Basic principles of Cell injury

and Adaptation

Dr. Jayesh V Beladiya

Assistant Professor
 Homeostasis
• A condition in which the internal environment
of the body remains relatively constant
despite changes in the external environment.

• Examples would be the maintenance of body

temperature and levels of glucose in the
blood.
 Homeostatic mechanisms
• Homeostasis is achieved through negative or
positive feedback mechanism.
 Homeostatic mechanisms
• Negative feedback:
• It includes most homeostatic control
mechanisms.
• Shuts off the original stimulus, or reduces its
intensity.
• Examples include stop insulin secretion on
decrease of blood glucose and body
temperature regulation.
 Homeostatic mechanisms
• Positive feedback:
• It increases the original stimulus to push the
variable farther
• e.g. insulin release on increase of blood
glucose and body temperature regulation.
• Homeostatic mechanisms are designed to
reestablish homeostasis when there is an
imbalance.
Homeostatic mechanisms
Components to a homeostatic system
• There are three components to a homeostatic
system:
1. The Sensor which detects the stress.
2. The Control Center which receives
information from the sensor and sends a
message to adjust the stress.
3. The Effectors which receives the message
from the control center and produces the
response which reestablishes homeostasis
 Components for Hyperthermia
• Heat receptor in skin- Sensor

