superficial introduction to the topic for bachelor level

1. Cell Injury,
Adaptation,
Ageing and
Death
Dr. Saugat Chapagain

2. Cell Injury
– Variety of stress that a cell encounters in response to
changes to internal and external environment.
– Response varies upon:
– The type of cell and tissue involved.
– Extent and type of cell injury.

3. Forms Of Cellular Injury
– Cellular adaptations:
– Increased functional demands leading to morphological changes
– May revert back to normal
– Reversible injury
– If stress is mild to moderate
– Evidence may stay persistent (subcellular changes)
– Metabolites may accumulate within the cell (intracellular accumulations)
– Irreversible injury (death)
– If injury is severe
– Two types:
– Necrosis (murder)
– Apoptosis (suicide)

5. Etiology
1. Oxygen deprivation: e.g. hypoxia, ischaemia
2. Physical agents: e.g. mechanical trauma, thermal trauma, pressure changes.
3. Chemicals and drugs: alcohol/poison/ high O2
4. Microbial agents: bacteria, virus, fungi, etc.
5. Immunological agents: hypersensitivity, autoimmune and anaphylaxis.
6. Nutritional derangements: e.g. PEM
7. Ageing
8. Psychogenic: drug addiction, alcoholism, alcoholism, etc.
9. Iatrogenic: hospital acquired
10. Genetic defects: Down’s synd., inborn error of metabolism, etc
11. Idiopathic diseases: HTN, Cancer, etc

6. Pathogenesis
– Severity and type of injury depends on:
– Type, duration and severity of injury.
– Type, status and adaptability of target cell.
• Skeletal muscles can withstand hypoxia for longer than cardiac muscles.
– Underlying intra cellular biochemical phenomenon
• Mitochondrial damage causing ATP depletion
• Cell membrane damage disturbing trans-membrane exchanges
• Releases of toxic free radicals
– Morphological consequences

7. Mechanism Of Damage
– Direct cytotoxicity:
– Chemicals mix with cellular components
– E.g. antibiotics, anti cancer drugs, cyanide, mercury chloride, etc
– By reactive free radicals and lipid peroxidation:
– Lipid soluble toxins
– O2
- (superoxide), H2O2, OH-
– NO2
-, NO3
-
– CCL3
-

8. Cellular Adaptations
– For survival on exposure to stress.
– Methods:
– By decreasing or increasing size (atrophy/ hypertrophy)
– Phenotypic differentiation (metaplasia)
– Types:
– Atrophy
– Hypertrophy
– Hyperplasia (increase in number)
– Metaplasia
– Anaplasia (lack of differentiation)

9. Atrophy
– Shrinkage of size my loss of cell or cellular substance.
– Types:
– Physiological atrophy:
– E.g. brain with ageing.
– Pathological atrophy:
– Local (d/t disuse, pressure, ischemia)
– generalized (d/t starvation, ageing)

11. Causes of Atrophy
Physiological – e.g. with ageing
Pathological:
– Starvation
– Ischemic
– Brain in cerebral atherosclerosis
– Disuse
– Wasting of unused muscles
– Neuropathic
– Poliomyelitis
– Endocrine
– Hypopituitarism  atrophy of endocrine glands
– Pressure
– Erosion of spine  tumor of nerve root
– Idiopathic Atrophy
– Myopathy, testicular atrophy

12. Morphology
– Gross:
– Organ is small, shrunken.
– Cells are smaller in size but not dead.
– Microscopic:
– Shrinkage due to reduction in cell organelles, chiefly mitochondria,
myofilaments and Endoplasmic reticulum.
– Increased number of autophagic vacuoles.

14. Hypertrophy
– Increase in size NOT in number.
– Types:
– Physiological:
– Enlargement of uterus during pregnancy.
– Pathological:
– In cardiac muscles (LVH)
– In smooth muscles (muscular arteries in HTN)
– In skeletal muscles (exercise)
– Compensatory (renal hypertrophy following unilateral nephrectomy)

15. Morphology
– Gross
– Enlarged and heavy organ
– E.g. heart of a pt. with hypertrophy (700-800 gm.) compared to
normal (350 gm.)
– Microscopic
– Enlargement of muscle fibres as well as of the nuclei.

16. Hyperplasia
– Increase in number of parenchymal cells leading to
increase in size of tissue/ organ.
– Due to increased mitosis (hence cells need to be capable of
DNA synthesis)
– Reversible and persists as long as stimulus is present
– Neoplasia – hyperplasia with loss of growth regulatory
mechanism d/t genetic alterations.

17. Causes
– Physiological
– Hormonal
– Breast at puberty
– Prostate in old age
– Compensatory
– Regeneration of skin after abrasion
– Regeneration of liver after partial hepatectomy.
– Pathological
– Endometrial hyperplasia during menstrual cycle
– Skin warts d/t hyperplasia of epidermis (HPV)
– Intraductal epithelial hyperplasia in fibrocystic breast disease.

18. Metaplasia
– Reversible cell change from one type to another.
– If stimulus persists for a long time, metaplasia may convert
into carcinoma.

19. Types
– Epithelial
– Squamous – most common
– Pseudostratified ciliated columnar epithelium of Bronchus in smokers.
– Simple columnar epithelium of uterus in old age.
– Simple columnar of gall bladder in chronic cholecystitis
– Columnar
– Intestinal metaplasia in healed chronic gastric ulcer.
– In barret’s oesophagus.
– Mesenchymal
– Osseous
– Arterial wall in old age
– Cartilage of larynx and bronchi in elderly
– Scar of chronic inflammation of prolonged duration.
– Cartilagenous
– In healing of fractures

20. Dysplasia
– a/k/a atypical hyperplasia.
– Disordered cellular development.
– Often accompanied with metaplasia and hyperplasia.

