Introduction to

pathology
Dr Hend Salah
Assistant Professor Of Pathology
WHAT IS PATHOLOGY?

• Pathology comes from an Ancient Greek roots of pathos : meaning "suffering“

(disease) logia "study of“
• So it is: The scientific study of disease!
• A bridge between science and medicine.
• It underpins every aspect of patient care, from diagnostic testing and treatment
advice to using cutting-edge genetic technologies and preventing disease.
• Pathologists play a critical role in research, advancing medicine and devising new
treatments to fight viruses, infections and diseases like cancer.
 WHAT IS PATHOLOGY?

• The field of pathology is dedicated to understanding the causes of disease and the
changes in cells, tissues, and organs that are associated with development of
disease.

• Thus, pathology provides the scientific foundation for the practice of medicine.
There are two important terms that students will encounter throughout their
study of pathology and medicine:
 ETIOLOGY

• It is the origin of a disease, including the underlying CAUSES and modifying

factors.
• Many diseases, such as hypertension, diabetes, and cancer, are caused by a
combination of INHERITED genetic susceptibility and various
ENVIRONMENTAL triggers.
• A major goal of modern medicine is to clarify and unravel the GENETIC and
ENVIRONMENTAL factors underlying diseases.
PATHOGENESIS

• The steps in the development of disease, from the initial etiologic trigger to the
cellular and molecular changes that give rise to the specific functional and
structural abnormalities which characterize any particular disease.

• SO…….
Etiology refers to why a disease arises and pathogenesis describes how a
disease develops
• Defining the etiology and pathogenesis of disease is essential not only for
understanding disease but is also the basis for developing rational
TREATMENTS.
• It is now appreciated that even diseases that present with similar morphologic
features (e.g., cancer of a particular organ) show important molecular
differences (e.g., mutations, epigenetic modifications) from case to case.
• This realization has launched the field of precision (or personalized) medicine,
in which therapies are designed for each individual’s disease rather than the
diseases as a whole.
• To render diagnoses and guide therapy in clinical practice, pathologists identify
changes:
• In the gross or microscopic appearance (morphology) of cells and tissues
• In their constituents (e.g., genes and proteins)
• Biochemical alterations in body fluids (such as blood and urine).

• Defining these alterations in diseased tissues aids in diagnosis as well as in predicting

outcomes and optimal therapies.
MORPHOLOGY
WHAT ARE THE BRANCHES OF PATHOLOGY?

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• Cellular pathology describes the group of pathology specialties
that study changes in cells and tissues to make a diagnosis.
• It includes 20 subspecialties, such as neuropathology,
dermatopathology and haematopathology.
WHAT ARE WE GOING TO TALK ABOUT IN THIS
SEMESTER?
• Cell injury, cell death and adaptation
• Cellular accumulations
• Inflammation and repair
• Neoplasia
• Hemodynamics
THE REFERENCE BOOK
THE RESPONSE OF THE CELL TO STRESS AND
NOXIOUS STIMULI
• Cells maintain a steady state called HOMEOSTASIS.
• They actively interact with their environment, adjusting their structure and
function to accommodate changing demands and extracellular stresses
• As cells encounter physiologic stresses or injurious stimuli, they can
undergo adaptation, achieving a new steady state and preserving viability
and function.
• If the adaptive capability is exceeded or if the external stress is inherently
harmful, cell injury occurs.
• Within certain limits, injury is reversible, and homeostasis is restored;
however, if the stress is severe or persistent, it results in irreversible injury and
death of the affected cells.
• Cell death is a crucial event in the development of many diseases.
CAUSES OF CELL INJURY:
1- Hypoxia and ischemia.
HYPOXIA: oxygen deficiency
ISCHEMIA: reduced blood supply.
Both deprive tissues of oxygen, the essential molecule for generating energy for cell function and
survival .
Ischemia also reduces the supply of nutrients.
Causes of hypoxia:
Ischemia resulting from blockage of an artery
Inadequate oxygenation of the blood, as in diseases of the lung,
Reduction in the oxygen-carrying capacity of the blood, as with anemia
 Causes of cell injury:

• Toxins: air pollutants, insecticides, carbon monoxide, asbestos, cigarette

smoke, ethanol, and drugs

• Infectious agents: viruses, bacteria, fungi, and parasites, can injure cells by
diverse mechanisms, including liberation of toxins and eliciting harmful
immune responses.
Causes of cell injury:
• Immunologic reactions:

Although the immune system defends the body against pathogenic microbes, immune
reactions can also result in cell and tissue injury.
• Autoimmune reactions against one’s own tissues
• Allergic reactions against environmental substances
• Excessive or chronic immune responses to microbes.

In all these situations, the immune responses elicit inflammatory reactions→→→→ cause of
damage to cells and tissues.
 Causes of cell injury:
• Nutritional imbalances.
• Protein-calorie insufficiency
• Vitamin deficiencies
• Excessive dietary intake may result in obesity→→→type 2 diabetes
and atherosclerosis.
• Physical agents
Trauma, extremes of temperature, radiation, electric shock, and
sudden changes in atmospheric pressure
SEQUENCE OF EVENTS IN CELL INJURY AND
CELL DEATH
• Reversible Cell Injury
Defined as a derangement of function and morphology that cells can recover from
if the damaging stimulus is removed.
In reversible injury, cells and intracellular organelles become swollen because they
take in water as a result of the failure of energy-dependent ion pumps in the
plasma membrane.
In some forms of injury, degenerated organelles and lipids accumulate inside the
injured cells.
©Elsevier Robbins and Kumar Basic Pathology 11th edition
 REVERSIBLE CELL INJURY

• Two morphologic features are characteristic of reversible cell injury:

• Cellular swelling:
Gross examination, there can be pallor of the organ (due to compression of
capillaries), and increased organ weight.
Microscopic examination may reveal small, clear vacuoles within the cytoplasm;
which represent distended and pinched-off segments of the endoplasmic reticulum
(ER) = hydropic change or vacuolar degeneration.

• Fatty change: lipid vacuoles in the cytoplasm, principally encountered in organs

that are involved in lipid metabolism, such as the liver
• LM: The cytoplasm of injured cells may become more eosinophilic on H & E staining which
becomes more pronounced with progression to necrosis
• EM:
(1) plasma membrane alterations such as blebbing, blunting, or distortion of microvilli, and loosening
of intercellular attachments
(2) mitochondrial changes such as swelling and the appearance of phospholipid-rich amorphous
densities
(3) dilation of the ER with detachment of ribosomes and dissociation of polysomes
(4) nuclear alterations, with clumping of chromatin.
(5) myelin figures, collections of phospholipids resembling myelin sheaths that are derived from
damaged cellular membranes.
PROGRESSION OF CELL INJURY
• Specific alterations in cellular organelles
Example:
The smooth ER is involved in the metabolism of various chemicals, including alcohol and drugs
such as barbiturates→→→ hypertrophy as an adaptive response that may have important
functional consequences.
Cells adapted to one drug may have increased capacity to metabolize other compounds handled
by the same system.
Thus, if patients taking phenobarbital for epilepsy, increase their alcohol intake, they may
experience a drop in blood concentration of the antiseizure medication to subtherapeutic levels
because of increased activity of the smooth ER in response to the alcohol.
NECROSIS
Dr Hend Salah

Assistant Professor Of Pathology

 IRREVERSIBLE CELL INJURY

• “Point of no return” → cell death and necrosis.

• Characterized by:
1. The inability to restore mitochondrial function (oxidative phosphorylation and adenosine
triphosphate [ATP] generation) even after resolution of the original injury.
2. Altered structure and loss of function of the plasma membrane and intracellular membranes.
3. Loss of structural integrity of DNA and chromatin.

Injury to lysosomal membranes results in the enzymatic digestion of the injured cell.
CELL DEATH

• Different mechanisms, depending on the nature and severity of the insult

1• Necrosis: Severe damage that is beyond salvage and is not thought to be regulated by specific
signals or biochemical mechanism
A RAPID AND UNCONTROLLABLE form of death that has been called “ACCIDENTAL” CELL
DEATH.
The major pathway of cell death in many commonly encountered injuries, such as those resulting
from:
ischemia, exposure to toxins, various infections, and trauma.

2 • Apoptosis
 NECROSIS
• Definition: Necrosis means death of
group of cells within a living body.

• It occurs either directly or following

reversible injury.
CAUSES OF NECROSIS

*Cutting of local arterial blood supply (infarction) .

*Bacterial toxins: as diphtheria .
*Chemical agents: as mercuric chloride, carbon tetrachloride .
*Physical agents: as excess heat, excess cold, excess
radiation.
*Hypersensitivity reaction: as in caseation necrosis
Mechanism of necrosis
1-Enzymatic digestion of cell by autolysis or heterolysis .
2- Denaturation of the protein.
MORPHOLOGIC EVIDENCE OF NECROSIS

Early changes: detected only on electron microscopy after 1-3 hours of cell death.
*, necrotic cells are characterized by
discontinuities in plasma and organelle membranes,
marked dilation of mitochondria with the appearance of large amorphous densities,
disruption of lysosomes,
intracytoplasmic myelin figures.
 MORPHOLOGIC EVIDENCE OF NECROSIS

Nuclear changes: the best evidence of cell

necrosis.
*Pyknosis :nucleus becomes shrunken, dense and
deeply basophilic (dark blue with H&E .
*Karyorrhexis: the pyknotic nucleus breaks up into
numerous small basophilic particles
• Karyolysis: in rapidly occurring necrosis the
nucleus undergoes lysis without a pyknotic stage
• Electron microscopy reveals profound nuclear
changes culminating in nuclear dissolution.
 MORPHOLOGIC EVIDENCE OF NECROSIS

Cytoplasmic changes: About 6 hours after necrosis, the cytoplasm becomes more
vacuolated, swollen, homogeneous and deeply acidophilic (Pink with eosin).
This is due to denaturation of cytoplasmic proteins and loss of ribosomes together with
autolysis by its own enzymes released from lysosomal injury
Biochemical changes: calcium influx into the cells denoting irreversible cell damage

9
• Cellular function may be lost long before cell death occurs
• The morphologic changes of cell injury (or death) lag behind
loss of function and viability
• Example:
• Myocardial cells become noncontractile after 1 to 2 minutes
of ischemia
• They die after 20 to 30 minutes
• Electron microscopy features: within 2 to 3 hours after the
death of the cells
• By light microscopy 6 to 12 hours later.
FATE OF NECROSIS

*Small areas of necrosis may undergo lysis and complete removal by phagocytosis
followed by regeneration or fibrosis .
• Large areas of necrosis are usually capsulated by fibrous tissue and may undergo
dystrophic calcification.

