General Pathology - II Cell Death Jaroslava Dušková Inst. Pathol.,1st Med. Faculty, Charles Univ....
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Transcript of General Pathology - II Cell Death Jaroslava Dušková Inst. Pathol.,1st Med. Faculty, Charles Univ....
General Pathology - II
Cell
Death
Jaroslava Dušková
Inst. Pathol. ,1st Med. Faculty, Charles Univ. Prague
http://www1.lf1.cuni.cz/~jdusk/
Deathirreversible damage of the
morphological & functional integrity of
organism cells
Cell Death
apoptosis necrosis
Apoptosis induced (from outside) or genetically programmed cell
death
(cell execution / suicide)
logical and functional contrary to mitosis a system for the removal of unnecessary,
aged, or damaged cells
Necrosis
cell death caused from external insult
ApoptosisBiochemistry
– expression of genes de novo– production of apoptosis related proteins
inductors of the cell death p53, MTS1 - Multiple Tumor Suppressor, c-myc, Fas
inhibitors of the cell death bcl-2,
– activation of endonucleases– fragmentation of DNA – polymerisation of actin
• Triggered by a wide range of stimuli.
• Cell surface receptors like Fas or
tumor necrosis factor receptor 1 (TNFR1).
• Interplay of proapoptotic (Bax, Bad, Bid, Bik,
and Bim) and antiapoptotic (Bcl-2 and Bcl-XL)
proteins
Apoptosis -1
http://www.sigmaaldrich.com
Oxidative Damage -1
• Endogenous production of reactive oxygen by mitochondria.
• Increased permeability transition (PT) in the mitochondrial membrane
Oxidative damage -2
Apoptogenic factors leak into the cytoplasm
cytochrome c and apo - inducing factor (AIF) a cascade of proteolytic
activity DNA
fragmentation mutations cell death.
Mitochondria in ApoptosisOxidative damage - 3
Bcl-2 and Bcl-X –prevent pore formation
–block the release of cytochrome c from the mitochondria
– prevent activation of the caspase cascade and apoptosis.
Caspase Cascade -1
Caspases - a class of cysteine
proteases involved in apoptosis.
A proteolytic cascade activates
enzymes that subsequently
degrade cellular targets.
Caspase Cascade - 2
The mitochondrial stress pathway - release of cytochrome c from mitochondria
Granzyme B and perforin (proteins
released by cytotoxic T cells) induce apoptosis in target cells by forming transmembrane pores
Caspase Cascade - 3
Caspase-activated DNAse (CAD) may be activated through the cleavage of its associated inhibitor ICAD. CAD is then able to interact with components such as topoisomerase II (Topo II) to condense chromatin and lead to DNA fragmentation.
Granzyme B forming transmembrane pores cleavage of effector caspases such as
caspase-3 In addition, caspase-independent
mechanisms of granzyme B-mediated apoptosis have been suggested.
Caspase-activated DNAse (CAD) is activated through the cleavage of its associated inhibitor ICAD by caspase-3.
CAD interacts with topoisomerase II (Topo II) to condense chromatin– DNA fragmentation and ultimately
apoptosis.
Fas Signaling Pathway
Fas/APO-1/CD95 is a member of the tumor necrosis factor (TNF) receptor superfamily– mediator of apoptotic cell death, – involved in inflammation.
Binding of the Fas ligand (Fas-L) induces trimerization of Fas in the target cell membrane.
Activation of Fas causes the recruitment of Fas-associated protein with death domain (FADD)
activation of caspase-8. Activated caspase-8 cleaves (activates) nine
other pro-caspases a caspase cascade leads to apoptosis.
TNF Signaling Pathway -1 TNF receptor (TNFR)
transduces growth regulatory signals into the cell.
TNF is mitogenic for normal cells
TNF initiates apoptosis in transformed cells causing DNA fragmentation and cytolysis.
