apoptosis and necrosis year 1

APOPTOSIS&NECROSIS

Pathmanathanpathma@pc.jaring.my

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