CELLULAR RESPONSES TO STRESS AND TOXIC INSULTS: ADAPTATION, INJURY AND

DEATH

BY: DR. JYOTIRMAYEE DASH

 CELL PROLIFERATION AND CELL CYCLE

• Cell proliferation is maintenance of steady-state tissue

homeostasis, and replacement of dead and damaged cells.
• The key elements are:-
a) Accurate DNA replication accompanied by coordinated
synthesis of all cellular components
b) Equal apportionment of DNA and other cellular constituents
to daughter cells by Mitosis and Cytokinesis.
 CELL CYCLE

• Cell cycle consists of :-

1. G1 (pre-synthetic growth) phase
2. S (synthesis) phase
3. G2 (pre-mitotic growth) phase
4. M (mitotic) phase
• Cell cycle is regulated by activators and inhibitors.
• It is driven by proteins called Cyclins and Cyclin-associated
enzymes called Cyclin dependent kinases.
• More than 15 cyclins have been identified:-- Cyclin D, E, A,
and B appear sequentially during the cell cycle and bind to
more than one CDKs.
• CDKs bind with the appropriate cyclin and forms a
complex which phosphorylates protein substrates.
• Checkpoints in cell cycle:-
a) G1-S checkpoint- monitors the integrity of DNA before
irreversibly committing cellular resources to DNA
replication.
b) G2-M checkpoint- ensures there has been accurate
genetic replication before cells actually divides.
• If the genetic derangement is too severe to be repaired,
the cell undergoes APOPTOSIS or may enter a non-
replicative state called SENESCENCE.
• Enforcing the cell cycle checkpoints is ensured by CDK
Inhibitors(CDKIs).
• Various CDKIs are:-
a) One family composed of three proteins called p21
(CDKN1A), p27 (CDKN1B) and p57 (CDKN1C)- inhibits
multiple CDKs.
b) Selective CDKIs (effects only on Cyclin CDK4 and Cyclin
CDK6)- p15 (CDKN2B), p16 (CDKN2A), p18 (CDKN2C) and
p19 (CDKN2D).
 STEM CELLS

• Stem cells are the cells that gives rise to various differentiated
tissues, replaces damaged cells and maintain tissue populations.
• 2 important properties:-
1. Self-renewal
2. Asymmetric division
• There are two varieties:-
a) Embryonic stem cells- limitless self-renewal capacity
Gives rise to every cell in the body, so they are called as Totipotent.
Can form specialized cells of all the three germ layers, including
neurons, cardiac muscle, liver cells, and pancreatic islet cells.
b) Tissue stem cells/ Adult stem cells:-
Normally protected within specialized tissue microenvironments
called Stem cell niches.
Can produce cells of only one type, specific to the individual tissue.
c) Mesenchymal stem cells:-
Present in bone marrow
These are multipotent cells that can differentiate into a variety of
stromal cells- like chondrocytes, osteocytes, adipocytes, and
myocytes.
 CELLULAR RESPONSE TO STRESS AND
NOXIOUS STIMULI

• Homeostasis- Ability of a cell to handle the physiologic

demands, maintaining a steady state is called as
homeostasis.
• Adaptation- the reversible functional and structural
responses to changes in physiologic states (e.g;
pregnancy) and some pathologic stimuli, allowing a cell to
survive and continue function is known as adaptation.
• Hypertrophy- increase in size of cells.
• Hyperplasia- increase in number of cells.
• Atrophy- decrease in size and metabolic activity of
cells.
• Metaplasia- change in the phenotype of the cells.
• Cell injury- if A) the limits of adaptive responses are exceeded/ if B)
cells are exposed to injurious agents and stress,
C) deprived of essential nutrients,
D) or become compromised by mutations that affect essential
cellular constituents, a sequence of events follow know as cell injury.
• If the stimulus persists or is severe the cell undergoes irreversible
injury and ultimately undergoes cell death.
• There are two principal pathways of cell death:-
1. Apoptosis
2. Necrosis
Nutrient deprivation triggers an adaptive response called
Autophagy.
 ADAPTATIONS OF CELLULAR GROWTH
• Adaptations are reversible.
• Changes constitutes of change in size, number, phenotype,
metabolic activity, or functions of cells.
• E.g., HYPERTROPHY
HYPERPLASIA
ATROPHY
METAPLASIA
 HYPERTROPHY

• Definition:- Increase in the size of cells, resulting in the

increase in the organ size.
• E.g; myocardial fibers, uterus in pregnancy
• Hypertrophy can be Physiological/ Pathological.
• Physiological is due to increased functional demand or by
stimulation by hormones and growth factors.
• MECHANISM:- It is the result of increased production of cellular
proteins.
• Three basic steps in molecular pathogenesis of cardiac hypertrophy:-
1) The integrated action of mechanical sensors, growth factors and
vasoactive agents.
2) Activation of a complex web of signal transduction pathways; like
PHOSPHOINOSITIDE 3-KINASE/AKT pathway and signaling
downstream of G-PROTEIN COUPLED RECEPTORS.
3) Activation of set of transcription factors( GATA4, Nuclear factor of
activated T cells[NAFT]), and Myocyte enhancer factor2(MEF2).
• Hypertrophy is also associated with a switch of contractile proteins
from adult to fetal or neonatal forms.
 HYPERPLA
SIA

