EXTRINSIC PATHWAY OF APOPTOSIS
Presented by
KRUPASAGAR P N
1st year M pharm
Dept of Pharmacology
NCP Shivamogga
ACTIVATION OF APOPTOSIS FROM OUTSIDE THE
CELL(EXTRINSIC PATHWAY)
The signal will be given from out side the cell means by extracellularly.
It is divided into two pathways based on signalling molecule and the
receptors,
i. TNF pathway (tumour necrosis factor)
ii. FAS pathway (first apoptosis signalling)
In the TNF path the extracellular apoptotic signaling molecule is TNF-α which
is cell signaling protein cytokine produced by activated macrophages.
It is the major extrinsic mediator of apoptosis.
Most cells in the human body have two receptors for TNF-alpha:
A. TNFR1
B. TNFR2
TNF pathway
Fas path
The Fas receptor(also known as Apo-1) is a transmembrane protein of the TNF family
which binds the Fas ligand(FasL).
The interaction between Fas and FasL results in the formation of the death inducing
signaling complex(DISC), which contains the FADD, caspase-8 and caspase-10.
FAS pathway
NECROSIS
Necrosis is defined as localized area of cell death followed by
degradation of tissue by hydrolytic enzyme liberated from
dead cell.
Necrosis caused by various agents such as hypoxia, physical
agents, chemical and microbiological agent and
immunological injury.
MORPHOLOGY
Increase eosinophilia
Myelin figures
Membrane disintegration
Internal organelle swelling
Nuclear changes
TYPES OF NECROSIS
i. Coagulative necrosis
ii. Colligative / liquefactive necrosis
iii. Caseous necrosis
iv. Fat necrosis
v. Fibrinoid necrosis
COAGULATIVE NECROSIS
This is a most common type of necrosis caused by
irreversible focal injury.
They may be preserved for few days.
It happen in ischemia except in CNS.
Commonly affected organs are heart, kidney, spleen
LIQUEFACTIVE NECROSIS
It is also occur commonly due to ischaemic injury and
bacterial or fungal infection but hydrolytic enzyme in
tissue degradation have dominant role in causing semi
fluid material. The common example are infract brain
and abscess cavity.
Caseous necrosis
It is found in centre of foci of tuberculous infection. It
combines features of both coagulative and liquefactive.
It looks like structure less mass fragment in
microscopically.
Also has amorphous granules debris enclosed with in
distinct inflammatory border.
FAT NECROSIS
It is a special type of cell death occurring at mainly fat rich
anatomic location in body.
Occurs due to leakage of lipase in pancreases to peritoneal
cavity.
Eg:- traumatic fat necrosis of the breast especially in heavy
and pendulous breast.
FIBRINOID NECROSIS
The deposition of fibrin like material which has staining
properties of fibrin such as phosphotungstic acid.
Haematoxylin (PTAH) stain. It is encountered in various
immunologic tissue injury, arterioles in hypertension,
peptic ulcer.
Eg; antibody-antigen complex deposit in wall of arteries
and combine with fibrin they create fibrinoid.
AUTOPHAGY
DEFINITION:
Auto means self, Phage means eating (self- degradative process)
Autophagy is a normal physiological process in the body that deals with the
destruction of cell in the body. It maintains homeostasis or normal functioning by
protein degradation turnover of the destroyed cell organelles for new cell formation.
During cellular stress the process of autophagy is up scaled and increased.
HISTORY
First time observed by keith R. Porter and his student thomas ashford at the
Rockefeller institute in 1962 soon after the discovery of rat liver.
They called this autolysis after Christian de Duve and Alex B. Novikoff
6426 article were published about from 2007 to 2012.
MECHANISM OF ACTION OF AUTOPHAGY
Induction of autophagy and phagophore formation.
Autophagopore elongation and formation.
Fusion, degradation and recycling.
MECHANISM OF ACTION OF AUTOPHAGY
Types of autophagy
i. Micro-autophagy
ii. Macro autophagy
iii. Chaperone mediated autophagy
Types of autophagy
i. Micro-autophagy
ii. Macro autophagy
iii. Chaperone mediated autophagy
Micro-autophagy
Microautophagy involves the engulfment of cytoplasmic cargo into the
lysosome through invagination of the lysosomal membrane.
Microautophagy is important in the maintainance of organellar size.
Macro autophagy
Macroautophagy is a process in which cells form double-membrane vesicles, called
autophagosomes, around a portion of cytoplasm.
These autophagosomes ultimately fuse with lysosomes, resulting in degradation of their
contents.
Chaperone mediated autophagy
Chaperone-mediated autophagy (CMA) refers to the Chaperone-dependent
selection of soluble cytosolic proteins that are then targeted to lysosomes and
directly translocated across the lysosome membrane for degradation.
The unique features of this type of autophagy are the selectively on the proteins
that are degraded by this pathway and the direct shutting of these proteins across
the lysosomal membrane without the requirement for the formation of additional
vesicles.
PROBLEMS IN AUTOPHAGY
Degradative disorders
Metabolic syndromes
Aging
Infection disease
Self immune problems
Diabetes
Cardiomyopathy
Cancer
QUESTIONS
1. Explain the various pathways of apoptosis. Write the differences between apoptosis
and necrosis. [DEC -2017]
2. Explain the intrinsic and extrinsic pathway of apoptosis. [NOV-2021].
