2. Cell Injury
â Variety of stress that a cell encounters in response to
changes to internal and external environment.
â Response varies upon:
â The type of cell and tissue involved.
â Extent and type of cell injury.
3. Forms Of Cellular Injury
â Cellular adaptations:
â Increased functional demands leading to morphological changes
â May revert back to normal
â Reversible injury
â If stress is mild to moderate
â Evidence may stay persistent (subcellular changes)
â Metabolites may accumulate within the cell (intracellular accumulations)
â Irreversible injury (death)
â If injury is severe
â Two types:
â Necrosis (murder)
â Apoptosis (suicide)
4.
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: Downâs synd., inborn error of metabolism, etc
11. Idiopathic diseases: HTN, Cancer, etc
6. Pathogenesis
â Severity and type of injury depends on:
â Type, duration and severity of injury.
â Type, status and adaptability of target cell.
âą Skeletal muscles can withstand hypoxia for longer than cardiac muscles.
â Underlying intra cellular biochemical phenomenon
âą Mitochondrial damage causing ATP depletion
âą Cell membrane damage disturbing trans-membrane exchanges
âą Releases of toxic free radicals
â Morphological consequences
7. Mechanism Of Damage
â Direct cytotoxicity:
â Chemicals mix with cellular components
â E.g. antibiotics, anti cancer drugs, cyanide, mercury chloride, etc
â By reactive free radicals and lipid peroxidation:
â Lipid soluble toxins
â O2
- (superoxide), H2O2, OH-
â NO2
-, NO3
-
â CCL3
-
8. Cellular Adaptations
â For survival on exposure to stress.
â Methods:
â By decreasing or increasing size (atrophy/ hypertrophy)
â Phenotypic differentiation (metaplasia)
â Types:
â Atrophy
â Hypertrophy
â Hyperplasia (increase in number)
â Metaplasia
â Anaplasia (lack of differentiation)
9. Atrophy
â Shrinkage of size my loss of cell or cellular substance.
â Types:
â Physiological atrophy:
â E.g. brain with ageing.
â Pathological atrophy:
â Local (d/t disuse, pressure, ischemia)
â generalized (d/t starvation, ageing)
10.
11. Causes of Atrophy
Physiological â e.g. with ageing
Pathological:
â Starvation
â Ischemic
â Brain in cerebral atherosclerosis
â Disuse
â Wasting of unused muscles
â Neuropathic
â Poliomyelitis
â Endocrine
â Hypopituitarism ï atrophy of endocrine glands
â Pressure
â Erosion of spine ï tumor of nerve root
â Idiopathic Atrophy
â Myopathy, testicular atrophy
12. Morphology
â Gross:
â Organ is small, shrunken.
â Cells are smaller in size but not dead.
â Microscopic:
â Shrinkage due to reduction in cell organelles, chiefly mitochondria,
myofilaments and Endoplasmic reticulum.
â Increased number of autophagic vacuoles.
13.
14. Hypertrophy
â Increase in size NOT in number.
â Types:
â Physiological:
â Enlargement of uterus during pregnancy.
â Pathological:
â In cardiac muscles (LVH)
â In smooth muscles (muscular arteries in HTN)
â In skeletal muscles (exercise)
â Compensatory (renal hypertrophy following unilateral nephrectomy)
15. Morphology
â Gross
â Enlarged and heavy organ
â E.g. heart of a pt. with hypertrophy (700-800 gm.) compared to
normal (350 gm.)
â Microscopic
â Enlargement of muscle fibres as well as of the nuclei.
16. Hyperplasia
â Increase in number of parenchymal cells leading to
increase in size of tissue/ organ.
â Due to increased mitosis (hence cells need to be capable of
DNA synthesis)
â Reversible and persists as long as stimulus is present
â Neoplasia â hyperplasia with loss of growth regulatory
mechanism d/t genetic alterations.
17. Causes
â Physiological
â Hormonal
â Breast at puberty
â Prostate in old age
â Compensatory
â Regeneration of skin after abrasion
â Regeneration of liver after partial hepatectomy.
â Pathological
â Endometrial hyperplasia during menstrual cycle
â Skin warts d/t hyperplasia of epidermis (HPV)
â Intraductal epithelial hyperplasia in fibrocystic breast disease.
18. Metaplasia
â Reversible cell change from one type to another.
â If stimulus persists for a long time, metaplasia may convert
into carcinoma.
19. Types
â Epithelial
â Squamous â most common
â Pseudostratified ciliated columnar epithelium of Bronchus in smokers.
â Simple columnar epithelium of uterus in old age.
â Simple columnar of gall bladder in chronic cholecystitis
â Columnar
â Intestinal metaplasia in healed chronic gastric ulcer.
â In barretâs oesophagus.
â Mesenchymal
â Osseous
â Arterial wall in old age
â Cartilage of larynx and bronchi in elderly
â Scar of chronic inflammation of prolonged duration.
â Cartilagenous
â In healing of fractures
20. Dysplasia
â a/k/a atypical hyperplasia.
â Disordered cellular development.
â Often accompanied with metaplasia and hyperplasia.
21.
22. Ageing
â Growing old
â Avg. age of death of primitive man was 20-25 yrs. Survival
being longer in women than in men.
â Life expectancy depends on:
â Intrinsic genetic process.
â Environmental factors.
