1. Cell injury, death and adaptation Yemen University Lectures 1 and 2
Dr Heyam Awad
FRCPath

3. Coordinator : Dr Heyam Awad
Lectures will be available on my university website
Office hours: Monday and Wednesday Office in hospital 3rd floor.

4. Lecture distribution Cell injury 4+lab Inflammation 6 +2labs
Repair 3 +lab
Haemodynamic diseases 5+lab
Neoplasia 8 +2 labs
Genetic diseases labs

5. EVALUATION
1 EXAM
THEORY AND PRACTICAL.
mock

6. What is pathology? Patho… disease Logy… study
Pathology = study of disease
involves: causes of disease.. Etiology
: mechanisms.. pathogenesis
:morphological changes.

7. Etiology: Origin of disease , underlying causes.
Pathogenesis: steps in the development of disease…… cellular and molecular changes .
Morphology: macroscopic and microscopic changes.

8. Why to study pathology???

9. Cellular adaptations and cell injury
Cells maintain a steady state.. Homeostasis.
Stresses .. Adaptation….. New homeostatic state with preservation of function.
Stress beyond capability of adaptation.. Cell injury.
Cell injury… reversible within certain limits
Then .. Irreversible…. Ends in cell death.
Two types of cell death: necrosis and apoptosis.

13. Adaptation
Hyertrophy
Hyperplasia
Atrophy
metaplasia

14. Adaptation Adaptive changes are reversible.
Can be physiologic or pathologic.

15. Hypertrophy: Increased cell size.
Hyperplasia: increased number of cells.. Cell division.
Metaplasia: change from one adult cell type to another
Atrophy: decreased size.

16. Hypertrophy versus hyperplasia

17. Hypertrophy Increased cell size.
Due to increased organelles and proteins.
Increased intracellular synthesis..
Caused by: increased demands, hormones or growth factors.

18. Physiologic hypertrophy
Uterus during pregnancy… due to estrogen
Skeletal muscle… due to increased demand

19. Physiologic hypertrophy

20. Pathologic hypertrophy
Cardiac.. Hypertensive heart disease
Pathogenesis.. Two types of signals: mechanical: stretch and trophic: growth factors and androgenic hormones

21. Pathologic hypertrophy

22. Pathologic hypertrophy

23. hyperplasia Only in tissues that can replicate.
Can be physiologic or pathologic.

24. Physiologic hyperplasia
Hormonal: uterus, breast.
Compensatory: after removal or loss of part of tissue.

25. Pathologic hyperplasia
Due to excess in hormones or growth factors.
E:g endometrial hyperplasia.
Controlled.. Responds to decreased stimulation. This differentiates it from cancer

26. Normal endometrium

27. Endometrial hyperplasia

28. atrophy Shrinkage in cell size due to loss of cell substance. Causes
decreased work load.
Loss of innervation
Loss of endocrine stimulation.
Aging

29. Atrophy Physiologic: endometrial atrophy during menopause
Pathologic: loss of innervation.

30. atrophy Mechanisms: Decreased protein synthesis.
Degradation of cellular proteins.
Autophagy…. Literally means self eating.

31. Brain atrophy

32. Muscle atrophy

33. metaplasia Adult cell type replaced by another adult cell type.
Arise in reprogrammed stem cells to differentiate along a new pathway.

34. Epithelial metaplasia
Respiratory epithelium to squamous.
Barrett's mucosa.. Esophegeal squamous to columnar

35. Barrett’s mucosa

36. Normal esophegeal mucosa

37. Metaplastic, Barrett’s mucosa

38. Metaplasia in mesenchymal tissue
Usually pathologic
Ossification of soft tissue due to injury.

39. Cell injury

40. Causes of cell injury/ 1 Chemical agents Infections. Immunologic
Genetic factors
Nutritional imbalances
Physical agents
Aging.

41. Causes of cell injury/ 2
Oxygen deprivation.. Hypoxia and ischemia. Hypoxia= oxygen deficiency Ischemia = loss of blood supply due to impaired arterial flow or reduced venous return. -Ischemia is the most common cause of hypoxia. -Other causes of hypoxia: *reduced oxygen carrying capacity in anemia or carbon monoxide deficiency. *inadequate oxygenation of the blood as in pnumonia.

42. Rules and principles/ 1
Cell response to injurious stimuli depend on type, duration and severity of the injury.
Example: low dose of a toxin can cause reversible injury whereas larger dosed can cause cell death.
Short-lived ischemia.. Reversible
Ischemia of long duration… death

43. Rules and principles/ 2
Response to injury also depends on type, status, adaptability and genetic makeup of the injured cell.
Example: skeletal muscle cells can stand 2-3 hours of ischemia without irreversible injury but cardiac muscles die in minutes .
Glycogen content in hepatocytes can determine their response to injury.. How?
Genetic polymorphism in cytochrome P-450 influences response to toxins.

44. Rules and principles/ 3
Cell injury results from functional and biochemical changes in essential cellular components, mainly:
Mitochondrial function
Calcium homeostasis
Cell and organelle membranes
DNA
Protein synthesis and folding.

45. Rules and principles/ 4
All injurious stimuli first affect the molecular or biochemical level.
Cellular functions lost before cell death occurs.
The morphologic changes of cell injury (or cell death) occur very late.

