Cell etiology : Cell death and Apoptosis.pptx

Cell Death Events and Apoptosis
Presented by : Priti Sah
M. Pharm (Pharmacology)
Guided by : Dr. Rishikesh S. Bachhav
From R. G. Sapkal college of pharmacy

 Introduction
 Types of cell death
 Apoptosis
 Apoptosis in physiology situation
 Apoptosis in pathological conditions
 Morphological features of apoptosis
 Mechanism of apoptosis
 Extrinsic pathway
 Intrinsic pathway
Content

 Cell death or loss of cell viability can be regarded as an irreversible failure
of vital cellular functions coupled with irreparable structural damage.
 Cell death can be induced by a variety of physiological or non
physiological conditions, such as ischemia, hypoxia, exposure to certain
drugs and chemicals, immune reactions, infectious agents, high
temperature, radiation, and various disease states.
 The biological and medical implications of cell death are becoming
increasingly evident as more information is learned concerning these
processes.
Introduction

 The major types of cell death are
1. Apoptosis (genetically programmed suicide),
2. Autophagy (housekeeping role),
3. Necrosis (unprogrammed trauma-induced death), and
4. Necroptosis (programmed necrosis).
Types of cell death :

 Apoptosis : A regulated process that eliminates damaged cells by
dismantling the entire cell within the cell unity.
 Autophagy : A cellular process that regulates almost all modes of
cell death in disease contexts.
 Necrosis : It is defined as a localised area of death of tissue followed
by degradation of tissue by hydrolytic enzymes liberated from dead
cells; it is invariably accompanied by inflammatory reaction.
 Necroptosis : A regulated cell death pathway that can be initiated in
response to cellular stress, damage, or infection.

 It is a Greek word which meaning ‘falling off’ or ‘dropping off’ which
was first introduced in 1972.
 It occurs normally in many situations and serves to eliminate unwanted or
potentially harmful cells and cells that have outlived their usefulness.
 Apoptosis is a pathway of cell death that is induced by a tightly regulated
intracellular program in which cells destined to die activate enzyme that
degrade the cells own nuclear DNA and cytoplasmic proteins.
 Cell plasma membrane remains intact , but it’s structure is altered in such
a way that the apoptotic cell becomes an avid target for phagocytosis.
Apoptosis

1. Programmed destruction of cell during embryogenesis, including implantation,
organogenesis, developmental involution, and metamorphosis.
2. Hormone-dependent involution in the adult , such as breakdown of endometrial
cell during menstrual cycle, ovarian follicular atresia in menopause.
3. Cell deletion in proliferating cell populations, such as intestinal crypt epithelia, in
order to maintain a constant number.
4. Death of host cells that have served their useful purpose, such as neutrophils in an
acute inflammatory response & lymphocytes as immune response.
5. Cell death induced by cytotoxic T cells, a defence mechanism against viruses and
tumours that serves to eliminate virus infected and neoplastic cells.
Apoptosis in physiological situations:

 Cell death in tumours exposed to chemotherapeutic agents.
 Cell death by cytotoxic T cells in immune mechanisms such as in graft-
versus-host disease and rejection reactions.
 Progressive depletion of CD4+T cells in the pathogenesis of AIDS.
 Cell death in viral infections e.g. Formation of councilman bodies in viral
hepatitis.
Apoptosis in pathologic conditions :

Pathologic atrophy of organs and tissues on withdrawal of
stimuli e.g. Prostatic atrophy after orchiectomy, atrophy of
kidney or salivary gland on obstruction of ureter or ducts,
respectively.
• Cell death in response to injurious agents involved in
causation of necrosis e.g. Radiation, hypoxia and mild
thermal injury.
• In degenerative diseases of CNS e.g. In Alzheimer’s disease,
Parkinson’s disease, and chronic infective dementias.
• Heart diseases e.g. Heart failure, acute myocardial infarction
(20% necrosis and 80% apoptosis).

The characteristic morphologic changes in apoptosis seen in histologic and
electron microscopic examination are as under
 Involvement of single cells or small clusters of cells in the background of
viable cells.
 The apoptotic cells are round to oval shrunken masses of intensely
Eosinophilic cytoplasm (mummified cell) containing shrunken or almost-
normal organelle .
 The nuclear chromatin is condensed or fragmented (Pyknosis or
Karyorrehexis).
 The cell membrane may show convolutions or projections on the surface.
Morphological features of apoptosis :

 There may be formation of membrane-bound near spherical
bodies on or around the cell called apoptotic bodies containing
compacted organelles.
 Characteristically, unlike necrosis, there is no acute
inflammatory reaction around apoptosis.
 Phagocytosis of apoptotic bodies by macrophages takes place
at varying speed. There may be swift phagocytosis, or loosely
floating apoptotic cells after losing contact, with each other and
basement membrane as single cells, or may result in major cell
loss in the tissue without significant change in the overall
tissue structure.