• Dead cells may be replaced by myelin figures, which are either phagocytosed by
other cells or further degraded into fatty acids.

• These fatty acids bind calcium salts, which may result in the dead cells ultimately
becoming calcified (dystrophic calcification).
PATTERNS OF TISSUE NECROSIS

• There are several morphologically distinct patterns of tissue necrosis, which may provide
clues about the underlying cause.
• Although the terms that describe these patterns do not reflect underlying mechanisms,
such terms are commonly used and their implications are understood by pathologists
and clinicians.
• Most of the types of necrosis have distinctive gross appearances
• exception:
• fibrinoid necrosis is detected only by microscopic examination.
TYPES OF NECROSIS

Coagulative
necrosis

Liquefactive
necrosis

Fibrinoid
necrosis
Types of
nerosis
Caseous
necrosis

Fat necrosis
 1-COAGULATIVE NECROSIS (ISCHAEMIC NECROSIS
OR INFARCTION:
definition : is a form of necrosis in which the underlying
tissue architecture is preserved for at least several days.
Appearance: The affected tissues take on a firm texture
with eosinophilic, anucleate cells
the injury denatures not only structural proteins but also
enzymes, thereby blocking the proteolysis of the dead cells;
Course: Leukocytes are recruited to the site of necrosis,
and the dead cells are digested by the action of lysosomal
enzymes of the leukocytes. The cellular debris is then
removed by phagocytosis.
Sites: Coagulative necrosis is characteristic of infarcts
(areas of ischemic necrosis) in all of the solid organs except
the brain.
 Coagulative necrosis

Coagulative necrosis. A, A
wedge-shaped kidney infarct I
(yellow) with preservation of
the outlines.
B, Microscopic view of the
edge of the infarct, with normal
kidney (N) and necrotic cells in N
the infarct (I). The necrotic cells
show preserved outlines with
loss of nuclei, and an
inflammatory infiltrate is
present.

A B
 2- LIQUEFACTIVE NECROSIS

Is seen at sites of BACTERIAL OR, OCCASIONALLY, FUNGAL

INFECTIONS, because microbes stimulate the accumulation of inflammatory
cells and the enzymes of leukocytes digest (“liquefy”) the tissue.

For obscure reasons, HYPOXIC DEATH OF CELLS WITHIN THE

CENTRAL NERVOUS SYSTEM often causes liquefactive necrosis
The dead cells are completely digested, transforming the tissue into a
viscous liquid that is eventually removed by phagocytes.

When the process is initiated by acute inflammation, as in a bacterial

infection, the material is frequently creamy yellow and is called pus.
A localized collection of pus is called an abscess

Liquefactive necrosis of the

brain
17
LIQUEFACTIVE NECROSIS

Liquefative necrosis in the brain (yellow arrow).

The left area is the normal
 3- GANGRENOUS NECROSIS

• NOT a distinctive pattern of cell death, however, the term is still commonly
used in clinical practice.
• Usually refers to the condition of a limb (generally the lower leg) that has
lost its blood supply and has undergone coagulative necrosis involving
multiple tissue layers.
• When bacterial infection is superimposed, the morphologic appearance is
often liquefactive because of destruction mediated by the contents of the
bacteria and the attracted leukocytes (resulting in so-called wet gangrene).
 4- CASEOUS NECROSIS :

Encountered most often in foci of tuberculous infection.

Caseous means “cheese-like,” the friable yellow-white appearance
On microscopic examination, the necrotic focus appears as a
collection of cellular debris with an amorphous granular pink
appearance in H&E-stained tissue sections.
Unlike coagulative necrosis, the tissue architecture is obliterated
and cellular outlines cannot be discerned.
It is often surrounded by a collection of macrophages and other
inflammatory cells forming a granuloma
5-FIBRINOID NECROSIS (DEGENERATION):

• A special form of necrosis, visible by light microscopy.

• It may be seen in immune reactions in which complexes of antigens and antibodies are
deposited in the walls of blood vessels
• Or in severe hypertension.
• Deposited immune complexes and plasma proteins that have leaked into the walls of injured
vessels produce a bright pink, amorphous appearance on H&E preparations called fibrinoid
(fibrin-like)
• Fibrinoid necrosis is seen most often in certain forms of vasculitis and in transplanted organs
undergoing rejection
22
FIBRINOID NECROSIS

Transmural fibrinoid
necrosis(arrow) in case of PAN in
a kidney specimen
 6-FAT NECROSIS :

Focal areas of fat destruction

Can be due to abdominal trauma or acute pancreatitis
Enzymes leak out of damaged pancreatic acinar cells and ducts and
digest peritoneal fat cells and their contents, including stored
triglycerides.
The released fatty acids combine with calcium to produce grossly
identifiable chalky white lesions
On histologic examination, the foci of necrosis contain shadowy outlines
of necrotic fat cells surrounded by granular basophilic calcium
deposits and an inflammatory reaction.
A- Enzymatic fat necrosis: occurs in acute pancreatitis and pancreatic
injuries
B-Non enzymatic fat necrosis (traumatic fat necrosis): occurs in the
breast, subcutaneous tissue and abdomen secondary to trauma.
ASSESSMENT:

An 11-year-old girl becomes infected with hepatitis A and experiences mild nausea for 1 week. On
physical examination, she has minimal right upper quadrant tenderness and scleral icterus.
Laboratory findings include a serum aspartate transaminase (AST) of 68 U/L and alanine
transaminase (ALT) of 75 U/L. Her laboratory findings most likely result from which of the following
changes in her hepatocytes?
A. Cell membrane defects
B. Lysosomal autophagy
C. Mitochondrial swelling
D. Nuclear chromatin clumping
E. Ribosomal dispersion
• WHICH of the following is not considered liquefactive necrosis?
• (A) Abscess
• (B) Brain infarct.
• (C) Amoebic liver abscess.
• (D) Renal infarct.
• (E) fungal infection
• 2- WHICH of the following is not considered post necrotic changes in the nucleus :
• (A) Pyknosis
• (B) Karyorrhexsis
• (C) Karyomegally
• (D) Karyolysis
• A 49-year-old man develops an acute myocardial infarction because of the sudden
occlusion of the left anterior descending coronary artery. The area of myocardial necrosis
within the ventricle can best be described as:
• (A) Coagulative necrosis
• (B) Liquefactive necrosis
• (C) Fat necrosis
• (D) Caseous nerosis
• (E) Fibrinoid necrosis
Thank you
Thank you
 CELL INJURY, CELL
DEATH & ADAPTATION 3
Dr Hend Salah
Assistant Professor Of Pathology
 DEFINITION OF APOPTOSIS
Apoptosis is a Greek word meaning dropping off of leaves of a tree.
It can be defined as
Programmed cell death in which there is death of single cell or cluster of cells
Apoptosis can be triggered by various stimuli from outside or inside the cell, e.g.
By ligation of cell surface receptors (death receptors)
By DNA damage as a cause of defects in DNA repair mechanisms,
Treatment with cytotoxic drugs or irradiation
Lack of growth factors
• o The plasma membrane of the apoptotic cell remains intact,
• o but the membrane is altered in such a way that the cell and
its fragments become avid targets for phagocytes.
• o The dead cell and its fragments are rapidly cleared before
cellular contents have leaked
CAUSES OF APOPTOSIS
CAUSES OF APOPTOSIS
 PATHOLOGICAL APOPTOSIS
Insufficient apoptosis:
·*cancer due to accumulation of cancer cells
*autoimmunity (accumulation of autoreactive cells).
*persistent infection (failure of get ridding of infected cells )
Excessive apoptosis:
*Neurodegeneration (Alzheimer's’ disease )
*AIDS (depletion of T lymphocytes)
*In liver cells in cases of viral hepatitis
 APOPTOSIS AND CANCER

• *Acquired ability to resist apoptosis is a hallmark of most, and perhaps

all types of cancer .
·*Many tumors are resistant to apoptosis induced by radiation and
chemotherapy .
·*A discovered oncogene (cancer causing gene) known as bcl-2
is an inhibitor of apoptosis in many types of cancer especially follicular
lymphoma.
* P53 is a tumour suppressor gene called as the guardian of the genome
is mutated in about 50% or more of human cancers and this will lead
to failure of apoptotic death of genetically damaged cancer cells
 MECHANISM
Through a complicated pathway, some enzymes named CASPASES (cysteine-dependent aspartate-specific
proteases) cause finally DNA fragmentation, leading to the morphological changes of apoptosis

1- Intrinsic pathway: Mitochondrial pathway

2- extrinsic pathway; death receptor pathway

MORPHOLOGY

The nuclei of apoptotic cells show various stages of chromatin condensation and aggregation and, ultimately,
karyorrhexis

The cells rapidly shrink, form cytoplasmic buds, and fragment into apoptotic bodies composed of membrane-bound
vesicles of cytosol and organelles

Because these fragments are quickly extruded and phagocytosed without eliciting an inflammatory response, even
substantial apoptosis may be histologically undetectable
A)INTRINSIC PATHWAY
(MITOCHONDRIAL PATHWAY)

1-When cells are deprived of growth factors a

number of
sensors are activated. Bcl2–>bh3–>proapotic bax—->caspace 9
2. These sensors are members of
the Bcl-2 family called ―BH3 proteinsǁ.
then activate two pro-apoptotic proteins called
Bax
and Bak, relases cytochrome c from
mitochondria
Cytochrome c, together with some
cofactors, activates caspase-9.
B)EXTRINSIC PATHWAY (THE DEATH RECEPTOR )

Death receptor Found on the cell fasl

Death receptors, that trigger apoptosis. TNF—>fas cd95–>caspace8—> bid

o (TNF) receptor family, which contain in their cytoplasmic

Proapotic member of Bcl2
regions a conserved ―death domain,ǁ
o Fas (CD95)
o Fas ligand (FasL) is a membrane protein expressed mainly on
activated T lymphocytes.
These in turn recruit and activate caspase-8.
In many cell types caspase-8 may cleave and activate a pro-
apoptotic member of the Bcl-2 family called Bid.

In apoptosis , apoptotic bodies are quickly extruded and

phagocytosed without eliciting any inflammatory response
 MORPHOLOGY OF APOPTOSIS
apoptosis necrosis
Single cell Large number of cells
Cell shrinkage swelling
Chromatin condensation Chromatin lysis
Cell fragmentation into Whole cell damage
apoptotic bd.
No inflammation Surrounding inf.
Plasma membrane Leaky and blebbing
budding
Activation of ATP depletion
endonucleases and Membrane injury
proteases
AUTOPHAGY (“SELF-EATING”)

• Lysosomal digestion of the cell’s own components.