• Hypothalamus- Control Center

• Sweat glands- Effectors

Pathways of Feedback mechanism
• Feedback mechanism is performed through
Hormonal and Neural pathways.
• Neural Pathway:
• Many homeostatic mechanisms use a nerve
pathway in which to produce their effects.
• These pathways involve an afferent path
which brings sensory messages into the brain
and an efferent path which carries outgoing
nerve messages to effectors.
Pathways of Feedback mechanism
• Hormonal Pathway:
• Hormones are produced by endocrine glands.
• Sensor and Control center initiate the release
of hormones.
• They enter in the blood after being produced
and travel throughout the body.
• However, hormones have their effect on
specific target tissues.
 Imbalance of Homeostasis
• Hypertension
• Diabetes mellitus
• Cancer
• Fever
• Dehydration
 Cell injury
• Cell injury is defined as a variety of stresses a
cell encounters as a result of changes in its
internal and external environment.
 Etiological factors for cell injury
• Genetic causes • Acquired causes
• Developmental defects: • Hypoxia and ischemia
Errors in morphogenesis • Physical agents
• Cytogenetic (Karyotypic) • Chemical agents and drugs
defects: Chromosomal • Microbial agents
abnormalities
• Immunologic agents
• Single-gene defects:
Mendelian disorders • Nutritional derangement
• Multifactorial inheritance • Aging
disorders • Psychogenic diseases
• Idiopathic diseases
 Acquired causes
• Hypoxic Injury:
• Loss of oxidative phosphorylation and ATP
generation by mitochondria.
• Decreased ATP and Depleted glycogen.
• Reduced intracellular pH due to increase of
Lactic acid and inorganic phosphate.
• Clumping of nuclear chromatin
 Acquired causes
• Physical agents:
• Trauma
• Heat
• Cold
• Radiation
• Electric shock
 Acquired causes
• Chemical agents:
• Medicines
• Hormones
• Endogenous urea
• Alcohol
• Heavy metals
 Acquired causes
• Microbial agents:
• Viruses
• Bacteria
• Fungi
• Parasites
• Rickettsiae
 Acquired causes
• Immunologic agents:
• The hypersensitivity reactions to various
substances can lead to localized lesion or
anaphylaxis reaction.
• Autoimmune reaction.
 Acquired causes
• Nutritional imbalance:
• Protein deficiency
• Vitamin deficiency
• Minerals deficiency
• Excess calories consumptions.
 Acquired causes
• Aging imbalance:
• Programmed aging whereby after a defined
number of divisions the cell undergoes
terminal differentiation.
• Development of an increasing population of
cells irreversibly committed to senescence and
death.
 Acquired causes
• Psychogenic disease:
• Excess stress
• Anxiety
• Depression
 Cellular adaptation
• Adaptations are reversible changes in the size,
number, phenotype, metabolic activity, or
functions of cells in response to changes in
their environment .
• Cells must constantly adapt, even under
normal conditions, to changes in their
environment.
 Types of Cellular adaptation
• Physiological:
• These physiological adaptations usually
represent responses of cells to normal
stimulation by hormones or endogenous
chemical substances.
 Types of Cellular adaptation
• Pathological:
• Pathologic adaptations may share the same
underlying mechanisms, but they provide the
cells with the ability to survive in their
environment and perhaps escape injury.
 Cellular adaptation
1. Hyperplasia
2. Hypertrophy
3. Atrophy
4. Metaplasia
5. Dysplasia
 Cellular Adaptation
• Hyperplasia:
• An increase in the number of cells in an organ
or tissue, which may then have increased
volume.
• Physiological:
• Physiologic growth of the uterus during
pregnancy.
 Cellular Adaptation
• Pathological:
• Excessive stimulation of hormones or growth
factors.
• Endometrial hyperplasia
• Benign tumor
 Cellular Adaptation
• Hypertrophy:
• An increase in the size of cells, and with such
change, an increase in the size of the organ.
• Physiological:
• Physiologic growth of the uterus during
pregnancy involves both hypertrophy and
hyperplasia.
 Cellular Adaptation
• Pathological:
• An increased workload, hormonal stimulation
and growth factors stimulation causes the
pathological hypertrophy.
• Cardiac hypertrophy.
 Cellular Adaptation
• Atrophy:
• A decrease in the size of a tissue or organ due
to cellular shrinkage.
• Physiological:
• A normal process of aging in some tissues,
which could be due to loss of endocrine
stimulation.
 Cellular Adaptation
• Pathological:
• Starvation atrophy- Long-term, severe
deprivation of nutrition
• Ischemic atrophy- Long-term, severe
deprivation of blood flow.
• Disuse atrophy- muscle atrophy due to a lack
of physical exercise
• Neuropathic atrophy-
 Cellular Adaptation
• Metaplasia:
• Metaplasia is a reversible change in which one
adult cell type is replaced by another adult
normal cell type.
• Physiological:
• Conversion of fibrous tissue into bone.
 Cellular Adaptation
• Pathological:
• Pseudostratified columnar epithelium is
converted into Squamous epithelium in the
Cigarette smokers.
• Squamous epithelium is converted into
Columnar epithelium in the GERD.
 Cellular Adaptation
• Dysplasia:
• An abnormal development of cells within
tissues or organs.
• It is also referred to as atypical hyperplasia.
• Epithelial dysplasia, Fibrous dysplasia of bone.
Cellular Adaptation
 Cellular injury
• Reversible injury:
• If the injured cell can regain homeostasis and
return to a morphologically (and functionally)
normal state is called reversible injury.
• Examples:
• Intracellular edema, Fatty change, Hyaline
change, Amyloidosis
 Pathogenesis of cell injury
• Four very interrelated cell systems are
particularly susceptible to injury:
a) Aerobic respiration decrease
b) Membranes (cellular and organelles)
c) Protein synthesis (enzymes, structural
proteins, etc)
d) Genetic apparatus (e.g., DNA, RNA)
 Pathogenesis of cell injury
• General mechanism for damage of cell
systems are:
a) Oxygen and oxygen-derived free radicals
b) ATP depletion
c) Loss of calcium homeostasis
d) Defects in membrane permeability
Pathogenesis of cell injury
 Morphological changes in Reversible
cellular injury
• Cell swelling
• Intracellular accumulation
• Calcification
• Enzyme leakage
• Acidosis & Alkalosis, Electrolyte
• Cell Death
 Cell swelling/Edema
• Also known as cloudy swelling.
• Accumulation of watery fluid in cells.
• Commonest and earliest form of cell injury
• Caused by bacterial toxins, chemicals, poisons,
burns, high fever, and intravenous
administration of hypertonic glucose or saline.
• Impaired regulation of sodium and potassium
at the level of cell membrane.
 Intracellular accumulation
• The normal cell accumulate abnormal
amount of substance either for temporary or
permanently which may be harmful to the cell
and may cause injury.
• Accumulation of
– Fat
– Protein
– Carbohydrates
– Pigments
 Calcification
• Abnormal deposits of calcium salts occur in
any tissues except bones and teeth.
• Two distinct types of pathologic calcification:
• Dystrophic calcification: characterized by
deposition of calcium salts in dead or
degenerated tissues with normal calcium
metabolism and normal serum calcium levels.
• Metastatic calcification: apparently normal
tissues and is associated with deranged
calcium metabolism and hypercalcaemia.
 Enzyme leakage
• Certain enzymes tend to leak into the
circulation from the injured cells and tissues.
• Example:
• Injury to the lysosomal membranes results in
leakage of their enzymes into the cytoplasm.
 Metabolic Acidosis
• A fall in the blood pH due to metabolic
components is brought about by fall
bicarbonate level and excess of H+ ions in the
blood.
• Example: Lactic acidosis
 Metabolic Alkalosis
• A rise in the blood PH due to rise in the
bicarbonate levels of plasma and loss of H+ is
called as metabolic alkalosis.
 Irreversible cell injury
• Irreversible injury:
• The injured cells are unable regain
homeostasis and return to a morphologically
(and functionally) normal state or death of
cells is called irreversible injury.
• Examples:
• Apoptosis and Necrosis
Cellular injury
 Cellular injury