46. Rules/4 example Ischemia of the heart… coronary artery occlusion.
Myocardial cells loose function ( become non-contractile) after 1-2 minutes of ischemia.
They die minutes after ischemia.
It takes 2-3 hours to recognise ultrastructural changes of death (EM)
6-12 hours by light microscope to appear dead.

48. Morphology of reversible cell injury
Cellular swelling : due to failure of energy-dependent ion pumps in the plasma membrane causing inability to maintain ion and fluid homeostasis.
Fatty change : small or large lipid vacuoles (hepatocytes and myocardial cells)

49. Cell swelling
The first manifestation of almost all forms of cell injury.
Reversible.
Grossly: organ affected becomes pale and gains weight.
Micro: small clear cytoplasmic vacuoles … which are distended endoplasmic reticulum.

50. Cell swelling

51. Fatty change
In cells participating in fat metabolism: hepatocytes and myocardial cells)
Reversible
Fat droplets.

52. Ultrastructural changes of reversible injury (EM)
(1) plasma membrane changes such as blebbing, blunting or distortion of microvilli, and loosening of intercellular attachments.
(2) mitochondrial changes such as swelling and the appearance of phospholipid-rich amorphous densities.
(3) dilation of the ER with detachment of ribosomes and dissociation of polysomes.
(4) nuclear alterations, with clumping of chromatin.

53. EM changes

54. Morphology of irreversible injury Necrosis
Necrosis = Morphologic changes that follow cell death in living tissues.

55. NECROSIS Denaturation of intracellular proteins.
Digestion of cells by lysosomal enzymes of dying cells ( autolysis) and leukocytes (heterolysis).

56. Protein denaturation

57. denaturation

58. LM changes 1) Increased cytoplasmic eosinophilia. Cause?
2) Vacoulation of cytoplasm, moth eaten. Cause?
3) Nuclear changes
4) Calcification

59. Nuclear changes one of three patterns
1. karyolysis: decreased chromatin basophilia secondary to deoxyribonuclease (DNAase) activity.
2. pyknosis: nuclear shrinkage and increased basophilia (DNA condenses into a solid shrunken mass.
3. karyorrhexis, fragmentation then disappearance of nucleus.

60. EM changes 1)Discontinuities in plasma and organelle membranes.
2) Marked dilation of mitochondria and large amorphous densities.
3)Disruption of lysosomes.
4) Intracytoplasmic myelin figures

61. Myelin figures
Myelin figures: aggregates of damaged cell membranes (phospholipids).
Fate of Myelin figures:
phagocytosed by other cells or further degraded
into fatty acids and calcify

63. Patterns of necrosis
Denaturation of protein predominates…. Coagulative necrosis.
Enzymatic digestion predominates… liquefactive necrosis.
Special circumstances: caseous necrosis and fat necrosis.

64. Coagulative necrosis preserved architecture of dead tissue .
Denaturation of structural proteins and enzymes… so no cellular proteolysis.
Eosiniphilic anucleated cells
Cells are removed by inflammatory cells. .

65. Ischemia in all solid organs except the brain may lead to coagulative necrosis.

66. Coagulative necrosis

67. Liquifactive necrosis
digestion of the dead cells resulting into a liquid jelly-like mass.
In focal bacterial or fungal infections and in hypoxic death in central nervous system.

68. Caseous necrosis White cheese like friable necrosis.
Prototype: Tuberculosis
Typical finding is granuloma :Collection of fragmented or lysed cells with amorphous granular eosinophilic debris surrounded by macrophages.

69. Caseous necrosis White cheese like friable necrosis.
Prototype: Tuberculosis
Typical finding is granuloma :Collection of fragmented or lysed cells with amorphous granular eosinophilic debris surrounded by macrophages.

70. Fat necrosis used as a clinical terms and not a specific type.
Necrosis of fat.
Typical example: pancreatic enzymes (lipases) release in acute pancreatitis.

71. Fate of necrotic tissue
Phagocytosis.
Replacement by scar.
Regeneration.
Calcification.

72. Mechanisms of cell injury
ATP depletion
Mitochondrial damage
Calcium influx
Oxygen derived free radicals
membrane defects
Damage to DNA and protein

73. ATP depletion ATP.. Importance? Sources of ATP? Causes of depletion?
Effects of ATP depletion?

74. Effects of ATP depletion
Membrane permeability affected due to effects on Na- K pump.
Increased acidity due to increased non oxidative phosphorylation.
Failure of calcium pump.. Increased intracellular calcium.
Structural disruption in protein synthesis apparatus.. Detacment of ribosomes and dissociation of polysomes

75. Mitochondrial damage
Failure of oxidative phosphrylation.. ATP depletion.
Abnormal oxidative phosphorylation.. ROS
Mitochondrial permeability transition pores.. Loss of membrane potentional and pH change
Release of proteins that initiate apoptosis

76. Calcium influx
Activates enzymes… phospholipases, proteases, endonucleases, ATPases… so cell destruction.
Calcium can directly activate caspases… apoptosis

77. Oxygen free radicals Lipid peroxidation Cross linking of proteins
DNA damage

78. Membrane permeability defects
Caused by:
Decreased phospholipid synthesis due to ATP depletion.
Increased phospholipid breakdown .. Due to increased calcium
ROS. .
Lipid breakdown products

79. DNA damage
Initiates apoptosis

80. mechanisms