• A survival mechanism in times of nutrient deprivation
• Enables the starved cell to live by eating its own contents and recycling these contents to
provide nutrients and energy.
• In this process, intracellular organelles and portions of cytosol are first sequestered
within an ER-derived double membrane (phagophore) →→→ matures into an
autophagosome which is initiated by cytosolic proteins that sense nutrient deprivation.
• The vacuole fuses with lysosomes →→ autophagolysosome,

• Autophagic vacuoles may also form around microbes in infected

cells, leading to destruction of these infectious pathogens.
• Autophagy is also involved in the clearance of misfolded
proteins, for instance, in neurons and hepatocytes.
• o Therefore, defective autophagy may be a cause of neuronal death
induced by accumulation of these proteins and, subsequently,
neurodegenerative diseases.
• o Conversely, pharmacologic activation of autophagy limits the
build-up of misfolded proteins in liver cells in animal models,
thereby reducing liver fibrosis.
 CELLULAR ADAPTATIONS TO
STRESS
Physiologic

Pathologic
PHYSIOLOGIC
The responses of cells to normal stimulation by
• Hormones
• Endogenous chemical mediators
Examples:
the hormone-induced enlargement of the breast and uterus during
pregnancy
the demands of mechanical stress in the case of bones and muscles
Pathologic
Allow cells to modulate their structure and function and thus escape injury,
but at the expense of normal function.
HYPERTROPHY→ HYPERTROPHY
• Enlargement of cells →→ increase in the size of the organ
• Pure hypertrophy is largely confined to cell types with a limited capacity to
divide.
The striated muscle cells in both the skeletal muscle and the heart undergo
only hypertrophy in response to increased workload
Mixed:
Hypertrophy & hyperplasia of smooth muscle of the uterus as a consequence of
estrogen-stimulation
PHYSIOLOGIC HYPERTROPHY
Pathologic hypertrophy

In the heart: disorders that increase intracardiac

pressures such as:
Hypertension
Narrowing of the aortic valve (stenosis)

Myocardial cells are subjected to a persistently

increased workload and adapt by enlarging to
generate the required higher contractile force.
 HHHHYYYYPPPPEEEERRRRPPPP
HYPERPLASIA

• Hyperplasia is an increase in the number of cells in an organ that

stems from increased proliferation:
of differentiated cells
OR
of progenitor cells.
• Happens if the tissue contains cell populations capable of replication
• May occur concurrently with hypertrophy
• It is stimulated by hormones or growth factors.
 PHYSIOLOGIC HYPERPLASIA

1. Hormonal hyperplasia: e.g: proliferation of the glandular

epithelium of the female breast at puberty and during
pregnancy
2. Compensatory hyperplasia: residual tissue grows after
removal or loss of part of an organ.
e.g: Partial liver resection: polypeptide growth factors produced by
uninjured hepatocytes as well as non parenchymal cells in the liver
PATHOLOGIC HYPERPLASIA

• Hormonal imbalances can lead to pathologic hyperplasia.

Endometrial hyperplasia by increased estrogenic stimulation
Benign prostatic hyperplasia induced by androgens and
estrogens.
 The hyperplastic process remains controlled; if the signals that initiate it abate, the
hyperplasia ceases.
 Nevertheless, pathologic hyperplasia may constitute a fertile soil in which cancers
may eventually arise.
 Patients with hyperplasia of the endometrium are at increased risk of developing
endometrial cancer
 ATROPHY→ATROP
• Atrophy is reduced size of an organ or tissue caused by
reduction in the size and number of cells
Causes of atrophy:
Decreased workload
Loss of innervation
Diminished blood supply
Inadequate nutrition
Loss of endocrine stimulation
Aging (senile atrophy).
• Physiologic (e.g., the loss of hormone stimulation in menopause)
• Pathologic (e.g., denervation)

Over time, as atrophy worsens, affected cells may pass a threshold

and undergo apoptosis.
• Mechanism of Atrophy
• Protein synthesis decreases because of reduced metabolic activity.
• Increased degradation of cellular proteins by the ubiquitin-proteasome
pathway.
Nutrient deficiency and disuse may activate ubiquitin ligases, which
attach multiple copies of the small peptide ubiquitin to cellular proteins
and target them for degradation in the proteasome.
• In many situations, atrophy is also accompanied by increased autophagy,
with resulting increases in the number of autophagic vacuoles.
 METAPLASIA

• Metaplasia is a change in which one adult cell type is replaced by

another adult cell type.
• A cell type sensitive to a particular stress is replaced by another
cell type better able to withstand the adverse environment.
• Metaplasia is thought to usually arise by reprogramming of stem
cells to differentiate along a new pathway rather than a
phenotypic change of differentiated cells (transdifferentiation).
• Prolonged cigarette smoking →→ ciliated columnar epithelial cells of the
trachea and bronchi →→ tough stratified squamous epithelial cells which
are better suited to withstand the noxious chemicals in cigarette smoke.

HOWEVER, epithelial metaplasia is a double-edged sword:

• Important protective mechanisms are lost, such as mucus secretion and
ciliary clearance of particulate matter.
• In chronic gastric reflux: the normal stratified squamous epithelium of
the lower esophagus →→ gastric or intestinal-type columnar epithelium.
• Does metaplasia only occur in epithelia?

NO

• Metaplasia may also occur in mesenchymal cells, but

generally a reaction to some pathologic alteration and
not an adaptive response to stress. For example, bone is
occasionally formed in soft tissues
• Again, the two edged sword:
• The influences that induce metaplastic change, if
persistent, predispose to malignant transformation of the
epithelium.
Squamous metaplasia of the respiratory epithelium is a
rich soil for the development of squamous cell lung
cancers
Intestinal metaplasia of the stomach is associated with
the development of gastric cancer.
THANK YOU
CELL INJURY, CELL
DEATH &
ADAPTATION 4
Dr Hend Salah
Assistant Professor Of Pathology
MECHANISMS OF CELL INJURY AND CELL DEATH

• The cellular response to injurious stimuli depends on the type of injury and its duration and severity
• The consequences of an injurious stimulus also depend on the type of cell and its metabolic state, adaptability,
and genetic makeup.
Examples:
Cardiac VS skeletal muscle.
• Cell injury usually results from functional and biochemical abnormalities in one or more essential cellular
components.
The principal targets and biochemical mechanisms of cell injury are:
(1) Mitochondria and their ability to generate ATP and ROS under pathologic conditions;
(2) Disturbance in calcium homeostasis;
(3) Damage to cellular (plasma and lysosomal) membranes; and
(4) Damage to DNA and misfolding of proteins
SITES OF DAMAGE IN CELL INJURY
 1-DEPLETION OF ATP

• Sources Of ATP:
• ATP, the energy store of cells, is produced mainly by oxidative phosphorylation of
adenosine diphosphate (ADP) in mitochondria.
• the glycolytic pathway can generate ATP in the absence of oxygen using glucose derived either
from the circulation or from the hydrolysis of intracellular glycogen.
• Causes of Depletion:
• 1. reduced supply of oxygen and nutrients,
• 2. mitochondrial damage,
• 3. The actions of some toxins (e.g., cyanide).
• Importance OF ATP:
• High-energy phosphate in the form of ATP is required for virtually all synthetic and degradative
processes within the cell, including
• membrane transport,
• protein synthesis,
• lipogenesis,
• the deacylation-reacylation reactions necessary for phospholipid turnover.
• It is estimated that in total, the cells of a healthy human burn 50 to 75 kg of ATP every day!
 MITOCHONDRIAL DYSFUNCTION AND DAMAGE

• Injurious stimuli: hypoxia, chemical

toxins, and radiation
• Major consequences
1. Failure of oxidative
phosphorylation, leading to
decreased ATP generation and
depletion of ATP in cells.
2. Abnormal oxidative
phosphorylation also leads to the
formation of reactive oxygen
species
OXIDATIVE STRESS

• Cellular damage induced by the accumulation of reactive oxygen species (ROS)

• Causes: Chemical, radiation injury, hypoxia, cellular aging, tissue injury caused by
inflammatory cells, and ischemia-reperfusion injury.
• Free radicals are chemical species with a single unpaired electron in an outer
orbital.
• Such chemical species are extremely unstable and readily react with inorganic and
organic compounds, such as nucleic acids, proteins, and lipids.
• During this reaction, the molecules that are “attacked” by free radicals are often
themselves converted into other types of free radicals, thereby propagating the chain of
damage.
REACTIVE OXYGEN SPECIES

• ROS are normally produced by two major pathways.

1. ROS are produced in small amounts in all cells during the reduction-oxidation
(redox) reactions that occur during energy generation
• Oxygen is reduced to produce water.
• Small amounts of highly reactive but short-lived toxic intermediates are generated.
• These include superoxide (O2 • ), which is converted to hydrogen peroxide (H2O2)
spontaneously and by the action of the enzyme superoxide dismutase.
• In the presence of metals, such as Fe2+, H2O2 is converted to the highly
reactive hydroxyl radical •OH by the Fenton reaction
2. ROS are produced in phagocytic leukocytes, mainly neutrophils, as a weapon for
destroying ingested microbes and other substances during inflammation.

In phagosomes and phagolysosomes to kill microbes.

O2 →superoxide → H2O2 →hypochlorite.
Myeloperoxidase (H2O2 into hypochlorite ). (the major component of household
bleach)
• Nitric oxide (NO) is another reactive free radical produced in leukocytes and other cells.
• It can react with O2 • to form a highly reactive compound, peroxynitrite, which also participates
in cell injury.
• Free radicals are unstable and decay spontaneously.
• There are also nonenzymatic and enzymatic systems (free radical
scavengers), that serve to inactivate free radicals :
• Superoxide dismutases (SODs).

• Glutathione peroxidases

• Catalase: highly efficient, being capable of degrading millions of molecules of

H2O2 per second.

• Endogenous or exogenous antioxidants (e.g., vitamins E, A, and

C and β-carotene)
 CELL INJURY CAUSED BY REACTIVE OXYGEN SPECIES

• Reactive oxygen species cause cell injury by damaging

multiple components of cells:

1. Peroxidation of membrane lipids:

Damage of plasma membranes as well as mitochondrial and
lysosomal membranes
2. Crosslinking and other changes in proteins.
• Enhanced degradation
• Loss of functional activity.
• May also directly cause fragmentation of polypeptides.
• Damaged proteins may fail to fold properly, triggering the
unfolded protein response
3. DNA damage:
Mutations and DNA breaks.
Such DNA damage has been implicated in apoptotic cell death,
aging, and malignant transformation of cells.