Necrosis Apoptosis
 Types of Necrosis
• Coagulation necrosis (typical necrosis after
myocardium infarct)
• Liquefaction necrosis (necrosis involving tissue
digestion; common in the brain)
• Fat necrosis (necrosis involving release of
enzymes in tissues containing or surrounded
by fat cells such as the pancreas)
• Caseous necrosis (typical of tuberculosis)
• Gangrene (ischemic injury in fingers, toes).
 Inflammation
• Inflammation is defined as the local response
of living mammalian tissues to injury due to
any agent.
• It is a body defense reaction in order to
eliminate or limit the spread of injurious agent
as well as to remove the consequent necrosed
cells and tissue.
Inflammation

• Rubor (redness)
• Tumor (swelling)
• Calor (heat)
• Dolor (pain)
 Causes
• Infective agents like bacteria, viruses and their
toxins, fungi, parasites.
• Immunological agents like cell-mediated and
antigen antibody reactions.
• Physical agents like heat, cold, radiation,
mechanical trauma.
• Chemical agents like organic and inorganic
poisons.
• Inert materials such as foreign bodies
 Types of Inflammation
• Main two types of inflammation
• Acute Inflammation
– Short duration
– Represents the early body reaction
– Followed by healing
• Chronic inflammation
– Longer duration
– Causative agent of acute inflammation persists for
a long time
 Acute inflammation
• The main two events occur in the acute
inflammation.
a) Vascular events
b) Cellular events
 Acute inflammation
a) Vascular events:
1. Haemodynamic Changes:
i. Transient Vasoconstriction:
 Immediate vascular response irrespective of
the type of injury, mainly arteriole.
ii. Vasodilatation:
 Arterioles, venules and capillaries.
 Obvious within half an hour of injury.
 Increase blood volume in microvascular bed.
 Redness and Warmth.
 Acute inflammation
iii. Progressive vasodilatation:
 Progressive vasodilatation elevate the local
hydrostatic pressure.
 Transudation of fluid into the extracellular
space.
 Swelling
iv. Slowing or stasis:
 Increased concentration of red cells, and
thus, raised blood viscosity.
 Acute inflammation
v. Leucocytic Migration
 Peripheral orientation of leucocytes (mainly
neutrophils) along the vascular endothelium
 Stick to the vascular endothelium briefly
 Move and migrate through the gaps between
the endothelial cells in extravascular space.
 This is known is emigration.
 Acute inflammation
2. Altered Vascular permeability:
 In normal circumstances fluid balance is
maintained by 2 opposing set of forces:
 Forces that cause OUTWARD MOVEMENT of
fluid from microcirculation are intravascular
hydrostatic pressure and osmotic pressure of
interstitial fluid.
 Forces that cause INWARD MOVEMENT of
interstitial fluid into circulation are intravascular
osmotic pressure and hydrostatic pressure of
interstitial fluid.
 Acute inflammation
• Accumulation of fluid - interstitial
compartment which comes from blood
plasma by its escape through the endothelial
wall of peripheral vascular bed.
• Escape of fluid is due to vasodilatation and
consequent elevation in hydrostatic pressure -
Transudate.
• Subsequently, the characteristic inflammatory
edema, appears by increased vascular
permeability of microcirculation – Exudate.
 Acute inflammation
• Mechanisms of Increased Vascular
Permeability:
i. Contraction of endothelial cells
ii. Retraction of endothelial cells
iii. Direct injury to endothelial cells
iv. Endothelial injury mediated by leucocytes
v. Leakiness and neo-vascularisation
 Acute inflammation
i. Contraction of endothelial cells
• Affects venules exclusively.
• Endothelial cells develop temporary gaps
• Contraction resulting in vascular leakiness.
• Mediated by the release of histamine,
bradykinin and other chemical mediators.
• Short duration (15-30 minutes) - immediately
after injury.
 Acute inflammation
ii. Retraction of endothelial cells
• Structural re-organization of the cytoskeleton
of endothelial cells.
• Reversible retraction at the intercellular
junctions.
• Mediated by cytokines such as interleukin-1
(IL-1) and tumor necrosis factor (TNF)-α.
 Acute inflammation
iii. Direct injury to endothelial cells:
• Causes cell necrosis and appearance of physical
gaps.
• Process of thrombosis is initiated at the site of
damaged endothelial cells.