• DEFINITION:- Increase in the number of cells in an

organ or tissue in response to a stimulus.
• It can be physiological or pathological.
• Occurs in cells that capable of dividing.
 PHYSIOLOGICAL
HYPERPLASIA
• Due to the action of hormones/ growth factors.
• When there is a need to increase functional capacity of
hormone sensitive organ.
• When there is need for compensatory increase after
damage or resection.
• E.g; breast during puberty , uterus in pregnancy
(hyperplasia followed by hypertrophy), marrow undergoes
rapid hyperplasia in response to a deficiency of terminally
differentiated blood cells.
 PATHOLOGICAL
HYPERPLASIA
• Caused by excessive or inappropriate actions of hormones or
growth factors acting on target cells.
• E.g; Endometrial hyperplasia (abnormal hormone induced
hyperplasia), Benign prostatic hyperplasia.
• Pathological hyperplasia can lead to cancerous proliferations,
like endometrial hyperplasia patients have a high risk of
developing endometrial carcinoma.
• Also seen in certain viral infections, such as papillomaviruses
which causes skin warts and several mucosal lesions.
• MECHANISM OF HPERPLASIA:-

It is the result of growth factor- driven proliferation of mature cells

and, in some cases, by increased output of new cells from tissue
stem cells.
 ATROP
HY
• DEFINITION:- Reduction in the size of an organ or tissue due to a decrease in
cell size and number.
• It can be physiologic or pathologic.
• Physiologic atrophy is common during normal development,
E.g; notochord, thyroglossal duct and decrease in size of the uterus shortly
after parturition.
• Pathologic atrophy has several causes:-
1) Decreased workload (disuse atrophy)
e.g; skeletal muscle atrophy in fracture cast immobilised patient.
2) Loss of innervation (denervation atrophy)
e.g; damage to the nerves lead to atrophy of the muscles
3) Diminished blood supply
e.g; Senile atrophy (reduced blood supply due to atherosclerosis) in
brain and heart.
4) Inadequate nutrition
e.g; PEM (Marasmus)
5) Loss of endocrine stimulation
e.g; loss of estrogen stimulation after menopause results in
physiological atrophy of the endometrium, vaginal epithelium and
breast.
6) Pressure
e.g; SOLs in brain can cause atrophy of the uninvolved surrounding
tissue.
MECHANISM OF ATROPHY:-
• It occurs due to decreased protein synthesis and increased protein
degradation in cells.
• The degradation of cellular proteins occur by the UBIQUITIN-
PROTEOSOME PATHWAY.
• Atrophy is sometimes accompanied by AUTOPHAGY.
• AUTOPHAGY means self eating, e.g: production of vacuolated
membrane bound vacuoles/residual bodies like LIPOFUSCIN
granules.
• Lipofuscin impart a brown discoloration to the tissue known as
BROWN atrophy.
 METAPLASIA

DEFINITION:- It is a reversible change in which one differentiated cell

type (epithelial or mesenchymal) replaced by another cell type.
E.g; 1) Epithelial metaplasia- columnar to squamous in respiratory
tract in response to chronic irritation (habitual smokers)
Salivary gland, pancrease and bile duct undergoes squamous
metaplasia from secretory columnar epithelium to stratified
squamous epithelium due to stones.
Vitamin A deficiency causes squamous metaplasia in respiratory
epithelium.
• Epithelial metaplasia is a “DOUBLE-EDGED SWORD”.
• METAPLASIA from SQUAMOUS to COLUMNAR occurs in
case of BARRET’S esophagus.
• 2) Connective tissue metaplasia/ Mesenchymal
metaplasia- there is formation of cartilage, bone, or
adipose tissue in the tissues that normally do not contain
these elements.
MECHANISM OF METAPLASIA

• It is the result of a reprogramming of stem cells that are

known to exist in normal tissues, or of undifferentiated
mesenchymal cells present in connective tissue.
 CELL
INJURY
Reversible cell injury-
 In this type of injury, if the stimulus is removed in the early
stages/mild forms of injury, then the morphological and fuctional
damages can be reversed.
 HALLMARKS of reversible injury:-
a) Reduced oxidative phosphorylation
b) Depletion of energy stores in the form of ATP, and
c) Cellular swelling due to changes in the ion concentrations and
water influx.
• Two features of reversible cell injury:-
1. Cellular swelling- result of failure of energy dependent ion pumps in
the plasma membrane.
2. Fatty change- occurs due to hypoxia, toxic or metabolic injury, which
is manifested by appearance of lipid vacuoles in the cytoplasm.
• Fatty change occurs in tissues that contain fat like- hepatocytes and
myocardial cells.
 MORPHOLOGY OF THE CELLS IN REVERSIBLE CELL INJURY