4. In addition to their role in cell injury and killing of microbes, ROS

at low concentrations may be involved in numerous signaling
pathways in cells and thus in physiologic reactions.
 MEMBRANE DAMAGE
Necrosis → increased membrane permeability and membrane
damage.
Cellular membranes may be damaged by
ROS
Decreased phospholipid biosynthesis (due to hypoxia and
nutrient deprivation)
Increased degradation (e.g., following phosphatase activation
due to increased intracellular calcium)
Cytoskeletal abnormalities that disrupt the anchors for plasma
membranes.
• The most important sites of membrane damage are the following:
• Mitochondrial membrane damage Energy source

• Plasma membrane damage, which leads to loss of osmotic balance and

influx of fluids and ions, as well as loss of cellular contents. Protecting wall
• Injury to lysosomal membranes, leading to leakage into the cytoplasm of
lysosomal enzymes ‫انقالب‬
 DISTURBANCE IN CALCIUM HOMEOSTASIS

• Calcium ions: normally second messengers in several signaling pathways but if released into
the cytoplasm of cells in excessive amounts are also an important source of cell injury.
• Cytosolic free Ca2+ is normally maintained at much lower concentrations (∼0.1 μmol) than
extracellular Ca2+ (1.3 mmol)
• Most intracellular Ca2+ is in mitochondria and the ER.
• Ischemia and certain toxins increase cytosolic Ca2+, initially due to release from intracellular
stores and later from increased influx across the dysfunctional plasma membrane.
• Excessive intracellular Ca2+ may cause cell injury by activating various enzymes,
e.g., proteases and phospholipases, that damage cellular components.
ENDOPLASMIC RETICULUM STRESS

• During protein synthesis, normally chaperones in the ER enhance the proper

folding of newly synthesized proteins, but this process is imperfect, and some
misfolded polypeptides are generated that are targeted for proteolysis by
ubiquitination.
• The accumulation of misfolded proteins in a cell →→ stress compensatory
pathways in the ER →→ lead to cell death by apoptosis.
• If misfolded proteins accumulate in the ER →→ induction of a protective cellular response = the
unfolded protein response.
• This adaptive response activates signaling pathways:
 that increase the production of chaperones
 retard protein translation
 reducing the levels of misfolded proteins in the cell

• However, if the quantity of misfolded protein exceeds what can be handled by the adaptive
response, additional signals are generated which activate proapoptotic sensors, leading to
apoptosis mainly by the mitochondrial (intrinsic) pathway.
• Causes: abnormalities that
• increase the production of misfolded proteins or reduce
the ability to eliminate them.
Gene mutations
Aging
Infections especially viral infections
Increased demand for secretory proteins such as insulin
in insulin-resistant states
Changes in intracellular pH in ischemia and hypoxia
Neurodegenerative disease
DNA DAMAGE

• Causes:
• Radiation
• Chemotherapeutic agents
• Intracellular generation of ROS
• Acquisition of mutations
• DNA damage →→ intracellular sensors →→ signals for accumulation of
p53

• p53 →→

arrests the cell cycle (at the G1 phase) to allow the DNA to be repaired
before it is replicated
• If the damage is too great to be repaired successfully, p53 →→
apoptosis, mainly by the mitochondrial pathway.
• If p53 is mutated or absent, cells with damaged DNA survive →→
genomic alterations →→ neoplastic transformation
ISCHEMIA-REPERFUSION INJURY

• Paradoxical increased cell injury and necrosis with reperfusion

HOW?
• Increased ROS production
• Influx of calcium
• Increased influx and activation of leukocytes
• Activation of the complement system
CELL INJURY CAUSED BY TOXINS

Environmental chemicals
Substances produced by infectious pathogens

Toxins cause cell injury by two general mechanisms:

• Direct-acting toxins
• Latent toxins
Direct-acting toxins:
• Mercuric chloride (HgCL2 ) due to ingestion of contaminated
seafood. Mercury binds to the sulfhydryl groups of various cell
membrane proteins, inhibiting ATP-dependent transport and
increasing membrane permeability.
• Chemotherapeutic drugs by direct cytotoxic effect on DNA
• Toxins made by infectious pathogens
Corynebacterium diphtheriae toxin
Bacillus anthracis toxin
Latent toxins:

• Only active after they have been converted to reactive metabolites,

which then act on target cells.
• Conversion carried out by cytochrome P-450 in the smooth ER of the
liver and other organs.
• The metabolites might cause membrane damage and cell injury by direct
covalent binding to protein and lipids BUT THE MOST IMPORTANT
MECHANISM OF CELL INJURY INVOLVES THE FORMATION OF FREE
RADICALS.
• Carbon tetrachloride (CCl 4 ) in the dry-cleaning industry (now banned).
CCl4 is converted to a toxic free radical CCl3•, principally in the liver, and
this free radical is the cause of cell injury, mainly by membrane
phospholipid peroxidation

• Poisoning by acetaminophen
Taken at recommended doses, metabolic pathways convert
acetaminophen to nontoxic products, but at high doses these pathways
become saturated and the drug is metabolized in the liver by the P-450
system to a highly toxic intermediate capable of causing hepatocyte injury.
THANK YOU
INTRA & EXTRACELLULAR DEPOSITIONS
& CELL AGING
Dr Hend Salah
Assistant Professor Of Pathology
 INTRACELLULAR AND
EXTRACELLULAR DEPOSITIONS
• Cells or tissues accumulate abnormal amounts of various
substances, which:
• may be harmless
OR
• may cause injury.
 INTRACELLULAR ACCUMULATIONS

• The main mechanisms of abnormal intracellular accumulations are:

Inadequate removal and degradation
Excessive production of an endogenous substance
Deposition of an abnormal exogenous material
• Intracellular deposits may be located in
a) the cytoplasm,
b) within organelles (typically lysosomes)
c) in the nucleus
In many cases, if the overload can be controlled or stopped, the accumulation is reversible.
In inherited storage diseases, accumulation is progressive and may cause cellular injury, leading in some instances
to death of the tissue and the patient.
 FATTY CHANGE (STEATOSIS)

• Fatty change refers to an abnormal accumulation of triglycerides within

parenchymal cells.
• Most often seen in the liver, since this is the major organ involved in fat
metabolism
• May also occur in the heart, skeletal muscle, kidney, and other organs.
• May be caused by toxins, protein malnutrition, diabetes, obesity, or anoxia.
• Alcohol abuse and diabetes associated with obesity are the most common
causes of fatty change in the liver (fatty liver) in higher-income nations.
 CHOLESTEROL AND CHOLESTEROL ESTERS
ATHEROSCLEROSIS
• In atherosclerotic plaques, smooth muscle cells and macrophages within the intimal layer
of the aorta and large arteries are filled with lipid vacuoles, most of which contain
cholesterol and cholesterol esters.
• Such cells have a foamy appearance (foam cells), and aggregates of them in the intima
produce the yellow cholesterol-laden atheromas characteristic of this serious disorder.
• Some of these fat-laden cells may rupture, releasing cholesterol and cholesterol esters
into the extracellular space, where they may form crystals.
 PROTEINS

• Intracellular accumulations of proteins usually appear as

rounded, eosinophilic droplets, vacuoles, or aggregates in
the cytoplasm.
• Increased uptake or increased synthesis.
• In the kidney, in disorders with heavy protein leakage across the
glomerular filter into the urine (e.g., nephrotic syndrome), the
excessive amounts of resorbed albumin accumulate in vesicles in
the tubular epithelial cells, in which they are seen as pink,
hyaline cytoplasmic droplets.
 PROTEINS

• Accumulation of immunoglobulins that

occurs in the rough ER of some plasma
cells, forming rounded, eosinophilic Russell
bodies.
 GLYCOGEN

• Abnormalities in the metabolism of either glucose or glycogen.

• In poorly controlled diabetes, the prime example of abnormal
glucose metabolism, glycogen accumulates in renal tubular
epithelium, cardiac myocytes, and β cells of the islets of
Langerhans.
• Genetic disorders collectively called glycogen storage
diseases
• In these diseases, enzymatic defects in the synthesis or
breakdown of glycogen result in massive accumulation, causing
cell injury and cell death.
PIGMENTS

• Pigments are colored substances that may be exogenous,

coming from outside the body, or endogenous, synthesized
within the body.
• Exogenous Pigments as carbon, tattooing, coal worker’s pneumoconiosis
• Endogenous Pigments as lipofuscin, melanin, hemosiderin
 CARBON

• The most common exogenous pigment

• An urban air pollutant.
• Phagocytosed by alveolar macrophages and
transported through lymphatic channels to the
regional tracheobronchial lymph nodes.
• Aggregates of the pigment blacken the draining
lymph nodes and pulmonary parenchyma
(anthracosis)
 LIPOFUSCIN

• Lipofuscin is an insoluble pigment, also known as

lipochrome or wear-and-tear pigment.
• Insoluble brownish-yellow granular intracellular
material that accumulates in a variety of tissues (heart,
liver, and brain) as a function of age or atrophy.
• Lipofuscin = complexes of lipid and protein produced
by the free radical–catalyzed peroxidation of
polyunsaturated lipids of intracellular membranes.
• Lipofuscin is not injurious to the cell or its functions.
 LIPOFUSCIN

• It is a marker of past free radical injury

• Is NOT injurious to the cell.
• When present in large amounts, imparts an appearance to the atrophic tissue,
particularly the heart “brown atrophy”.
 MELANIN

• Endogenous, brown-black pigment

• Synthesized by melanocytes located in the
epidermis
• A screen against harmful ultraviolet
radiation.
 HEMOSIDERIN

 Hemoglobin-derived golden yellow to brown granular

pigment
 local or systemic excess of iron

Iron is normally carried by a specific transport protein called

transferrin.
In cells, it is stored in association with a protein, apoferritin, to
form ferritin micelles
HEMOSIDERIN

 Bruise: local pathologic deposition of heamosiderin from hemorrhage

 Hemosiderosis: systemic pathologic deposition of hemosiderin
(hemochromatosis, hemolytic anemias, repeated blood transfusions)

 Physiologic in small amounts in the mononuclear phagocytes of the BM, spleen,

and liver, from RBC turnover
PATHOLOGIC CALCIFICATIONS

• The abnormal tissue deposition of calcium salts, together with

smaller amounts of iron, magnesium, and other mineral salts
• DYSTROPHIC calcification: deposition of calcium at sites of cell injury and
necrosis
• METASTATIC calcification: deposition of calcium in normal tissues, caused
by hypercalcemia (usually a consequence of parathyroid hormone excess)
 DYSTROPHIC CALCIFICATION

• Dystrophic calcification is encountered in areas of necrosis, whether they are of

coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat.
• Calcification is almost always present in the atheromas of advanced atherosclerosis.
• It also commonly develops in aging or damaged heart valves, further hampering their
function.
• Grossly: the calcium salts appear macroscopically as fine, white granules or clumps,
often felt as gritty deposits.
• Sometimes a tuberculous lymph node is virtually converted to stone
 DYSTROPHIC CALCIFICATION

• Histologically, with the usual H&E stain, calcium salts have a

• basophilic, amorphous granular, sometimes clumped
appearance.
• They can be intracellular, extracellular, or in both locations.
• The progressive acquisition of outer layers may create
lamellated configurations, called psammoma bodies
EXAMPLES OF SITES OF DYSTROPHIC CALCIFICATION:

• •Tuberculous necrosis and caseation.