22. Ageing
– Growing old
– Avg. age of death of primitive man was 20-25 yrs. Survival
being longer in women than in men.
– Life expectancy depends on:
– Intrinsic genetic process.
– Environmental factors.
– Lifestyles of the individual
– Age related diseases

23. Organ changes
– CVS
– Atherosclerosis, loss of vasular elasticity  dialation.
– Nervous system
– alzheimer’s disease, parkinsonism, atrophy of gyri and sulci.
– MSK
– Degenerative bone diseases
– loss of bone density  frequent fractures
– Eyes
– Cataract
– Hearing
– Otosclerosis, SNHL
– Immune system
– Frequent and severe response, reduced IgG response
– Skin
– Laxity d/t loss of elasticity
– Cancers
– 80% cancers appear after 50 years of age

25. Irreversible Cell Injury
– Autolysis
– Necrosis
– Apoptosis
– Gangrene formation
– Pathological calcification
– Dystrophic
– In dead tissues or degenerated tissues
– Metastatic
– Due to hypercalcemic calcium deposits.

26. Autolysis
– Self digestion/ destruction
– Disintegration of cell by its own hydrolytic enzymes from lysosomes.
– Can occur in live body in case of severe inflammatory response
– Generally in post mortem changes with no inflammatory response
– Rapid in pancreas, gastric mucosa
– Intermediate in heart, liver and kidney
– Slow in fibrous tissue
– Morphology – eosinophilic cytoplasm with loss of details (tombstone)

27. Necrosis
– Spectrum of morphologic changes that follows cell death in
living tissue, largely resulting from progressive degradative
action of enzymes on the lethally injured cells.
– Characteristic changes:
– Cell digestion by lytic enzymes
– Denaturation of proteins

29. Types of Necrosis
– Coagulative
– Liquefactive (colliquative)
– Caseous
– Fat
– Fibrinoid
– Necrosis of muscle (Zenker’s degeneration) –particularly
occurs in rectus abdominis muscle in typhoid
fever

31. Coagulative Necrosis
– Most common type
– Irreversible focal injury (commonly sudden ischemia)
– Gross-
– Foci in early stage- pale, firm and slightly swollen
– Later- yellowish, softer and shrunken
– Microscopic-
– Hallmark ‘Tombstone’ appearance – outlines only retained
– E.g. hypoxic death of cells in all (heart, kidney, spleen, liver,
adrenal gland) except CNS

34. Liquefaction (Colliquative)
Necrosis
– Due to ischemic injury and bacterial/ fungal infections.
– E.g. infarct in brain (CNS) and abscess cavity.
– Gross:
– Area is soft wit liquefied center containing necrotic debris
– Later, a cyst wall is formed.
– Microscopic:
– Cystic space contains necrotic cell debris and macrophages.
– Cyst wall formed by proliferating capillaries, inflammatory cells and
gliosis (in CNS) and proliferating fibroblasts (in abscess)

36. Caseous Necrosis
– In center of foci of tuberculous infections.
– combines features of both coagulative and liquefactive
necrosis.
– Gross-
– Resembles dry cheese
– Soft, granular and yellowish
– Microscopic-
– Structure less, eosinophilic with granular debris.
– Granulomatous inflammatory reaction in surrounding tissue.
– Epithelioid cells with giant cell of Langhan’s

39. Fat Necrosis
– Following acute pancreatic necrosis or traumatic fat
necrosis (commonly in breasts)
– Gross-
– Yellowish white firm deposits
– Formation of calcium soaps firm and chalky white appearance
– Microscopic-
– Cloudy appearance
– Surrounded by inflammatory reaction
– Calcium soaps seen (amorphous, granular basophilic material)

41. Fibrinoid Necrosis
– Necrosis of collagen fibers
– Deposit of fibrin like material
– Seen in immunological tissue injury
– E.g. vasculitis, auto immune disease, peptic ulcer, etc.
– Microscopy-
– Bright, eosinophilic hyaline like deposit in vessel wall.
– Necrotic focus surrounded by nuclear debris of neutrophils

43. Gangrene
– Necrosis of tissue with superadded putrefaction.
– Types-
– Dry gangrene- esp. in lower limbs due to ischemia with
minimal/no liquefaction. E.g. Buerger’s dis (TAO), Raynaud’s
dis.
– Wet gangrene- complicated by infection and liquefaction
(diabetic foot, bed sores)
– Gas gangrene- variant of wet gangrene caused by gas forming
clostridia (GP anaerobic bacteria)

45. Apoptosis
Co-ordinated and internally programmed cell death
– Physiological process
– Organized cell destruction in sculpting of tissues during development of
embryo.
– Involution of cells (in menstrual cycle, regression of lactating breast after
withdrawal of breast feeding)
– Normal cell destruction e.g. replacement of old cells by new
– Involution of thymus in early age.
– Pathological process
– Cell death in tumors after use of chemo.
– Cell death in immunology (graft rejection)
– Depletion of CD4+T cells in pathogenesis of AIDS
– Prostatic atrophy after orchiectomy.
– Death in response to injury (radiation, hypoxia)
– Degenerative CNS diseases

47. Molecular Mechanism
1. Initiator of apoptosis
– Withdrawal of survival signals
– Extracellular signals triggering cell death
– Intracellular stimuli (heat, radiation)
2. Process of programmed cell death
– Activation of caspases (proteolytic enzymes)
– Activation of death receptors (TNF-R)
– Activation of growth controlling genes
– Dell death
3. Phagocytosis

48. Thank you