• Affects all levels of microvasculature.
• Either appear immediately after injury and last
for several hours or days – severe bacterial
infections.
• Delay of 2-12 hours and last for hours or days -
moderate thermal and radiation injury.
 Acute inflammation
iv. Endothelial injury mediated by leucocytes:
• Adherence of leucocytes to the endothelium
at the site of inflammation.
• Activation of leucocytes - release proteolytic
enzymes.
• Cause endothelial injury and increased
vascular leakiness.
• Affects mostly venules and is a late response.
 Acute inflammation
v. Leakiness and neovascularisation:
• Newly formed capillaries under the influence
of vascular endothelial growth factor (VEGF).
• Process of repair and in tumors are excessively
leaky.
Acute inflammation
 Acute inflammation
b) Cellular Events:
• Cellular phase of inflammation consists of 2
processes;
i. Exudation of leucocytes
ii. Phagocytosis
 Acute inflammation
i. Exudation of leucocytes:
a. Changes in the formed elements of blood
b. Rolling and adhesion
c. Emigration
d. Chemotaxis
 Acute inflammation
a. Changes in the formed elements of blood:
• Central stream of cells comprised by leucocytes
and RBCs and peripheral cell free layer of plasma
close to vessel wall.
• Later, central stream of cells widens and
peripheral plasma zone becomes narrower
because of loss of plasma by exudation.
• This phenomenon is known as margination.
• Neutrophils of the central column come close to
the vessel wall - pavementing
 Acute inflammation
b. Rolling And Adhesion:
• Peripherally marginated and pavemented
neutrophils slowly roll over the endothelial
cells lining the vessel wall (rolling phase).
• Transient bond between the leucocytes and
endothelial cells becoming firmer (adhesion
phase).
• The following molecules bring about rolling
and adhesion phases; Selectins, Integrins,
Immunoglobulin gene superfamily adhesion
molecule.
 Acute inflammation
c. Emigration:
• After sticking of neutrophils to endothelium.
• The former move along the endothelial
surface till a suitable site between the
endothelial cells is found where the
neutrophils throw out cytoplasmic
pseudopods.
• Cross the basement membrane by damaging it
locally – collagenases and escape out into the
extravascular space - emigration
 Acute inflammation
c. Emigration:
• Diapedesis - escape of red cells through gaps
between the endothelial cells.
– Passive phenomenon
– Raised hydrostatic pressure
A B

C
 Acute inflammation
d. Chemotaxis:
• After extravasating from the blood,
Leukocytes migrate toward sites of infection
or injury along a chemical gradient by a
process called chemotaxis.
• Cross several barriers like endothelium,
basement membrane, perivascular
myofibroblasts and matrix.
 Acute inflammation
d. Chemotaxis:
• Potent chemotactic substances for neutophils
are;
– Leukotriene B4 (LT-B4)
– Arachidonic acid metabolites
– Components of complement system - C5a
and C3a in particular
– Cytokines
– Interleukins, in particular IL-8
Events of Exudation of leucocytes
 Acute inflammation
ii. Phagocytosis:
• The process of engulfment of solid
particulate material by the cells.
• This phagocytic cells releases proteolytic
enzymes such as lysozyme, protease,
collagenase, elastase, lipase, proteinase,
gelatinase and acid hydrolases.
 Acute inflammation
ii. Phagocytosis:
• The microbe undergoes the process of
phagocytosis in following 3 steps:
– Recognition and attachment
– Engulfment
– Killing and degradation
 Acute inflammation
ii. Phagocytosis:
 Acute inflammation
• Chemical mediators involved in the acute
inflammation:
Chemical mediators that are responsible for
vascular and cellular events.
Knowledge of this mediators – basis of anti-
inflammatory drugs
Acute inflammation
 Chronic inflammation
• Chronic inflammation is defined as a long
lasting inflammatory responses in which
inflammation and tissue destruction occur at
the same time.
• Persisting or recurrent acute inflammation or
infection of low pathogenicity microbes
(mycobacterium tuberculosis).
Chronic inflammation
 Events of chronic inflammation
• The following common steps are characterized
in the chronic inflammation.
a) Mononuclear cell filtration
b) Tissue destruction or Necrosis
c) Proliferative changes