• Fat necrosis with acute hemorrhagic pancreatitis.
• Dead bilharzial ova and hydatid cysts.
• Dead foetus.
• In the wall of blood vessels in atherosclerosis.
• In the wall of chronic abscess or an old scar.
• In certain tumours with degeneration e.g. leiomyoma & meningioma.
• In degeneration in the thyroid (nodular goiter).
 METASTATIC CALCIFICATION

• Associated with hypercalcemia

• In normal tissues.
• The major causes of hypercalcemia are
(1) Increased secretion of parathyroid hormone: primary parathyroid tumors or
hyperplasia, or production of parathyroid hormone–related protein by malignant
tumors
(2) Destruction of bone: accelerated turnover (e.g., Paget disease), immobilization, or
tumors (increased bone catabolism associated with multiple myeloma, leukemia,
skeletal metastases)
METASTATIC CALCIFICATION

(1) Vitamin D–related disorders: vitamin D intoxication & sarcoidosis

(2) Renal failure: phosphate retention → secondary hyperparathyroidism.

 MORPHOLOGY

• On gross examination: fine white granules or gritty

clumps
• On histologic examination: basophilic deposits
• Over time, heterotopic bone may form
• Metastatic calcification can occur widely throughout
the body but principally affects vessels, kidneys,
lungs
 AMYLOIDOSIS
Dr Hend Salah
Assistant Professor Of Pathology
Lecture outlines

• Pathogenesis of Amyloid Deposition

• Classification of Amyloidosis
• Mechanisms of Amyloid Formation
 Amyloidosis

• Amyloidosis is a condition associated with a number of

inherited and inflammatory disorders in which
extracellular deposits of fibrillar proteins are
responsible for tissue damage and functional compromise.
• These abnormal fibrils are produced by the aggregation of
misfolded proteins (which are soluble in their normal
folded configuration).
• Do not elicit an inflammatory reaction
Pathogenesis of Amyloid Deposition

Amyloid

95% 5%
Non branching P component
fibrils glycoproteins
 STRUCTURE OF AMYLOID

• Even though all amyloid deposits have a similar microscopic

appearance, amyloid is not a single chemical entity.
• In fact, more than 20 different proteins can aggregate to form amyloid.
• By electron microscopy, all types of amyloid, regardless of clinical
setting or chemical composition, consist of continuous, nonbranching
fibrils forming characteristic cross-β-pleated sheet conformation
• This conformation is responsible for the distinctive Congo red staining
and birefringence of amyloid
 THE THREE MOST COMMON FORMS OF AMYLOID

• AL (amyloid light chain) : complete or part

of immunoglobulin light chains mostly λ light chains (secreted by a
monoclonal population of plasma cells, and its deposition is associated with certain plasma
cell tumors)

• AA (amyloid-associated) : a unique non-Ig protein made by the liver.

By proteolysis of serum amyloid-associated (SAA) protein.
It is produced in inflammatory states as part of the acute phase response;
therefore, this form of amyloidosis is associated with chronic inflammation,
and is often called secondary amyloidosis.
 THE THREE MOST COMMON FORMS OF AMYLOID

•• β-amyloid protein (Aβ) from the transmembrane

glycoprotein called amyloid precursor protein.
It constitutes the core of cerebral plaques found in Alzheimer disease
as well as the amyloid deposited in walls of cerebral blood vessels in
individuals with this disease.
OTHER RARE FORMS

• Transthyretin (TTR) is a normal serum protein that binds and transports thyroxine and
retinol.
• mutant forms of TTR (and its fragments) form amyloid in a group of genetically
determined disorders referred to as familial amyloid polyneuropathies, and in the
heart of aged individuals (senile systemic amyloidosis).
• • β2-microglobulin, a component of MHC class I molecules and a normal serum protein,
it deposits in or around the joints or soft tissues of patients on long-term hemodialysis.
Classification of amyloidosis and mechanisms of amyloid
formation

• Abnormal folding of proteins (misfolding)→ β-pleated sheet

conformation →aggregate →deposit as fibrils
• FAILURE of degradation and uptake by macrophages
• The proteins that form amyloid:
(1) normal proteins which self-associate and form fibrils when
produced in increased amounts
(2) mutant proteins that are prone to misfolding and aggregation.
Pathogenesis of amyloidosis
CLASSIFICATION

• Amyloid
Systemic (generalized)
Localized to a single organ

• The systemic subclassified into

Primary amyloidosis: clonal plasma cell proliferation
Secondary amyloidosis: chronic inflammatory process.
 PRIMARY AMYLOIDOSIS: PLASMA CELL PROLIFERATIONS
ASSOCIATED WITH AMYLOIDOSIS

Most common form of amyloidosis

Caused by a clonal proliferation of plasma cells that synthesize abnormal Ig
molecules.
The free, unpaired κ or λ light chains (Bence Jones protein) aggregate and
deposit in tissues as amyloid.
 λ light chains are approximately 6 times more likely to deposit as amyloid
than κ light chains.
 REACTIVE SYSTEMIC AMYLOIDOSIS

• Secondary to an associated inflammatory condition.

• Rheumatoid arthritis most frequent. Tuberculosis, bronchiectasis, chronic
osteomyelitis, other connective tissue disorders such as ankylosing spondylitis, and
inflammatory bowel disease.
• Long-term subcutaneous heroin injection can also lead to generalized AA amyloidosis.
• Also, Some cancers: renal cell carcinoma and Hodgkin lymphoma.
• In AA amyloidosis, SAA synthesis by liver cells is stimulated by cytokines such as IL-6
and IL-1 that are produced during inflammation
 HEREDOFAMILIAL AMYLOIDOSIS

• Most common: familial Mediterranean fever (FMF) autosomal recessive disease

• Armenian, Sephardic Jewish, and Arabic origins.
• “Autoinflammatory” syndrome associated with excessive production of the
cytokine IL-1.
• Intermittent fevers + inflammation of serosal surfaces
• The gene for FMF encodes a protein called pyrin
• AA type.
HEMODIALYSIS ASSOCIATED AMYLOIDOSIS

• Patients on long-term hemodialysis for renal failure can develop amyloidosis as a result
of deposition of β2- microglobulin.
• This protein is present in high concentrations in the serum of persons with renal disease,
and in the past it was retained in the circulation because it could not be filtered through
dialysis membranes.
• Patients usually present with symptoms related to β2-microglobulin deposition in joints,
muscle, tendons, or ligaments; one relatively common presentation is as carpal tunnel
syndrome.
• With new dialysis filters, the incidence of this complication has decreased substantially.
LOCALIZED AMYLOIDOSIS

• Nodular
• Lung, larynx, skin, urinary bladder, tongue, and the region about the eye.
• Lymphocytes and plasma cells associated with these amyloid masses.
• AL protein, may represent a localized form of plasma cell–derived
amyloid.
ENDOCRINE AMYLOID

• Microscopic deposits of localized amyloid may be found in certain endocrine tumors, such as
medullary thyroid carcinoma, pancreatic islet tumor, and pheochromocytoma, and in the
islets of Langerhans in individuals with type 2 diabetes mellitus.
• In these settings, the amyloidogenic proteins seem to be derived either from polypeptide
hormones (e.g., medullary carcinoma) or from unique proteins (e.g., islet amyloid
polypeptide).
• In medullary carcinoma of the thyroid, the presence of amyloid is a helpful diagnostic feature.
 AMYLOID OF AGING

• Senile systemic amyloidosis

• Dominant involvement and related dysfunction of the
heart
• Restrictive cardiomyopathy and arrhythmias
MORPHOLOGY

• AA amyloidosis secondary to chronic inflammatory disorders: kidneys,

liver, spleen, lymph nodes, adrenal glands, thyroid glands, and many other
tissues are typically affected
• AL amyloidosis more likely to involve the heart, gastrointestinal tract,
respiratory tract, peripheral nerves, skin, and tongue.
• In the hereditary syndromes is varied according to the type of amyloid
Macroscopically
• The organ is frequently enlarged, and the tissue appears gray and has a waxy, firm
consistency.

Histologically
• Amyloid deposition is always extracellular and begins between cells, often
closely adjacent to basement membranes
• As the amyloid accumulates, it encroaches on the cells, in time surrounding
and destroying them.
• In the form associated with plasma cell proliferation, perivascular and
vascular deposits are common.
• The histologic diagnosis of amyloid is based almost entirely on its staining characteristics.
• The most common staining technique uses the dye Congo red, which under ordinary light
imparts a pink or red color to amyloid deposits.
• Under polarized light, the Congo red–stained amyloid shows so-called apple-green birefringence
• This reaction is shared by all forms of amyloid and is caused by the cross-β-pleated configuration
of amyloid fibrils.
• Confirmation can be obtained by electron microscopy, which reveals amorphous nonoriented thin
fibrils.
• AA, AL, and ATTR types of amyloid can also be distinguished by specific immunohistochemical
staining.
Thank you
 CELL AGING
Dr Hend Salah
Assistant Professor Of Pathology
 CELLULAR AGING

• Cellular aging is the result of a progressive decline in the life span and functional capacity of cells.
• Several mechanisms are thought to be responsible for cellular aging