• Cellular swelling:-
Microscopic features->
 small clear vacuoles within the cytoplasm called as hydropic change/
vacuolar degeneration.
 Cells show increased eosinophilic staining.
 Ultrastructural changes of reversible cell injury are:-
1. Plasma membrane alterations
2. Mitochondrial changes
3. Dilation of ER
4. Nuclear alterations
MORPHOLOGIC ALTERATIONS IN
CELL INJURY
E.g:- Myocardial cells become non contractile after 1 to 2 minutes
of ischemia

Morphological alteration in cell death appears in electron

microscopy after 1-2 hrs

Then the changes appear on light microscopy after of 6-12 hrs

of ischemia
 CAUSES OF CELL
INJURY
1. Oxygen deprivation
2. Physical agents
3. Chemical agents and drugs
4. Infectious agents
5. Immunologic reactions
6. Genetic derangements
7. Nutritional imbalances
8. Aging
Cell death-
 With continuing damage the injury becomes irreversible, the cell cannot
recover and dies.
 Two types of cell death:- NECROSIS and APOPTOSIS.

1. NECROSIS-
Results from the damage to cell membranes and loss of ion homeostasis.
Elicit host reaction leads to inflammation.
Accidental and unregulated cell death.
E.g; ischaemia, exposure to toxins, various infections, and trauma.
2. APOPTOSIS-
When the cell’s DNA or proteins are damaged beyond repair the cell kills
itself.
Characterised by Nuclear dissolution, Fragmentation of the cell without
complete loss of membrane integrity, and rapid removal of the cellular
debris.
No inflammatory reaction is seen.
It is driven by a series of genetic pathways, so known as “PROGRAMMED
CELL DEATH”.
 When necrosis, like apoptosis occurs as a programmed cell death it is
called as NECROPTOSIS.
 NECROSIS

• The morphologic appearance of necrosis as well as necroptosis

is the result of denaturation of intercellular proteins and
enzymatic digestion of the lethally injured cell.
• Necrotic cells are unable to maintain their membrane integrity
and their contents often leak out leading to inflammation.
• Digestion of the cellular contents and host response takes
hours to develop.
E.g; the earliest histologic evidence of myocardial necrosis
doesn’t become evident before 4-12 hrs.
 MORPHOLOGY OF NECROSIS
• In H&E stain necrotic cells shows increased eosinophilia.
• Have a glassy homogenous appearance.
• Cytoplasm becomes vacuolated and appears MOTH EATEN.
• Dead cells may be replaced by large, whorled phospholipid masses
called MYELIN figures.
• Calcification/ Calcium soaps may be seen.
• In electron microscopy, necrotic cells characterized by discontinuities in
plasma and organelles.
• Nuclear changes:-
1. KARYOLYSIS
2. PYKNOSIS
3. KARYORRHEXIS followed by total disappearance of nucleus.
 PATTERNS/TYPES OF TISSUE NECROSIS:-

1. COAGULATIVE NECROSIS-
 The architecture of the dead tissues preserved for some days
 Eosinophilic, anucleate cells may persist for days to weeks.
 Ischemia due to obstruction of vessels leads to this type of
necrosis, except BRAIN.
 A localised area of coagulative necrosis is called as an INFARCT.
2. LIQUEFACTIVE NECROSIS-
 Digestion of the dead cells resulting in transformation of
the tissue into a liquid viscous mass.
 Seen in focal bacterial / fungal infections.
 The necrotic material is creamy yellow because of the
presence of dead leukocytes and is called PUS.
 Seen in CNS, i.e; BRAIN.
3. GANGRENOUS NECROSIS-
 Not a specific pattern of cell death.
 Applied to a limb, generally lower limb that has lost its
blood supply and has undergone coagulative necrosis
involving multiple planes.
 On superadded bacterial infection, there is action of
degradative enzymes and the attracted leucocytes that
cause liquefactive necrosis giving rise to WET GANGRENE.
4. CASEOUS NECROSIS-
 Seen in the foci of tuberculous infection.
 The area of necrosis appears friable and white, so called as
CASEOUS/ CHESSE-LIKE.
 The necrotic area is a collection of fragmented and
amorphous granular debris enclosed within a inflammatory
border; this is called as a GRANULOMA.
5. FAT NECROSIS-
 Refers to focal areas of fat destruction, typically due to release
of pancreatic lipases into the substance of pancreas and
peritoneum.
 Leads to a abdominal emergency called as acute pancreatitis.
 The fatty acid combines with calcium to produce visible chalky
white areas ( FAT SAPONIFICATION).
 So there is foci of shadowy outlines of necrotic fat cells+
basophilic calcium deposits+ surrounding inflammatory
reaction.
6. FIBRINOID NECROSIS-
 It is a special form of necrosis, seen in immune reactions
involving blood vessels.
 Occurs when complexes of antigens and antibodies are deposited
in the walls of the arteries
 Deposits of these immune complexes+ fibrin that has leaked out
of the vessels, gives a BRIGHT PINK AMORPHOUS appearance in
H&E stain, called as Fibrinoid/ fibrin-like.
 E.g; Immunologically mediated vasculitis syndrome.