Fibrosis Angiogenesis
Mononuclear cell filtration
 Chronic inflammatory cells
• Macrophages
• Lymphocyte
• Plasma cells (Eosinophils, Monocyte, mast
cells)
 Macrophage origin
• Hematopoietic stem cells of bone marrow
• Progenitor cells
• Circulating cells are called monocytes
 Functions of Macrophage
• Phagocytosis
• Initiation of tissue repair
• Secrets inflammatory mediators (TNF, IL1,
chemokines)
• Display antigen to lymphocyte
• Respond to signal from T lymphocyte
Pathways of Macrophage activation
 Events of chronic inflammation
b) Tissue destruction or Necrosis:
• Tissue destruction and necrosis are central
process of the chronic inflammation.
• This is brought about by activation of the
macrophages, which release the variety of
biologically substances such as proteases
(elastate, collagenases, lipase) free radicals,
cytokines and angiogenesis growth factors.
 Events of chronic inflammation
c) Proliferative changes:
• As a result of necrosis, proliferation of small
blood vessels and fibroblasts is stimulated
resulting in formation of inflammatory
granulation tissue.
 Types of chronic inflammation
a) Chronic nonspecific inflammation
b) Chronic granulomatous inflammation
 Types of chronic inflammation
a) Chronic nonspecific inflammation:
• When the irritant substance produces a non
specific chronic inflammatory reaction with
formation of granulation tissue and tissue
repair by fibrosis called chronic nonspecific
inflammation.
 Types of chronic inflammation
b) Chronic granulomatous inflammation:
• Granulomatous inflammation is a form of
chronic inflammation characterized by
collections of activated macrophages, often
with T lymphocytes, and sometimes
associated with central necrosis.
 Cells in granulomatous inflammation
• Epithelioid cells: The activated macrophages
may develop abundant cytoplasm and begin
to resemble epithelial cells, and are called
epithelioid cells.

• Giant cells: Some activated macrophages may

fuse, forming multinucleate giant cells.
 Wound healing
• Wound healing refers to the body’s
replacement of destroyed tissue by living
tissue.
• It can be achieved by scar formation and
tissue regeneration.
 Wound healing
• Wound healing occurs in three phases.
a) Hemostasis phase
b) Inflammatory phase
c) Proliferative phase
d) Remodeling phase
 Wound healing
a) Hemostasis phase:
• Clotting or coagulation Phase
 Wound healing
b) Inflammatory Phase:
• Immediate to 2-5 days.
• Recruitment of inflammatory cells into the
wound by potent chemoattractants.
• Neutrophilic infiltrate appears: removes dead
tissue & prevent infection.
• Monocytes/macrophages follow neutrophils:
made production of growth factors &
phagocytosis activity.
 Wound healing
c) Proliferative Phase:
• 2 days to 3 weeks.
• Granulation tissue formation (composed of
fibroblasts, macrophages and endothelial
cell)
• Angiogenesis
• Contraction: Wound edges pull together to
reduce the defect.
 Wound healing
c) Proliferative Phase:
• Epithelialization: Epithelial cells migrate across
the new tissue to form a barrier between the
wound and the environment.
• Fibroblasts are the major mesenchymal cells
involved in wound healing, although smooth
muscle cells are also involved.
• Replacement of provisional fibrin matrix with
type III collagen.
 Wound healing
c) Remodeling phase:
• 3 weeks to 2 years
• New collagen forms which increases the tensile
strength of the wound.
• There are 19 types identified.
• Type 1 (80-90%) most common, found in all
tissue. The primary collagen in a healed wound.
• Type 3 (10-20%) seen in early phases of wound
healing.
 Wound healing
c) Remodeling phase:
• The number of intra and intermolecular
crosslinks between collagen fibers increases
dramatically to enhance the strength.
Thank you