There are two main routes of cell death,
1. Death receptor pathway (extrinsic pathway) : stimulation of death
receptor by external ligands, and
2. Mitochondrial pathway (intrinsic pathway) : arising within the
cell and involving the mitochondria.
Both the routes activate initiator caspases and both converges on a final
common effector caspase pathway.
Mechanism of apoptosis :

 Apoptosis induced by these pathways is initiated by the activation of
transmembrane receptors, known as death receptors, by death ligands.
 Death receptors are present on the cell surface are the members of the tumour
necrosis factor receptor (TNF receptor) family that contain a cytoplasmic domain
involved in protein – protein interactions that is called the death domain &it is
essential for delivering apoptic signal.
 Best know death receptors are the Type I TNF receptor (TNFR 1) & a related
protein called Fas (CD95).
 When Fas is cross linked by its ligand, membrane bound Fas ligand (FasL).
 Three or more molecules of Fas come together and their cytoplasmic death
domains from a binding site for an adapter protein that also contains a death
domain and is called FADD (Fas associated death domain).
Extrinsic pathway or Death receptor pathway:

 FADD that is attached to the death receptor in turn binds an inactive
form of caspase 8 ( in human caspase 10) again via a death domain.
 Multiple Pro Caspase 8 molecule are thus brought into proximity and
they cleave one another to generate active caspase 8.
 Enzyme triggers cascade of caspase activation by cleaving and
activating other Pro caspase and the active enzyme mediate the
execution phase of apoptosis.
 This pathway of apoptosis can be inhibited by a protein called FLIP
which binds to Pro caspase but cannot cleave or activate the enzyme
because it lacks enzymatic activity.

 The intrinsic pathway is also known as the mitochondrial pathway.
 Increase in mitochondrial permeability results to release of Pro-apoptotic
molecule into the cytoplasm.
 Growth factors and other survival signals stimulate the production of anti
apoptotic members Bcl-2 family of protein (Bcl-2 is an oncogene in B cell
lymphoma).
 More than 20 proteins of this family which functions and regulate
apoptosis. Bcl-2 & Bcl-x are the two main anti apoptotic protein molecule
which mainly reside in mitochondrial membrane and the cytoplasm.
Intrinsic pathway :

 When cells are deprived of survival signals or subjected to stress, Bcl-2
or Bcl-x are lost from mitochondrial membrane and are replaced by pro
apoptotic members of family such as Bak, Bax and Bim.
 When the Bcl-2 or Bcl-x level decreases permeability of mitochondrial
membrane increases cytochrome C that can activate caspase cascade leak
out.
 In cytosol cytochrome C binds to a protein called Apaf-1 ( Apoptosis
activating factor 1) and the complex activates caspase 9.
 Apoptosis may be initiated by caspase activation upstream of
mitochondrial & the subsequent increase in mitochondrial permeability
and release of Pro-apoptotic molecule amplify the death signal.

 The intrinsic and extrinsic pathways are distinct in terms of how they
induce apoptosis, but they both end at the execution phase.
 This phase of apoptosis is initiated by the activation of the execution
caspases. These caspases (caspases-3, -6, -7) activate cytoplasmic
endonucleases. Which degrade nuclear material, and proteases that break
down nuclear and cytoskeletal proteins.
 The stereotypical, morphological, and biochemical changes observed
during apoptosis are caused by degradation of substrates such as
cytokeratins, PARP, the nuclear protein NuMA, the plasma membrane
cytoskeletal protein alpha fodrin, and others.
Execution pathway :

Considered the most important executioner caspase, caspase-3 can be
activated by any of the initiator caspases, such as caspase-8, -9, and-10.
The inhibitor of endonuclease CAD, ICAD, is cleaved by caspase-3. Active
CAD then degrades chromosomal DNA in the nucleus and induces
chromatin condensation.
 Caspase-3 also plays a role in the reorganization and breakdown of the
cell into apoptotic bodies.

1. Stanley L. Robbin, Ramzi S. Cotran, “Pathologic basis of disease “,
published by Elsevier India Private Limited, 7th
edition (2008) , page
no. 26-27.
2. James M. Ritter, Rod Flower, Graeme Henderson, Yoon Kang Loke,
David Macewan, Humphrey D. Rang, “Rang and Dale’s
Pharmacology ”, published by Elsevier churchill stone, 9th
edition
(2020), page no. 86-88.
3. Harsh Mohan, “Textbook of Pathology”, published by Jaypee brothers
Medical publishers (P) LTD, 6th
edition (2016), Page no. 44-49.
Reference’s

Cell etiology : Cell death and Apoptosis.pptx

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