Download - Apoptosis And Necrosis - Year 1
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.
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
CELLS THAT ARE EITHER (a) NO LONGER REQUIRED
OR
(b) POTENTIALLY HARMFUL TO THE BODY ARE ELIMINATED BY APOPTOSIS
CELLS THAT ARE NO LONGER REQUIRED
CELL DEATH AS A PART OF NORMAL EMBRYONIC DEVELOPMENT MANY CELLS DIE DURING EMBRYONIC
DEVELOPMENT
APOPTOSIS (PHYSIOLOGICAL CELL DEATH)
The body needs to get rid of cells
that are useless
CELL DEATH AS A PART OF NORMAL CELL DEVELOPMENT
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
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
APOPTOSIS IS USED TO GET RID OF CELLS THAT ARE POTENTIALLY HARMFUL
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
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
TRIGGERS OF APOPTOSIS
-1- DNA DAMAGE (Leads to cancer because of
mutations in oncogenes and tumour suppressor genes)
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)
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
APOPTOSIS INVOLVES AN ORDERLY
INTRACELLULAR PATHWAY
In other words,
apoptosis is not an accident, but rather a
complex genetic program for regulation of cell
destruction
APOPTOSIS INVOLVES AN ORDERED CASCADE OF INTRACELLULAR EVENTS The commonest pathway of activation of apoptosis is via activation of latent proteases (caspases)
CaspaseCysteine rich aspartate protease
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
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)
Robbins Pathological Basis of Disease 7th Edn
Robbins Pathological Basis of Disease 7th Edn
APOPTOSIS AND VIRAL INFECTIONS
EVASION OF APOPTOSIS-1 Some viruses make proteins that
inhibit apoptosis This allows viral replication to continue,
because cell survives)
APOPTOSIS ANDNEOPLASIA
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
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.
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
A MINORITY OF CANCERS RESPOND TO CHEMOTHERAPY
RESPONSIVE:LEUKAEMIAS, LYMPHOMAS, TESTICULARCARCINOMA
RESISTANT:BREAST, LUNG, BOWEL, SKIN
(ie the commonest cancers)
MORPHOLOGY OF APOPTOSIS
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
INFARCTION
NECROSIS DUE TO SUDDEN CUTTING OFF OF BLOOD SUPPLY
Typically due to obstruction of an artery eg myocardial infarction
= “heart attack”
MORPHOLOGYOF NECROSIS
Normal myocardium
Myocardial infarction
Polymorphs
Normal Renal Parenchyma
Renal infarction
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
SUMMARY-2
TWO MECHANISMS OF CELL DEATH:
NECROSIS UNEXPECTED, SEVERE INSULT, ACCOMPANIED BY INFLAMMATION