Accumulation of DNA damage and mutations

Replicative senescence: reduced capacity of cells to divide secondary to progressive
shortening of chromosomal ends (telomeres)
Defective protein homeostasis: loss of normal proteins and accumulation of
misfolded proteins
• Age is one of the strongest independent risk factors for many chronic diseases, such
as cancer, Alzheimer disease, and ischemic heart disease
• Not simply an inevitable consequence of cells “running out of steam” because of the
passage of time, but, in fact, is the consequence of alterations in genes and signaling
pathways that are evolutionarily conserved from yeast to mammals.
• Experimental work: aging can be postponed
1- DNA damage:
• Nuclear and mitochondrial DNA frequently undergo mutations.
• Accelerated by endogenous stresses (e.g., ROS) and exogenous insults (e.g., exposure
to UV radiation, chemotherapeutic agents).
• Most DNA alterations are sensed by the cell and corrected by DNA repair enzymes
• If not → mutations accumulate as cells age.
• Several inherited syndromes characterized by premature aging are caused by
mutations in genes that encode DNA repair proteins thus cannot maintain genomic
stability.
2- Decreased cellular replication.
• Normal cells (other than stem cells) have a limited capacity for replication
• After a fixed number of divisions cells become arrested in a terminally nondividing
state, known as replicative senescence.
• Aging is associated with progressive replicative senescence of cells.
• Cells from children have the capacity to undergo more rounds of replication than do
cells from older people.
• cells from patients with Werner syndrome, a rare disease characterized by
premature aging, have a markedly reduced in vitro life span.
Replicative senescence
Occurs in cells as they age because of progressive shortening of telomeres, which ultimately
results in cell cycle arrest.
• Telomeres are short, repeated sequences of DNA
• Present at the ends of chromosomes
• Function : 1- Ensuring the complete replication of chromosome ends
2- Protects the ends from fusion and degradation.
• When somatic cells replicate, a small section of the telomere is not duplicated, and
telomeres become progressively shortened.
• Once the ends of telomeres are completely eroded the ends of chromosomes are no
longer protected and are sensed in cells as broken DNA, which signals cell cycle arrest
• Telomere length is maintained by nucleotide addition mediated by an enzyme called
telomerase.
• Telomerase: specialized RNA-protein complex that uses its own RNA as a template
for adding nucleotides to the ends of chromosomes.
• Telomerase is active in germ cells and present at low levels in stem cells but is
absent in most somatic cells.
• Therefore, as somatic cells age, their telomeres become shorter and they exit the cell
cycle, resulting in an inability to generate new cells to replace damaged ones.
• Conversely, in immortalized cancer cells telomerase is usually reactivated and
telomere length is stabilized, allowing the cells to proliferate indefinitely.
3- Altered protein homeostasis:
Over time, cells are unable to maintain normal protein homeostasis because of
increased turnover
decreased synthesis of proteins
defective activity of chaperones (which promote normal protein folding) and
proteasomes (which degrade misfolded proteins).
Abnormal protein homeostasis may lead to accumulation of misfolded proteins,
which can trigger pathways of apoptosis
Mechanisms Counteracting aging:
• Biochemical alterations associated with calorie restriction may counteract
aging and prolong lifespan.
• Specific agents that reduce aging in experimental models include: inhibitors
of insulin-like growth factor (IGF-1) and the molecular target of
rapamycin (mTOR), both of which affect signaling pathways that regulate
cellular metabolism.
• Partial inhibition of these pathways may switch cells from focusing on growth
and proliferation to concentrating on repairing damage.
Persistent inflammation:
• As individuals age, the accumulation of damaged cells, lipids, and DNA
may activate the inflammasome pathway → low-level inflammation.
• Sustained inflammation → chronic diseases, such as atherosclerosis and
type 2 diabetes.
• Cytokines produced during inflammatory reactions may induce cellular
alterations that exacerbate aging
• Chronic metabolic disorders may further accelerate the process.
 Inflammation

Dr/ Hend Salah Abo Safia

Assistant professor of pathology
 ILO s
• Define inflammation and classify it.
• List causes of inflammation
• Describe events of acute inflammation
• List the five cardinal signs of inflammation.
• Describe the events that occur during acute inflammation.
DEF. :
• Response of vascularized tissues to infections and tissue damage

• Brings cells and molecules of host defense from the circulation to the

sites where they are needed, In order to eliminate the offending agents.

It is indicated by adding the suffix “itis” to the Latin name of the affected organ or

tissue.
E .G. : • Glossitis means inflammation of the tongue.
• Gastritis means inflammation of the stomach.
• Cystitis means inflammation of the urinary bladder.
• Pancreatitis means inflammation of the ……
• Hepatitis means inflammation of the ……….
• Few exceptions are present as:
• Pneumonia = inflammation of the lung.

• Pleurisy = inflammation of the pleura.

• Causes:
• Infections bacteria, viruses, parasites
• Tissue necrosis caused by ischemia, trauma, physical and chemical injury and this is
called sterile inflammation
• Foreign body Granuloma
• Immune reaction: hypersensitivity reaction

• Protective
• With no inflammation:
• a. Infections can be fatal
• b. Wounds would never heal
• c. Injured tissue may sustain permanent damage
 TYPES
According to the onset and duration of inflammation, it is divided into:
1- Acute: sudden onset and short duration: hours
Characterized by polymorph nuclear leucocytes (PMNL) polymorphs or
neutrophils.

2- Chronic: gradual onset and long duration: days, months to years

Characterized by lymphocytes, plasma cells& histiocytes
(macrophages).
 MANIFESTATIONS OF ACUTE
INFLAMMATION:
1- GENERAL 2-LOCAL

FEVER: caused by bacterial toxins &

products of leucocytes result in release
of PGE2 by hypothalamus

Headache , malaise , loss of appetite

& rapid pulse

Leucocytosis
Plasma proteins
 1- Recognition of the noxious agent
• The cells involved in inflammation (tissue-resident sentinel cells, phagocytes,
and dendritic cells) are equipped with receptors (Toll-like receptors (TLRs) that
recognize microbial products and substances released from damaged cells.
• Engagement of the receptors leads to the production of mediators of
inflammation
• Activation of TLRs →production of cytokines → trigger inflammation
• Activated cytosolic NOD-like receptors (NLRs) →recruit and activate a
multiprotein complex (the inflammasome) → biologically active cytokine
interleukin-1 (IL-1).
• NLRs recognize microbial products and indicators of cell damage such as leaked
DNA and ↓ cytosolic potassium levels.
2- Recruitment of leukocytes and plasma
proteins into the tissues
• leukocytes and proteins such as complement can be delivered through
blood to any site of microbial invasion or tissue injury.
• leukocytes (first mainly neutrophils, later monocytes and lymphocytes) and
plasma proteins are rapidly recruited from the circulation to the
extravascular site where the offending agent is located.
• The exodus of cells and plasma proteins from blood requires coordinated
changes in blood vessels and secretion of mediators.
3- Removal of the stimulus for inflammation is accomplished mainly by
phagocytic cells, which ingest and destroy microbes and dead cells.
4- Regulation of the response is important for terminating the reaction
when it has accomplished its purpose.
5- Repair consists of a series of events that heal damaged tissue.
In this process the injured tissue is replaced through regeneration of surviving
cells and filling of residual defects with connective tissue (scarring).
 Acute inflammation has three major
components
• (1) Dilation of small vessels leading to an increase in blood flow
• (2) Increased permeability of the microvasculature enabling plasma proteins
and leukocytes to leave the circulation
• (3) Emigration of leukocytes from the microcirculation, their accumulation
in the focus of injury, and their activation to eliminate the offending agent
 Reactions of Blood Vessels in Acute
Inflammation

• Increasing the flow of

blood (redness and
warm)
• Increasing the
permeability of vessels
• Formation of
inflammatory exudate
• An exudate is an extravascular fluid that has a high protein concentration
and contains cellular debris.
• Its presence implies the existence of an inflammatory process that has
increased the permeability of small blood vessels. (it is responsible for the
swelling sign)
• In contrast, a transudate is a fluid with low protein content (most of which is
albumin), little or no cellular material, and low specific gravity.
 Functions of inflammatory exudate
• Dilution & neutralization of bacterial toxins

• Helps in localization of infection by formation of fibrin threads around the area of

injury

• Cells in the inflammatory exudates engulf microorganisms &secrete proteolytic

enzymes that liquefy dead tissues &prepare the area for healing

• Bring antibodies from the blood to the site of inflammation

 Changes in Vascular Flow and Caliber
• Vasodilation is induced by the action of several mediators, notably histamine, on
vascular smooth muscle.
• It is one of the earliest manifestations of acute inflammation.
• Vasodilation first involves the arterioles and then leads to opening of new capillary
beds in the area.
• The result is increased blood flow, which is the cause of heat and redness
(erythema) at the site of inflammation.
• • Vasodilation is quickly followed by increased permeability of the microvasculature,
with the outpouring of protein-rich fluid into the extravascular tissues
 Changes in Vascular Flow and Caliber
• • The loss of fluid and increased vessel diameter lead to slower blood flow,
concentration of red cells in small vessels, and increased viscosity of the blood.
(stasis )
• • As stasis develops, blood leukocytes, principally neutrophils, accumulate along the
vascular endothelium.
• At the same time, endothelial cells are activated by mediators produced at sites of
infection and tissue damage and express increased levels of adhesion molecules.
• Leukocytes then adhere to the endothelium, and soon afterward they migrate
through the vascular wall into the interstitial tissue.
 Increased Vascular Permeability (Vascular
Leakage)

• mechanisms for the increased permeability:

• 1- Contraction of endothelial cells: resulting in opening of
interendothelial gaps is the most common mechanism of vascular leakage.
• It is elicited by histamine, bradykinin, leukotrienes, and other chemical
mediators.
• It is called the immediate transient response because it occurs rapidly after
exposure to the mediator and is usually short-lived (15 to 30 minutes).
 Increased Vascular Permeability (Vascular
Leakage)

• But in burns, increased vascular permeability may result from direct

endothelial injury →leakage starts immediately and is sustained for several
hours until the damaged vessels become thrombosed or are repaired
• Often the immediate and delayed responses occur along a continuum.
 Responses of Lymphatic Vessels and Lymph
Nodes
• The system of lymphatics and lymph nodes filters and polices the extravascular fluids.
• In inflammation, lymph flow is increased and helps drain edema fluid that accumulates
because of increased vascular permeability.
• In addition to fluid, leukocytes and cell debris, as well as microbes, may find their
way into lymph.
• The lymphatic vessels may become secondarily inflamed (lymphangitis), as may the draining
lymph nodes (lymphadenitis).
• Inflamed lymph nodes are often enlarged because of hyperplasia of the lymphoid
follicles and increased numbers of lymphocytes and macrophages.
• This is termed reactive, or inflammatory, lymphadenitis .
Inflammation 2
By
Dr/ hend salah abo safia
Assistant professor of pathology
 Objectives
1. Understand Recurtment of leukocytes to the site of injury

2. List examples of non suppurative inflammation.

3. Classify suppurative inflammation

4. Be able to define: pus, an abscess, and an ulcer.

5. Describe the morphology of an ulcer, fistula, sinus and differentiate between them

6. Analyze the fate of abscess

 Leukocyte Recruitment and Activation

• The sequence of events in the recruitment of leukocytes from the vascular lumen
to the extravascular space consists of
• (1) margination and rolling along the vessel wall;
• (2) firm adhesion to the endothelium;
• (3) transmigration between endothelial cells;
• (4) migration in interstitial tissues toward a chemotactic stimulus.
• o Rolling, adhesion, and transmigration are mediated by the interactions of
adhesion molecules on leukocytes and endothelial surfaces.
• Margination: This process of leukocyte accumulation at the periphery of
vessels