TNF Signaling Pathway - 2 The TNF-induced cell survival
pathway is mediated by the transcription factor NF-kB.
cells in which the NF-kB signaling pathway is blocked are more likely to undergo apoptosis in response to TNF.
The availability of NF-kB may play a critical role in the ability of TNF to act as an apoptosis-inducer and anti-tumor agent.
ATM/p53 Signaling Pathway
The ataxia telangiectasia-mutated gene (ATM) encodes a protein kinase that acts as a tumor suppressor.
ATM activation stimulates DNA repair and blocks cell cycle progression.
ATM-dependent phosphorylation of p53 p53 can cause growth arrest of the cell
at a checkpoint to allow for DNA damage repair or can cause the cell to undergo apoptosis if the damage cannot be repaired.
p53 is mutated in over 50% of all human cancers.
Integrin Signaling in Cell Survival and Death Integrins are heterodimeric
transmembrane receptors composed of a- and b-subunits.
Approximately 20 integrins have been identified
Focal adhesion kinase (FAK) is activated via autophosphorylation when cells interact through integrins.
Depending on the integrin interactions, the cell can either survive or undergo apoptosis.
Caspase Activation Intristic Pathway -1
Cytochrome c release from the mitochondria of pre-apoptotic cells
Binding to Apaf-1 in the presence of dATP/ATP.
Conformational change in Apaf-1 allowing the molecules of Apaf-1 to associate with each other.
Caspase Activation Intristic Pathway - 2
A wheel-like structure that contains 7 molecules each of Apaf-1, cytochrome c and ATP.
Pro-Caspase-9 autoactivation Mature caspase-9 remains bound
to the apoptosome
Activation of executioner caspases such as caspase-3 and caspase-7.
ApoptosisMorphology
– chromatin condensation
– cell shrinkage– budding and forming of apoptotic bodies
(emission of pseudopodia)
– karyorrhexis (not pathognomonic for apoptosis)
ApoptosisMeaning
physiological process necessary for right organ formatting and life course
pathological process leading to organism damage - e.g. atrophy
ApoptosisOntogenesis
intestinal mucose, genit. tract, immune system - T lymphocytes
Tissue & organ structures turnover intestinal mucose, blood, endometrium
Physiological involution neonatal adrenal cortex, thymus, breast after lactation period
Atrophy preassure, hyperplasia regression, slight ischemia
ApoptosisDetection
TUNEL = Terminal deoxynukleotidyl transferase-
mediated dUTP Nick End Labeling
silver methenamin impregnation
NecrosisBiochemistry
– no expression of genes de novo– energy dependent membrane
systems damaged hypoxia, toxins
– changes in concentrations of ions– increased water volume (oncosis)
– autolysis
NecrosisMorphology
– pyknosis, karyorhexis, karyolysis
– denaturation of proteins - eosinophilia
– cell swelling– cell budding (cytoplasmic protrusions)
NecrosisMeaning
pathological process
leading to a temporary
organism damage or death
Necrosis Classification according to the tissue macroscopy:
– simple– liquefaction– coagulation
+ special types: caseation, Zenker´s of waxy appearance
Necrosis - further development:
– no death of organism
– gangrene sicca humida emphysematosa (gas
g.)– demarcation, sequestration
regeneration repair
Necrosis - Causes:
chemical– chlorinated hydrocarbons, heavy metal
compounds, ethyl- alcohol, aphlatoxins, ... physical
– mechanical trauma, UV light, ionizing radiation, heat, cold, ….
biologic– bacteria, viruses, fungi...
Atrophy diminution of organ or tissue after full development has been attained (versus hypoplasia, aplasia) simple (x hypertrophy) numerical (x hyperplasia)
Atrophy - causes:
vascular pressure inactivity inanition neurogenic ionizing radiation
involution senile postinflammatory endocrine
unknown cause
Atrophy - meaning:
may be reversible loss of specialised structures
& hypofunctionclinically silent or unimportant
(involution)clinically apparent
metaplasia, increase of the supportive tissues - pseudohypertrophy