â Lifestyles of the individual
â Age related diseases
23. Organ changes
â CVS
â Atherosclerosis, loss of vasular elasticity ï dialation.
â Nervous system
â alzheimerâs disease, parkinsonism, atrophy of gyri and sulci.
â MSK
â Degenerative bone diseases
â loss of bone density ï frequent fractures
â Eyes
â Cataract
â Hearing
â Otosclerosis, SNHL
â Immune system
â Frequent and severe response, reduced IgG response
â Skin
â Laxity d/t loss of elasticity
â Cancers
â 80% cancers appear after 50 years of age
24.
25. Irreversible Cell Injury
â Autolysis
â Necrosis
â Apoptosis
â Gangrene formation
â Pathological calcification
â Dystrophic
â In dead tissues or degenerated tissues
â Metastatic
â Due to hypercalcemic calcium deposits.
26. Autolysis
â Self digestion/ destruction
â Disintegration of cell by its own hydrolytic enzymes from lysosomes.
â Can occur in live body in case of severe inflammatory response
â Generally in post mortem changes with no inflammatory response
â Rapid in pancreas, gastric mucosa
â Intermediate in heart, liver and kidney
â Slow in fibrous tissue
â Morphology â eosinophilic cytoplasm with loss of details (tombstone)
27. Necrosis
â Spectrum of morphologic changes that follows cell death in
living tissue, largely resulting from progressive degradative
action of enzymes on the lethally injured cells.
â Characteristic changes:
â Cell digestion by lytic enzymes
â Denaturation of proteins
28.
29. Types of Necrosis
â Coagulative
â Liquefactive (colliquative)
â Caseous
â Fat
â Fibrinoid
â Necrosis of muscle (Zenkerâs degeneration) âparticularly
occurs in rectus abdominis muscle in typhoid
fever
30.
31. Coagulative Necrosis
â Most common type
â Irreversible focal injury (commonly sudden ischemia)
â Gross-
â Foci in early stage- pale, firm and slightly swollen
â Later- yellowish, softer and shrunken
â Microscopic-
â Hallmark âTombstoneâ appearance â outlines only retained
â E.g. hypoxic death of cells in all (heart, kidney, spleen, liver,
adrenal gland) except CNS
32.
33.
34. Liquefaction (Colliquative)
Necrosis
â Due to ischemic injury and bacterial/ fungal infections.
â E.g. infarct in brain (CNS) and abscess cavity.
â Gross:
â Area is soft wit liquefied center containing necrotic debris
â Later, a cyst wall is formed.
â Microscopic:
â Cystic space contains necrotic cell debris and macrophages.
â Cyst wall formed by proliferating capillaries, inflammatory cells and
gliosis (in CNS) and proliferating fibroblasts (in abscess)
35.
36. Caseous Necrosis
â In center of foci of tuberculous infections.
â combines features of both coagulative and liquefactive
necrosis.
â Gross-
â Resembles dry cheese
â Soft, granular and yellowish
â Microscopic-
â Structure less, eosinophilic with granular debris.
â Granulomatous inflammatory reaction in surrounding tissue.
â Epithelioid cells with giant cell of Langhanâs
37.
38.
39. Fat Necrosis
â Following acute pancreatic necrosis or traumatic fat
necrosis (commonly in breasts)
â Gross-
â Yellowish white firm deposits
â Formation of calcium soapsï firm and chalky white appearance
â Microscopic-
â Cloudy appearance
â Surrounded by inflammatory reaction
â Calcium soaps seen (amorphous, granular basophilic material)
40.
41. Fibrinoid Necrosis
â Necrosis of collagen fibers
â Deposit of fibrin like material
â Seen in immunological tissue injury
â E.g. vasculitis, auto immune disease, peptic ulcer, etc.
â Microscopy-
â Bright, eosinophilic hyaline like deposit in vessel wall.
â Necrotic focus surrounded by nuclear debris of neutrophils
42.
43. Gangrene
â Necrosis of tissue with superadded putrefaction.
â Types-
â Dry gangrene- esp. in lower limbs due to ischemia with
minimal/no liquefaction. E.g. Buergerâs dis (TAO), Raynaudâs
dis.
â Wet gangrene- complicated by infection and liquefaction
(diabetic foot, bed sores)
â Gas gangrene- variant of wet gangrene caused by gas forming
clostridia (GP anaerobic bacteria)
44.
45. Apoptosis
Co-ordinated and internally programmed cell death
â Physiological process
â Organized cell destruction in sculpting of tissues during development of
embryo.
â Involution of cells (in menstrual cycle, regression of lactating breast after
withdrawal of breast feeding)
â Normal cell destruction e.g. replacement of old cells by new
â Involution of thymus in early age.
â Pathological process
â Cell death in tumors after use of chemo.
â Cell death in immunology (graft rejection)
â Depletion of CD4+T cells in pathogenesis of AIDS
â Prostatic atrophy after orchiectomy.
â Death in response to injury (radiation, hypoxia)
â Degenerative CNS diseases
46.
47. Molecular Mechanism
1. Initiator of apoptosis
â Withdrawal of survival signals
â Extracellular signals triggering cell death
â Intracellular stimuli (heat, radiation)
2. Process of programmed cell death
â Activation of caspases (proteolytic enzymes)
â Activation of death receptors (TNF-R)
â Activation of growth controlling genes
â Dell death
3. Phagocytosis