apoptosis and necrosis - year 1

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  • APOPTOSIS&NECROSIS

    [email protected]

  • 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 THATS 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

    APOPTOSIS&NECROSISALL HUMANS ARE MORTALALL CELLS ARE MORTALSlide Number 3Slide Number 4Cancer : Unregulated Cell GrowthSlide Number 6Slide Number 7 CELLS THAT ARE NO LONGER REQUIREDAPOPTOSIS (PHYSIOLOGICAL CELL DEATH)CELL DEATH AS A PART OF NORMAL CELL DEVELOPMENTCell LifespanCELL DEATH AS A PART OF NORMAL CELL DEVELOPMENTSlide Number 13Slide Number 14PHYSIOLOGICAL CELL DEATHAPOPTOSIS IS OFTEN A DEFENCE AGAINST A THREAT TO THE BODYTRIGGERS OF APOPTOSISTRIGGERS OF APOPTOSISTRIGGERS OF APOPTOSISSlide Number 20In other words, Slide Number 22Slide Number 23PROTEASE CASCADESSlide Number 25Slide Number 26Slide Number 27Slide Number 28APOPTOSIS AND VIRAL INFECTIONSAPOPTOSIS ANDNEOPLASIAEVASION OFAPOPTOSIS -2EVASION OF APOPTOSIS -3Slide Number 33MECHANISM OF CTION OF CHEMOTHERAPYDRUGS FOR CANCER AND LEUKAEMIASlide Number 35MORPHOLOGY OF APOPTOSISSlide Number 37Slide Number 38NECROSIS(PATHOLOGICAL CELL DEATH)INFARCTIONMORPHOLOGYOF NECROSISNormal myocardiumMyocardial infarctionNormal Renal ParenchymaRenal infarctionSUMMARY-1SUMMARY-2