cell.

16. 1. EPITHELIAL METAPLASIA:
Columnar → Squamous
Eg: respiratory tract, salivary duct, pancreatic
duct, bile duct
Squamous → Columnar
Eg: Barrett’s oesophagus
2. CONNECTIVE TISSUE METAPLASIA:
Myositis ossificans

17. CELL INJURY
 Sequence of events when cells have no
adaptive response or the limits of adaptive
capability are exceeded.

18. CAUSES OF CELL INJURY
Oxygen deprivation
Physical agents
Chemical agents and drugs
Infectious disease
Immunological reactions
Genetic derangements
Nutritional imbalance

19. TYPES OF CELL INJURY:
1. REVERSIBLE INJURY: in early stages or mild forms of
injury, the functional and morphological changes
are reversible if the damaging stimulus is removed.
2. IRREVERSIBLE INJURY: If the injurious stimulus
persists or is severe enough, the cell suffers
irreversible injury and ultimately undergoes cell
death.
Necrosis
Apoptosis

20. REVERSIBLE CELL INJURY
• Swelling of the cell and its organelles
• Blebbing of plasma membrane
• Detachment of ribosome from RER
• Clumping of nuclear chromatin
• Changes seen on LM- cellular swelling and
fatty changes

21. NECROSIS
• Denaturation of intracellular proteins and
enzymatic digestion of the injured cell
• Loss of membrane integrity and their contents
leak out
• Inflammation is present

22. MORPHOLOGY
1. ON LIGHT MICROSCOPE:
 Increased esinophilia
 Glassy homogenous appearance
 Moth eaten appearance
 Myelin figures.
2. ON ELECTRON MICROSCOPY:
 Disruption of plasma and organelle membrane
 Dilatation of mitochondria with large amorphous
densities
 Myelin figures
 Nuclear changes: karyolysis, pyknosis, karyorrhexis

24. TYPES OF NECROSIS
1. Coagulative necrosis
2. Liquefactive necrosis
3. Gangrenous necrosis
4. Caseous necrosis
5. Fat necrosis
6. Fibrinoid necrosis

25. COAGULATIVE NECROSIS
• Ischemia caused by obstruction in a vessel
may lead to coagulative necrosis in all solid
organs except in brain
• Architecture is preserved for few days
• Necrotic cells are removed by phagocytosis of
the cellular debris by infilterating leukocytes
and by lysosomal enzymes of leukocytes

27. LIQUEFACTIVE NECROSIS
• Seen in focal bacterial or occasionally fungal
infection
• Microbes activates leukocytes and lysosomal
enzymes of leukocytes
• Hypoxic injury of CNS manifests as liquefactive
necrosis
• Digestion of dead cells→ necrotic liquid
viscous mass(pus), creamy yellow in colour

29. GANGRENOUS NECROSIS
DRY GANGRENE: distinct variant of coagulative
necrosis, then why is it called gangrene and not
coagulative necrosis??
extent of vascular occlusion is so global that it
prevents migration of leukocytes
Dead tissue is not digested and removed but
remains mummified
WET GANGRENE: when overlying skin of dry
gangrene is devitalised, bacterial infection
superimposed and coagulative necrosis is
modified by liquefactive necrosis

30. CASEOUS NECROSIS
• Seen in TB
• Caseous means cheeselike
• Necrotic area appears as a structure less
collection of fragmented or lysed cells and
amorphous granular debris enclosed within a
distinctive inflammatory border, this
appearance is characteristic of a focus of
inflammation known as a granuloma

32. FAT NECROSIS
Release of activated pancreatic lipases
Area of fat destruction
Triglycerides Fatty acids
Fat saponification
LIPASE

33. Fat necrosis

34. FIBRINOID NECROSIS
• Seen in blood vessels
Antigen antibody complex + fibrin
Deposited in wall of arteries
Bright pink and amorphous on H & E stain
(“fibrinoid” is fibrin like)

