apoptosis and necrosis year 1
TRANSCRIPT
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ALL HUMANS ARE MORTALALL CELLS ARE MORTAL
If you inhibit a vital metabolic pathway, a cell will die. This process is pathological.
Upon appropriate stimulus (or lack of stimulation), mammalian cells are programmed to kill themselves. This normal process is known as apoptosis.
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Cancer : Unregulated Cell Growth
Autonomous/deregulated cell growth defining feature of all cancers (neoplasms)
Deregulated cell growth not necessarily due to increased cell proliferation - critical balance between
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CELLS THAT ARE EITHER (a) NO LONGER REQUIRED
OR
(b) POTENTIALLY HARMFUL TO THE BODY ARE ELIMINATED BY APOPTOSIS
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CELLS THAT ARE NO LONGER REQUIRED
CELL DEATH AS A PART OF NORMAL EMBRYONIC DEVELOPMENT MANY CELLS DIE DURING EMBRYONIC
DEVELOPMENT
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APOPTOSIS (PHYSIOLOGICAL CELL DEATH)
The body needs to get rid of cells
that are useless
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CELL DEATH AS A PART OF NORMAL CELL DEVELOPMENT
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Cell Lifespan Body cell Types
~210 types Lifespan
Born Differentiate Function Die
In humans about 5 x 1011 blood cells are eliminated by apoptosis daily
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CELL DEATH AS A PART OF NORMAL CELL DEVELOPMENT
Neutrophils 6-7 hrs circulating 4 days in tissue
Erythrocytes 120 days
Brain neuron 5-100 years
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APOPTOSIS IS USED TO GET RID OF CELLS THAT ARE POTENTIALLY HARMFUL
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PHYSIOLOGICAL CELL DEATH
The body needs to get rid of cells that are potentially harmful eg mutant cells that could become
cancerous self destruct by apoptosis (works via p53;“the guardian of the
genome”)
Auto-reactive lymphocytes die by apoptosis
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APOPTOSIS IS OFTEN A DEFENCE AGAINST A THREAT TO THE BODY
DNA DAMAGE CANCER
THREAT TO THE BODY
INCOMING FOREIGN DNA or RNA
INFECTION
APOPTOSIS
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TRIGGERS OF APOPTOSIS
-1- DNA DAMAGE (Leads to cancer because of
mutations in oncogenes and tumour suppressor genes)
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TRIGGERS OF APOPTOSIS
-2- REMOVAL OF GROWTH FACTOR OR HORMONE THAT THE CELL IS DEPENDENT ON ACTION OF KILLER T LYMPHOCYTES SPECIAL “DEATH RECEPTORS” ON THE
CELL SURFACE (eg Fas)
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TRIGGERS OF APOPTOSIS
-3- IF A VITAL METABOLIC PATHWAY IS ONLY PARTIALLY INHIBITED, A CELL WILL BECOME “STRESSED” FOR EXAMPLE, HYPOXIA
(inadequate oxygen supply) A COMMON STRESS RESPONSE IS
ACTIVATION OF APOPTOSIS THAT’S WHY THERE ARE LOTS AND
LOTS OF AGENTS THAT INDUCE APOPTOSIS
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APOPTOSIS INVOLVES AN ORDERLY
INTRACELLULAR PATHWAY
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In other words,
apoptosis is not an accident, but rather a
complex genetic program for regulation of cell
destruction
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APOPTOSIS INVOLVES AN ORDERED CASCADE OF INTRACELLULAR EVENTS The commonest pathway of activation of apoptosis is via activation of latent proteases (caspases)
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CaspaseCysteine rich aspartate protease
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PROTEASE CASCADES
A SERIES OF PROTEASES ARE PRESENT IN EITHER INACTIVE (pro-caspase) OR ACTIVE FORMS
CONVERSION TO THE ACTIVE FORM IS MEDIATED BY PROTEOLYTIC CLEAVAGE
EACH ACTIVE PROTEASE CLEAVES THE INACTIVE PROTEASE NEXT IN THE SERIES,MAKING IT ACTIVE
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Protease cascades are seen in apoptosis (caspases) and also in blood clotting and activation of
complement
They act as molecular amplifiers (a small initiating signal becomes a
large final response)
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Robbins Pathological Basis of Disease 7th Edn
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Robbins Pathological Basis of Disease 7th Edn
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APOPTOSIS AND VIRAL INFECTIONS
EVASION OF APOPTOSIS-1 Some viruses make proteins that
inhibit apoptosis This allows viral replication to continue,
because cell survives)
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APOPTOSIS ANDNEOPLASIA
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EVASION OFAPOPTOSIS -2
Some tumours are caused by suppression of apoptosis, allowing cells
that would normally die to accumulate. Oncogene bcl-2 overexpression
Follicular lymphoma
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EVASION OF APOPTOSIS -3
p53 detects DNA damage and induces apoptosis.
About half of human tumours have inactivating p53 mutations, allowing further DNA damage to persist.
Hence, tumours develop more and more mutations, going from bad to worse.
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MECHANISM OF CTION OF CHEMOTHERAPYDRUGS FOR CANCER AND LEUKAEMIA
CURRENT CONCEPT:MANY DRUGS WORK BY INDUCTION OF APOPTOSIS
REASON FOR SELECTIVE KILLINGOF NEOPLASTIC CELLS IS NOT FULLY UNDERSTOOD
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A MINORITY OF CANCERS RESPOND TO CHEMOTHERAPY
RESPONSIVE:LEUKAEMIAS, LYMPHOMAS, TESTICULARCARCINOMA
RESISTANT:BREAST, LUNG, BOWEL, SKIN
(ie the commonest cancers)
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MORPHOLOGY OF APOPTOSIS
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NECROSIS(PATHOLOGICAL CELL DEATH)
NECROSIS IS GENERALLY UNEXPECTED,AND DUE TO AN EXTREME INSULT TO CELLS, SUCH AS: SUDDEN CUTTING OFF OF BLOOD SUPPLY
(INFARCTION) EXTREMES OF HEAT, COLD, pH MANY OTHER CAUSES
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INFARCTION
NECROSIS DUE TO SUDDEN CUTTING OFF OF BLOOD SUPPLY
Typically due to obstruction of an artery eg myocardial infarction
= “heart attack”
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MORPHOLOGYOF NECROSIS
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Normal myocardium
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Myocardial infarction
Polymorphs
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Normal Renal Parenchyma
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Renal infarction
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SUMMARY-1
TWO MECHANISMS OF CELL DEATH: APOPTOSIS
PROGRAMMED PHYSIOLOGICAL NO INFLAMMATION TRIGGERED BY MINOR EVENTS
BIOLOGICAL ROLE IS TO GET RID OF CELLS THAT ARE EITHER:
(a) NO LONGER REQUIRED (b) POTENTIALLY HARMFUL
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SUMMARY-2
TWO MECHANISMS OF CELL DEATH:
NECROSIS UNEXPECTED, SEVERE INSULT, ACCOMPANIED BY INFLAMMATION