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Cell Injury Patho
1. LMP 300Y – Lecture 1
Cell injury, adaptation & death
Douglas M. Templeton, Ph.D., M.D.
doug.templeton@utoronto.ca
References
Kumar, Cotran & Robbins, Basic Pathology, 7th ed.Saunders, 2003.
Apoptosis - Nature, Oct. 12, 2000; Annu. Rev. Pharmacol. Toxicol., 42:259 (2002)
Some images from http://medlib.med.utah.edu/WebPath/webpath.html
2002/2003; revised 2005
2. Cell death -- good and bad
- good: development, T cell clones, cancer cells
- bad: tissue destruction, atrophy
Four terms:
Necrosis
Apoptosis
Necrapoptosis
Anoikis
7. “Cellular function is lost far before cell death occurs,
and the morphologic changes of cell injury (or death)
lag far behind both.”
8. "Even at the level of the light microscope, it is apparent
that cells exhibit a finite number of morphologic
reactions to a wide range of internal and external
environmental stresses."
"This … implies common biochemical and molecular
mechanisms responsible for cell adaptation and failure of
adaptation, or cell death."
9. Different cells show different sensitivities/thresholds.
Exam ples:
• Brain cells, heart cells susceptible to hypoxia and ischemia; liver cells
susceptible to chem injury
ical .
• Calf muscle tolerates 2-3 h of ischemia, cardiac muscle dies in 20-30
min.
• Highly differentiated surface epithelial cells of the respiratory tract more
susceptible to cigarette smoke than less differentiated basal epithelia.
• Nutritional status – glycogen-replete hepatocyte more resistant to
ischem than depleted one.
ia
10. • Hypoxia - Oxygen deficiency
• Ischemia - Impaired blood supply
(arterial or venous occlusion)
• Infarction - Area of necrosis due to ischemia
11. Some basic types of tissues
• Epithelium, endothelium
• Connective tissue, fibroblasts
• Muscle tissue – smooth, skeletal, cardiac
• Nervous tissue
• Blood and lymph
13. FOUR VULNERABLE SYSTEMS:
• Cell membrane integrity
• ATP generation / mitochondrial function
• Protein synthesis / enzyme function
• Genetic integrity
14. SIX GENERAL MECHANISMS:
• ATP depletion (ox/phos or glycolysis)
• Oxygen (i) – ischemia/hypoxia
• Oxygen (ii) – ROS
• Loss of Ca2+ homeostasis
• Plasma membrane integrity
• Mitochondrial damage
39. OVERVIEW
i) Atrophy
– decreased testosterone –> prostatic atrophy (apoptosis)
ii) Hypertrophy
– exercise / skeletal muscle; hypertension / cardiac myocyte
iii) Hyperplasia
– hyperthyroidism, effect of excess TSH on thyroid gland
iv) Metaplasia
– ciliated epithelium –> squamous epithelium in smoker.
(Point for argument: Is the myofibroblast a metaplastic cell?)
v) Storage
– Gaucher's disease (glucocerebrosidase),Haemochromatosis
(Fe), Fatty liver (EtOH)
40. Some terms in the histology of cell injury:
Fluid or fat accumulates in vacuoles – cloudy swelling / hydropic degeneration
e.g., disruption of ion transport/pumping (loss of ATP –> Na+/K+ ATPase,
oxidation of thiols on pumps, disorganization of membrane lipids, …)
Fat accumulation – fatty change
- fatty acid synthesizing/transporting cells (heart, liver, kidney)
- ER membrane damage, ↓FA oxid'n, ↑TG synth., ↓lipoprotein synth., …
Irreversible injury:
A cell may be irreversibly injured long before any changes are apparent in the microscope.
Coagulation necrosis – influx of water and ions, mitochondrial swelling, general loss
of membrane integrity, influx of Ca2+ (coagulation of proteins, activation of enzymes),
release of lysosomal enzymes (autolysis)
46. APOPTOSIS
Membrane blebbing, cell shrinkage, protein fragmentation, chromatin
condensation, DNA degradation, engulfment
- central role of caspases, cysteine proteases cleaving Asp-Xxx bond
- upstream (initiator) and downstream (effector) caspases
- may inactivate (e.g., lamins) or activate (e.g., nucleosomal nuclease) substrate
47. Apoptosis vs. Coagulation Necrosis
Apoptosis Necrosis
Stimulus Physiological (Developmental, Hyppoxia, Toxins
Atrophy, …)
Selected Pathological
Histology Single cells, shrinkage, chromatin Cell swelling, groups of cells,
condensation, apoptotic bodies tissue disruption
Organelles Intact Swelling of mitochondria & ER
Nucleus Chromatin condensation, inter- Disappearance,
nucleosomal breaks, laddering Random DNA breaks
(karyorrhexis) (karyolysis)
Outcome Phagocytosis of apoptotic bodies Inflammation, regeneration or
repair by fibrosis
49. Bcl-2 family members – balance between pro-apoptotic (e.g., Bax, Bak)
and anti (e.g., Bcl-2, Bcl-x) determines outcome.
Hydrophobic C-terminal domain localizes them to outer mitochondrial
membrane.
With other proteins, form channels to facilitate release of Cyt c.
Mitochondrial permeability transition pore – MPTP
50.
51.
52. Caspases are synthesized as inactive zymogen; pro-domain, p20,
and p10 domains. Activated by cleavage between p20 and p10, and pro-
domain and p20. Active as tetramer of 2 p10 and 2 p20 domains.
Three models for caspase activation.
i) caspase cascade, e.g. downstream effectors caspase-3, -6, -7
ii) induced proximity, e.g., on ligand binding CD95 receptors aggregate to form
signaling complexes, which through adapter proteins bring about high local
concentrations of procaspase-8
iii) association with a regulatory subunit, e.g., caspase-9 and Apaf-1
53.
54. DNA damage can initiate apoptosis.
Dual function of p53:
If damage detected, cell cycle arrest.
If damage not repaired, iniates apoptosis.
How is damage sensed? Proteins of the ATM (ataxia telangiectasia-
mutated) and DNA-PK contain DNA binding domains and protein
kinase activity. Both phosphorylate p53.
55. Signals for ingestion:
i) altered sugars recognized by lectins on macrophages
ii) Thrombospondin – secreted by macrophages, binds to
apoptotic cells (mechanism not known), then macrophage
integrins bind to thrombospondin.
iii) phosphatidyl serine (annexin V)
56. Apoptosis can be suppressed
• at the level of caspases
• at the level of the mitochondria
• by ionic control
57. QuickTime™ and a
GIF decompressor
are needed to see this picture.
58.
59.
60. Necrapoptosis – Lemasters, Am. J. Physiol. 276: G1-G6 (1999).
Cell balanced between apoptosis and necrosis depending on
production of ATP.
Anoikis – Frisch & Ruoslahti, Current Opin. Cell Biol. 9: 701-706 (1997).
"Homelessness". Apoptosis initiated by detachment of epithelial cell
from matrix.