36. MECHANISM OF INJURY
Cellular response depends on
Nature, duration and severity of injury
Type, state and adaptability of the injured
cell

37. BIOCHEMICAL MECHANISMS
RESULTING IN CELLULAR INJURY
Depletion of ATP
Mitochondrial damage
Influx of calcium
Oxidative stress
Defect in membrane permeability
Damage to DNA and Proteins

38. DEPLETION OF ATP

39. MITOCHONDRIAL DAMAGE
Plays major role in all types of cell injury
Major consequences
Formation of mitochondrial permeability transition
pore
Abnormal oxidative phosphoryation ROS
&
Leakage of proapoptotic protein into cytosol will
lead to death by apoptosis

41. INCREASED CYTOSOLIC CALCIUM

42. OXIDATIVE STRESS
• Free radicals are chemical species that have
unpaired electrons in an outer orbit
O₂ O₂⁻ H₂O₂ H₂OOH+ 1 E + 1 E + 1 E + 1 E
FREE
01 ELECTRON
FREE
02 ELECTRON
FREE
03 ELECTRON
SUPEROXIDE
ANION
HYDROGEN
PEROXIDE
HYDROXYL
RADICAL
PARTIAL REDUCTION

43. GENERATION OF FREE RADICALS
Free radicals are produced during normal
physiological process
Eg : oxidative phosphorylation during oxygen
reduction to water
Ionising radiation
Inflammation
Metals like iron and copper donate or accept free
electrons during intracellular reactions and
catalyze free radical formation
Drugs and chemicals
Nitric oxides

44. REMOVAL OF FREE RADICALS
1) Antioxidants
2) Metal carrier proteins
3) Enzymes:
Catalase
Superoxide dismutase
Glutathione peroxidase

45. FREE RADICAL-SCAVENGING ENZYMES
SYSTEM
CATALASE:
2H₂O₂ O₂ + 2H₂O
 SUPEROXIDE DISMUTASE
MAGNESE SOD (MITOCHONDRIA)
 COPPER SOD (CYSTOSOL)
2O₂⁻ + 2H H₂O₂ + O₂

46. FREE RADICAL-SCAVENGING ENZYMES
SYSTEM
GLUTATHIONE PEROXIDASE:
H₂O₂ + 2GSH GSSG + 2H₂O
2OH + 2GSH GSSG + 2H₂O
GSH – REDUCED GLUTATHIONE
GSSG – OXIDISED GLUTATHIONE

48. DEFECT IN MEMBRANE
PERMEABILITY

49. CONSEQUENCES OF MEMBRANE
DAMAGE
1. Mitochondrial membrane damage:
Decreased ATP generation and release of proteins
which triggers apoptosis
2. Plasma membrane damage:
Loss of osmotic balance, influx of fluids and ions
as well as loss of cellular contents
3. Lysosomal membrane damage:
Leakage and activation of acid hydrolases in the
cytoplasm, lysosomes contains RNAases,DNAases,
Proteases, phosphatases, glucosidases.

50. DAMAGE TO DNA AND PROTEINS
• DNA is too sever to repair Apoptosis
• Improperly folded proteins ER stress
Apoptosis

51. APOPTOSIS
• Pathway of cell death that is induced by a
tightly regulated suicide program in which
cells destined to die activate intrinsic enzymes
that degrade the cells own nuclear DNA and
nuclear and cytoplasmic proteins.
• Also called “programmed cell death”

52. CAUSES OF APOPTOSIS
1. Physiologic:
During embryogenesis
Involution of hormone dependent tissues
Cell loss in proliferative cell population
Removal of self reactive lymphocytes
Death of host cells which have served their
purpose

53. 2. PATHOLOGIC
DNA damage
ER stress
In certain infections
In parenchymal organ after prolonged duct
obstruction
During tumor development, P53 is activated and
forces cell to undergo apoptosis(protective
mechanism)