• Rolling :The cells bind and detach and thus begin to tumble on the
endothelial surface
• The weak and transient interactions involved in rolling are mediated by the
selectin family of adhesion molecules (Selectins )
• E-selectin expressed on endothelial cells;
• P-selectin present on platelets and endothelium;
• L-selectin on the surface of most leukocytes.
• Adhesion:

• The firm adhesion is mediated by integrins expressed on leukocyte cell surfaces

interacting with their ligands on endothelial cells.
• Integrins are normally expressed in a low-affinity form and do not adhere to their
specific ligands until the leukocytes are activated by chemokines.
• TNF and IL-1 activate endothelial cells to ↑expression of ligands for integrins.
• Engagement of integrins by their ligands delivers signals to the leukocytes that
lead to cytoskeletal changes that mediate firm attachment to the substrate.
• oTransmigration.
• leukocytes migrate through the vessel wall primarily by squeezing between
cells at intercellular junctions.
• This extravasation of leukocytes, called diapedesis
• Migration of leukocytes is driven by chemokines produced in extravascular
tissues, which stimulate movement of the leukocytes toward their chemical
gradient.
• After passing through the endothelium, leukocytes secret collagenases that
enable them to pass through the vascular basement membrane.
 Chemotaxis
• leukocytes movement toward sites of infection or injury along a chemical gradient
• Chemotactic agents:
• Both exogenous and endogenous substances can be chemotactic for leukocytes, including
• Bacterial products and pathogenic organisms
• Cytokines, especially chemokines
• Components of the complement system ***** C5a
• Leukotrienes from neutrophils
 Type of Emigrating Leukocytes :
• Cocci attract PMNL.
• Bacilli attract monocytes.
• Viruses attract lymphocytes.
• Parasites and hypersensitivity reactions attract eosinophils
 Phagocytosis and Clearance of the Offending Agent

• Phagocytosis means ingestion of particulate material by cells.

• Phagocytosis consists of three steps
• (1) recognition and attachment of the particle to the ingesting leukocyte;
• (2) engulfment, with subsequent formation of a phagocytic vacuole;
• (3) killing and degradation of the ingested material
• • Most important phagocytes: neutrophils (microphages) and macrophages
• • ↑↑↑ efficiency by opsonization of the microbes
Opsonins: coat microbes and target them
for phagocytosis
a) Antibodies
b) C3b cleavage product of complement
c) plasma lectins called collectins
 Intracellular Destruction of Microbes and Debris

• • Reactive oxygen species (ROS) (oxidative burst)

• • Reactive nitrogen species derived from nitric oxide [NO]
• • Lysosomal enzymes (acid hydrolases and elastase)
 Neutrophil Extracellular Traps (NETs).

• Definition: These traps are extracellular fibrillar networks that are produced
by neutrophils in response to :
• infectious pathogens (mainly bacteria and fungi)
• inflammatory mediators (such as chemokines, cytokines, complement
proteins, and ROS).
• NETs contain a framework of nuclear chromatin with embedded granule
proteins, such as antimicrobial peptides and enzymes.
• Role
• The traps provide a high concentration of antimicrobial
substances at sites of infection
• prevent the spread of the microbes by trapping them in the
fibrils.
• Formation:
• In the process, the nuclei of the neutrophils are lost, leading
to death of the cells.
• NETs also have been detected in blood neutrophils during
sepsis.
• The nuclear chromatin in the NETs, which includes histones
and associated DNA, has been postulated to be a source of
nuclear antigens in systemic autoimmune diseases, particularly
lupus, in which affected persons react against their own DNA
and nucleoproteins
 Types of acute inflammation:
1- Abscess.
Localized 2- Furuncle (boil).
Suppurative 3- Carbuncle.
Diffuse Cellulitis( Phlegmonous )
Types

Non-suppurative  Catarrhal
 Pseudo-membranous
 Serous inflammation
 Fibrinous inflammation
 Serofibrinous inflammation
 Hemorrhagic
 Allergic
 I – Non suppurative inflammation:
Catarrhal inflammation:
• *Affect the mucous membranes (mild type).

• *The best example is common cold or coryza.

• *characterized by formation of abundant exudates rich in mucous.

• *Microscopically:

• The mucous lining cells are swollen, some cells are ruptured.

• The submucosa shows hyperaemia, oedema and cellular

infiltration with leucocytes.

 Pseudo-membranous inflammation :

 This is a severe type of acute inflammation characterized by formation of a membrane like structure on the
affected area.

 Examples: Diphtheria and bacillary dysentery .The causative bacteria remain on the mucosal surface and
produce powerful exotoxin which causes patchy mucosal necrosis.

• *Grossly: the mucosa is congested and shows a yellowish pseudo-membrane which is adherent to the
underlying structures and if it is removed it leaves a bleeding surface.

• *Microscopically:
 The pseudomembrane is formed of fibrin threads, causative microorganisms, necrotic mucosal cells, acute
inflammatory cells and some RBCs.

 The submucosa is hyperaemic, oedematous and infiltrated by polymorphs.

 Serous inflammation :

 Characterized by the formation of abundant fluid exudate rich in proteins

in serous sacs.
 Examples: Pleural effusion and epidermal blisters following burns.
 Fibrinous inflammation :
 In this type the exudate is rich in fibrin.
 Increased vascular permeability → fibrinogen accumulates
within exudates. →fibrin forms.

 In inflammation of the lining of body cavities: meninges,

pericardium, and pleura.

 Histologically: Fibrin = eosinophilic meshwork of threads or as

an amorphous coagulum

 Resolution through fibrinolysis + clearance by macrophages

 If not resolved: organization → scarring→ deleterious effect.
within the pericardial cavity→restrictive cardiomyopathy
Hemorrhagic inflammation:

The exudate is rich in blood and is

caused by virulent organisms that
cause damage of blood vessels
as in cases of small pox.
• Hemorrhagic enteritis
• Hemorrhagic pneumonia
 Allergic inflammation

It is characterized by exudation
of abundant fluid containing
eosinophils e.g. urticaria.

It is caused by antigen antibody

reaction.
 Suppurative inflammation
*Definition: it is a severe type of acute inflammation which is characterized by formation of pus.
• It may be primary or complicate any other type of inflammation.
•*Causative organism: staphylococci, streptococci, gonococci and meningococci.
•*Pathogenesis of pus formation:
 Bacterial toxins necrosis of the tissue particularly in the center.
 The causative bacteria strongly chemotactic, they attract a large number of polymorphs.
 Some polymorphs will be killed in the battle against the microorganism  pus cells (Pus cell is a dead
polymorph).
 The dead polymorphs and bacteria release proteolytic enzymes which liquefy necrotic tissues and result in
the formation of pus.
•Pus is composed of:

• Living and dead microorganisms

• Living and dead polymorphs.

• Liquefied Necrotic tissues.

• Some blood cells and globules of fat.

• Inflammatory exudate.
 A- Localized suppurative inflammation:
• 1- Abscess:
• *Definition: localized area of suppurative inflammation.
• *Causative organism: pyogenic microorganisms particularly: staphylococci produce coagulase enzymes
 fibrin threads  surround and localize the area of inflammation.

• • Its center is a mass of necrotic leukocytes and tissue cells.

• • Rim of preserved neutrophils around the necrotic focus
• • Surrounded by vascular congestion and parenchymal and fibroblastic
proliferation
• *Fate of abscess:
 If the abscess is not evacuated it will rupture at the point of least mechanical
resistance.

 If the abscess is evacuated the swelling subsides, cavity collapses , healing by

granulation tissue .

• *Complications of abscess:
• 1-Complications of healing:

• a- Ulcer: Which is an area of epithelial discontinuity.

• b- Sinus: Which is blind ended tract opening to the surface and discharging

pus.

• c- Fistula: which is a tract with two openings e.g. one to the surface and the

second to a mucous membrane.

2 -Chronicity: If the abscess is not completely drained.

3-Spread of infection by:

• a- Lymphatics causing lymphangitis and lymphadenitis.

• b- Blood causing toxaemia, or septicaemia.

• c- Septic thrombophlebitis causing pyaemia.

• 2 - Boil or Furuncle:
• It is a localized suppuration in hair follicle or
sebaceous gland.

• 3 - Carbuncle:
 It is a type of localized suppuration in the
subcutaneous tissue, particularly in the region of the
back.
 It is characterized by formation of multiple loculi
containing pus which open on the surface by
multiple openings (sinuses).
 It is a serious condition and it occurs in diabetic
patients.
 B- Diffuse suppurative
inflammation:

• Phlegmonous inflammation:
 It is a diffuse form of acute inflammation which
occurs in the subcutaneous tissues (cellulitis) and
mucous membranes e.g. the appendix.
 It is caused by streptococcal infection 
spreading factor (hyaluronidase enzyme and
fibrinolysin) dissolve fibrin, thus helping the
spread of infection.
Inflammatory mediators

By
Dr/ hend salah abo safia
Assistant professor of pathology
Mediators of inflammation

Definition

Mediators of inflammation are the substances that

initiate and regulate inflammatory reactions.
Mediators of inflammation
➔ Active mediators are ➔ The major cell types that
produced in response to produce mediators of acute
various stimuli. inflammation are tissue
macrophages, dendritic
➔ One mediator can cells, and mast cells, but
stimulate the release of platelets, neutrophils,
other mediators. endothelial cells, and most
epithelia also can be
➔ most of these mediators induced to elaborate some
are short-lived. of the mediators.
➔
Mediators of inflammation

Classification

Cell derived Plasma derived

Classification
Cell derived mediators
of inflammation
1 Vasoactive amines

2 Arachidonic Acid metabolites

3 Platelet activating factor

4 Reactive oxygen species
5 Nitric oxide
6 cytokines
 Vasoactive Amines
1 (Histamine and Serotonin)

• so named because they have

important actions on blood
vessels
• stored as preformed molecules
in cells and among the first
mediators to be released during
inflammation.
 Stimuli OF
HISTAMINE
RELEASE

Binding of Products of
Physical injury
antibodies to mast complement called
such as trauma,
cells in allergic anaphylatoxins
cold, or heat. reactions. (C3a and c5a).

Effects:
• Dilation of arterioles and increases the
permeability of venules by producing inter-
endothelial gaps in postcapillary venules.
• Contraction of some smooth muscles
 Stimuli of
serotonin

Release from platelets is stimulated when platelets

aggregate

Effect
It induces vasoconstriction during clotting.
It is produced mainly in some neurons and
enterochromaffin cells, and is a neurotransmitter
and regulates intestinal motility
 2 Arachidonic Acid (AA)
Metabolites
Arachidonic Acid Metabolites are produced from arachidonic acid present in
membrane phospholipids, and they stimulate vascular and cellular reactions in
acute inflammation.
When cells are activated, membrane AA is rapidly converted by the actions of
enzymes to produce prostaglandins, leukotrienes and lipoxin.

