L4: Pathology of Cell Injury, Cell Death and Acute Inflammation

Learning objectives

• Identify stimuli that may cause injury to cells

• Describe the biochemical mechanisms of cell injury

• Explain the concept of reversible & irreversible cell damage

• Identify morphological features found in common types of reversible and irreversible cell injury

• Describe the complications of cell death

Causes of Cell Injury

Stimuli causes cell injury

• hypoxia or anoxia

• physical energy (heat)

• chemicals

• biological agents

• immune reactions

• nutritional imbalance

• genetic defects

Mechanism of cell injury

Damage to nucleus

• damage of DNA

  • ionising radiation

  • viruses

  • hereditary mutation

• extreme temperature & toxic chemicals → affect DNA and protein folding

• result: abnormal protein formation

Depletion of ATP

• insufficient glucose for glycolysis

• no O2 as electron acceptor → no ATP can be generated

• toxic stopping the Kreb cycle

Damage to mitochondria

• leakage of Ca and pro-apoptotic proteins → cell apoptosis

• no generation of ATP

Free radicals

• electron transport chain unable to function properly

• generation of free radicals → superoxides

• cause

  • inflammation

  • ionising radiation

Cell membrane damage

• cause

  • mechanical trauma

  • chemicals and toxins

  • free radicals

  • viruses

  • immune cells

  • lack of ATP

• result: influx of water and other materials → swelling and lysis

Calcium influx

• activate enzyme → membrane and nuclear damage

  • e.g. phospholipase, protease, endonuclease

• increase mitochondrial permeability transition → ATP depletion

DNA and protein damage

• cause

  • ionising radiation

  • heat or freezing

  • poisons

  • free radicals

• Result

  • apoptosis

  • cancer

Cell Adaptation to Stress

Hypertrophy

• increase size of cells

• examples

  • body builders: hypertrophic skeletal muscles

  • pregnant uterus: hypertrophic smooth muscles

Metaplasia

• cells change phenotype

• example

  • epithelial cells in respiratory tract: columnar -> squamous metaplasia (due to irritation by cigarette toxin)

Hyperplasia

• incraese of cell number

• example

  • breast tissue when pregnancy (proliferation)

Atrophy

• decrease of cell number

• example

  • atrophic breast tissue when aged

  • cerebrovascular disease: shrunk cerebrum

Cell Injury

Reversible cell injury

Features

• characteristic changes when injured

• also called degeneration

• can revert back to normal if stimulus is removed

Types

• cellular oedema

  • lack of ATP or cell membrane damage

  • ions accumulation in cell

  • water entry by osmosis

  • swelling

  • example

    • kidney tubules cuboidal -> swollen and paler (ischaemia)

• fatty change

  • abnormal metabolism -> fat accumulation

  • often seen in liver cells, heart cells and kidney cells

  • cause by

    • hypoxia

    • toxin (alcohol)

    • metabolic disorders (diabetes)

    • malnutrition

  • example: fatty liver due to drinking

Irreversible cell injury

Features

• caused by injurious stimuli → cell death

• severe or persistent injury

Apoptosis

• affect scattered single cells

• physiological or pathological

  • eliminate unwanted cells

  • due to DNA damage,virus, misfold proteins or tumour cell death

• initiated by mitochondria or lymphocytes

• process

  • condensation of chromatins and membrane blebs formation

  • cellular fragmentation → apoptotic body

  • phagocytes engulf apoptotic cells and fragments

  • keeping materials inside the membrane → not affect other neighbouring cells → no inflammation

Nercrosis

• death of groups of cells while still part of a living body

• cellular content leaks ourtwhen cells die → attract WBCs → inflammation

• cellular features

  • karyolysis: nuclear fading

  • pykinposis: nucleus shrinkage

  • karyorrhexis: nuclear fragmentation

• major tissue patterns

  • coagulative necrosis

    • red/ pink tissue due to inflammation

    • example

      • acute myocardial infarction → neutrophils accumulation

      • infarct placenta

  • liquefactive necrosis: ‘liquefying’

    • dead brain cells (cerebral infarction: stroke)

  • caseous necrosis (cream cheese)

    • lung tuberculosis:

      • caseating granulomas

      • langham giant cells

  • fat necrosis

    • acute pancreatitis (enzymatic): yellow ‘soap’ formation due to fatty acid reacting with Ca

    • fat necrosis in breast (traumatic): macrophages eating up leaked lipids

  • fibrinoid nercrosis

    • blood vessel wall (vasculitis): muscle cells broken down & fibrin activation

Differentiation between reversible and irreversible injury

• type of injury

  • duration

  • severity

• cell type

  • state

  • adaptiability

• examples (ischemia withstand duration)

  • neurons: 5min

  • heart, liver, kidney cells: 30min-1hr

  • skin and skeletal muscles: hours

Detection of cell injury

• few min or hr after injury

  • electron microscopy

  • enzyme histochemistry

• several hrs of days

  • light microscopy

• few days to months

  • grossly visible with naked eyes

Impact of cell death

• organ loses its function

• if necrosis → inflammation

• leakage of materials into bloodstream → detectable in blood tests

• scarring after clearing up dead cells → affect organism function

• molecules leaked to bloodstream -> blood test

• dystrophic calcification → hard lumps or shows up on X-ray