54. MORPHOLOGIC CHANGES
• Cell shrinkage
• Chromatin condensation
• Cytoplasmic blebs Apoptotic bodies
• Phagocytosis of apoptotic bodies by
macrophages

55. MECHANISMS OF APOPTOSIS
• Apoptosis results from the activation of
enzymes called caspases (cysteine proteases
that cleave proteins after aspartic residues)
Caspases exists as inactive proenzyme
Active enzymes
ENZYMATIC
CLEAVAGE

56. TWO PHASES OF APOPTOSIS
1. INITIATION PHASE: Caspases becomes
catalytically active
Intrinsic pathway (mitochondrial)
Extrinsic pathway (death receptor pathway)
2. EXECUTION PHASE: Caspases trigger the
degradation of critical cellular components.

57. INTRINSIC (MITOCHONDRIAL)
PATHWAY
↑mitochondrial outer membrane permeability
Release of death inducing molecules from
mitochondrial intermembrane space into
cytoplasm
[cytochrom C, apoptotic inducing factor(AIF)]

58. • Release of mitochrondrial proapoptotic
proteins is highly controlled by BCL 2 family of
proteins.
• BCL 2 family of proteins-named after BCL2
gene which is overexpressed in case of B Cell
Lymphoma
• >20 members in BCL2 family of
proteins,divided into 3 groups
– Proapoptotic
– Antiapoptotic
– BCL-2 homology (BH) domains

59. PROAPOPTOTIC ANTIAPOPTOTIC SENSORS
BAX, BAK
Has 4 BH Domains
BCL-2, BCL-XL AND MCL-1
Has 4 BH Domains
BAD,BIM,BID,Puma,Noxa
Only one BH Domain,the
3rd one of the four BH
Domains
Also called BH-3 only
protein
They balance between
proapoptotic and antiapoptic
proteins

60. Growth factors/survival signals
Production of antiapoptotic proteins
prevention of leakage of death inducing proteins
from mitochondrial intermembrane space
cell survives

61. No Growth factors/survival signals/DNA
damage/ER Stress
BH3 proteins is activated and senses stress and
activates proapoptotic proteins and blocks
antiapoptotic proteins
Increased outer membrane permeability of
mitochondria
Leakage of death inducing proteins
(cytochrom C and AIF)

62. Cytochrom C + APAF-1
Apoptosome
Apoptosomes + Caspases 9
Activated caspases 9
Activates adjacent caspases 9(autoamplification)
Activates executioner caspases
In Cytoplasm

64. EXTRINSIC (DEATH RECEPTOR INITIATED)
PATHWAY
• Initiated by engagement of plasma membrane
death receptors
• Death receptors are members of TNF receptor
family
• Death receptor has cytoplasmic domain called
death domain.
• Death receptors: Type I TNF receptor(TNFR-I)
& a related protein called FAS
• Ligand for FAS- FAS Ligand (death inducer)

66. • Pathway of apoptosis can be inhibited by a
protein called FLIP which binds to procaspase
8 but can’t activate and cleave procaspase 8

67. EXECUTION PHASE
• Two initiating pathways converge to a cascade
of caspase activation, which mediate the final
phase of apoptosis
Intrinsic pathway Extrinsic pathway
activates executioner caspases 3 and 6

68. Activated Executioner caspases 3 and 6
Activates DNAases and degrade structural
components of nuclear matrix
apoptotic bodies are formed, which undergo
changes in their membranes that actively
promote their phagocytosis

70. NECROPTOSIS
This form of cell death is hybrid that shares
aspects of both necrosis and apoptosis.
morphologically and to some extent
biochemically it resembles necrosis.
mechanistically it is triggered by genetically
programmed signal transduction events that
culminate in cell death.
there is no caspase activation in necroptosis,
and its called caspase independent
programmed cell death

73. IRREVERSIBLE CELL INJURY