This document summarizes various types of cell injury, adaptation, aging and death. It describes reversible injuries like cellular adaptations that allow cells to survive stress through changes in size or differentiation. More severe injuries lead to irreversible cell death through necrosis, apoptosis or gangrene formation. The causes of cell injury include lack of oxygen, physical or chemical insults, microbes, immunological reactions and aging. Adaptations include atrophy, hypertrophy, hyperplasia and metaplasia. Apoptosis and necrosis are types of programmed and unprogrammed cell death respectively. Aging causes changes to various organs over time.

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