Called eicosanoids (because they are derived from 20-carbon fatty acids; Greek
eicosa = 20).
There are 2 enzymes :

Cyclooxygenase (COX1 and COX2)

Lipoxygenase

These AA-derived mediators act locally at the site of generation and then decay
spontaneously or are enzymatically destroyed.
 Membrane
phospholipid

Phospholipase

Arachidonic Acid

cyclooxygenase
Lipoxygenase

Prostaglandin

Leukotrienes

Lipoxin
 Effects of
PGs
Thrombaxane

- TxA2: a potent platelet-aggregating agent and vasoconstrictor and

thus promotes thrombosis.

- Prostacyclin (PGI2): a vasodilator, a potent inhibitor of platelet

aggregation .

A thromboxane– prostacyclin imbalance has been implicated in

coronary and cerebral artery thrombosis .
- PGD2: is the major prostaglandin made by mast cells
along with PGE2, it causes vasodilation and increases the
permeability of post-capillary venules, thus potentiating
edema formation. PGD2 also is a chemoattractant for
neutrophils.

- Prostaglandins are involved in the pathogenesis of pain

and fever in inflammation.
 Leukotrienes
Sources

Mast cells Leukocytes

by the actions of lipoxygenase.

 Effects

Vascular and smooth muscle reactions and leukocyte

recruitment.

LTB4 is produced by neutrophils and some macrophages and is a

potent chemotactic agent and activator of neutrophils, causing
aggregation and adhesion of the cells to venular endothelium,
generation of ROS, and release of lysosomal enzymes.

Leukotrienes C4, D4, and E4: are produced mainly in mast

cells and cause intense vasoconstriction, bronchospasm.
 Lipoxins
Sources

Leukocytes,
particularly platelets
neutrophils

by the actions of lipoxygenase.

 Effects

Inhibitors of inflammation

Inhibit leukocyte recruitment and the cellular components

of inflammation.

They inhibit neutrophil chemotaxis and adhesion to

endothelium.
 Reactive Oxygen Species

Sources

Oxygen-derived free radicals may be released from leukocytes

after exposure to microbes, chemokines, and immune
complexes, or following a phagocytic challenge.

types

Superoxide anion, hydrogen peroxide (H2O2), and hydroxyl

radical (•OH)
 Effects

-Destroy phagocytosed microbes.

-Vasoconstriction and bronchoconstriction.

-Endothelial cell damage, with increased vascular

permeability.
-Injury to other cell types (parenchymal cells, red blood
cells).

-Inactivation of antiproteases, such as α1-antitrypsin

 Nitric Oxide (NO)

Sources

Endothelial Some neuron

macrophages
cells in the brain

Synthesized by the enzyme nitric oxide synthase (NOS).

- Effects: it relaxes vascular smooth muscle and
promotes vasodilation.
- It reduces platelet aggregation and adhesion
- NO and its derivatives are microbicidal
 Cytokines
Some cytokines act to make disease worse (proinflammatory),
whereas others serve to reduce inflammation and promote
healing (anti-inflammatory).

Pro inflammatory Anti inflammatory

cytokines cytokines
IL-1α 
➔ IL-4
TNF 
➔ IL-10
IL-2 
➔ IL-11
IL-6 
➔ IL-13
IL-8 
➔ TGF-β
IL-12 
IL-2β 
IFN-γ 
 Sources

Activated
macrophages Dendritic cells
lymphocytes

Connective
Endothelial cells Epithelial cells
tissue cells
 Effects
- Some mediate communication between WBCs
(Interleukins)

- Some play role in inflammation (TNF, IL-1,Chemokines,

IFN-Y ‚IL-12)

- Mediate and regulate immune and inflammatory

reactions
Chronic Inflammation
By
Dr/ hend salah abo safia
Assistant professor of pathology
 Outcomes of Acute
Inflammation

• 1. Complete resolution if:

• the injury is limited or short- lived
• little tissue destruction
• the damaged parenchymal cells can regenerate.
• Resolution involves:
• removal of cellular debris and microbes by macrophages
• resorption of edema fluid mainly through lymphatics
• 2. Healing by connective tissue replacement (scarring,
or fibrosis) if:
• massive tissue destruction
• the involved tissues are incapable of regeneration
• when there is abundant fibrin exudation in tissue or in
serous cavities (pleura, peritoneum) that cannot be fully
cleared.
• 3. Progression to chronic inflammation
• either the persistence of the injurious agent
• interference with the normal process of healing.
 Definition of chronic
inflammation:
Chronic inflammation is a response of prolonged duration
( weeks or months) in which inflammation, tissue injury
and attempts at repair coexist in varying combination
De novo or secondary after acute inflammation (recurrent or
persistent inciting agent).
Gradual onset.
The cardinal signs, general manifestations and the major
microscopic signs of acute inflammation are absent.
 Causes of chronic inflammation

Persistant infection by microorganisms that difficult

to eradicate such as mycobacteria and certain fungi and
viruses
Hypersensitivity diseases as in autoimmune
diseases such as rheumatoid arthritis or allergic
diseases as bronchial asthma.
Prolonged exposure to potentially toxic agents,
either exogenous (silica) or endogenous (cholesterol).
Glass factory workers
 Morphological Features of
chronic inflammation
 Infiltration with mononuclear cells, which include
macrophages, lymphocytes and plasma cells.
 Tissue destruction, induced by persistent offending agents
or by the inflammatory cells.
 Attempts at healing by connective tissue replacement of
damaged tissue by fibrosis.
 End Arteritis Obliterans (EAO) (subintimal fibrous
proliferation of end arteries narrowing their lumena)
 Angiogenesis (formation of new vessels from pre-
existing vessels)
 Cells involved in chronic inflammation:

 Macrophages
 Lymphocytes
 Plasma cells
 Eosinophils
(allergic diseases)
• Giant cells
• Fibroblasts
 Chronic inflammation

Non specific (non-granulomatous) Specific (granulomatous)

Usually complicates acute Granuloma: accumulation (usually

inflammation, or it may focal) of macrophages (usually
begins de novo activated) with/out surrounding
Fibrosis and chronic lymphocytic infiltrate.
inflammatory cellular infiltrate. Fibrosis may be found surrounding
The microscopic picture does the granuloma.
not indicate the cause of the Causes of granuloma:
inflammation i.e. the Infective: TB, Leprosy, syphilis etc.
microscopic picture is not Foreign body: Talc granuloma.
specific. Unknown origin: Sarcoidosis & Crohn’s
disease
Classification and Types:

A) Bacterial : - tuberculosis
infective - Syphilis
- Leprosy
- Actinomycosis
- Rhinoscleroma
*Granulomatous inflammation
B) Parasitic: - Bilharziasis .
- Leishmaniasis
C)Fungal : - candidiasis
- histoplasmosis

- Silicosis
A) Organic metals dusts - Asbestosis

Non infective B) Foreign body - wood, glass,

talk powder
C) Unknown cause - sarcoidosis.
 Giant Cells

TB intestine Healed granuloma histoplasmosis FB granuloma

(GOUT)
 Role of macrophages

 The dominant cells in most chronic inflammation :

 secreting cytokines and growth factors
 destroying foreign invaders and tissues
 activating other cells, notably T lymphocytes.
 Macrophages act as professional phagocytes that act as
filters for particulate matter and microbes.
 Maturation of mononuclear
phagocytes
• Macrophages are tissue cells derived from hematopoietic
stem cells in the bone marrow.
• Circulating cells of this lineage are known as monocytes.
 Mononuclear phagocytic system

• Macrophages are normally diffusely scattered in

most connective tissues. In addition, they are
found in specific locations in organs such as
Liver (kupffer cells)
Spleen and lymph nodes (sinus histocytes)
Central nervus system (microglial cells)
Lungs (alveolar macrophages)
 Macrophage-Activation pathways

Macrophage
activation

Alternative
Classical pathway
pathway
 Classical pathway activation

 induced by microbial products such as endotoxins, which

engage TLRs and other sensors, and by T cell-derived signals,
importantly the cytokine IFN-y in immune responses.
 Classically activated macrophages (also called M1)produce NO
and ROS and upregulate lysosomal enzymes, all of which
enhance their ability to kill ingested organism, and secrete
cytokines that stimulate inflammation.
 These macrophages are important in host defense against
microbes and in many inflammatory reactions.
 Alternative pathway activation

• induced by IL-4 and IL-13, produced by T

lymphocytes and other cells.
• These macrophages are called macrophages(M2)
and mainly involved in tissue repair.
• They secrete growth factors that promote
angiogenesis, activate fibroblasts, and
collagen synthesis.
 General complications of bacterial
infection
[blood infection]

• Bacteraemia
• Toxaemia: Acute & Chronic
• Septicemia
• Pyaemia: Systemic & Portal
 Bacteraemia
• Prescence of small number of bacteria in the blood without causing
toxic manifestations.
• Causes:
 septic focus: septic (i.e. infected) tooth [especially after extraction], Tonsillitis,
sinusitis or cholecystitis.
 As a stage of certain infections e.g. typhoid fever
Fate:
 Handeled by the reticuloendothelial system.
 Settled in certain predisposed tissue:
Diseased cardiac valve.
Metaphysis of long bone especially in children
after trauma.
 Toxaemia
• Prescence of bacterial toxins in the blood associated with the
production of clinical and pathological manifestations.
• Two types:
 Acute
 Chronic

Acute Type: In the course of acute infection especially the following:

 Diphtheria
 Bacillary dysentery
 Clostridia infection (Tetani and Welchii)
 Toxaemia
Acute Type
• Severe constitutional (generalized) manifestations: Fever,
rigor, malaise, headache, tachycardia
• Degeneration [cloudy&fatty] of the parenchymatous
organs (heart, liver & kidney).
• Hemolytic anemia
• Severe cases leads to toxic myocarditis & heart failure.
 Toxaemia
Chronic Type
• In cases of chronic infection, esp. Tuberculosis
• Manifestations:
 Low grade fever, loss of weight.
 Anemia, leucopenia [bone marrow depression]
 Amyloid degeneration of the parenchymatous organs.
 Septicemia
• Large number of multiplying bacteria together with
their toxins in the blood leading to severe clinical
manifestations.
• Low immunity with severe infection (strept.
‘Puerperal sepsis’, staph. ‘Acute osteomyelitis’,
pneumo ‘pneumonia’, gonococci ‘meningitis’)
• Manifestations (5H&4S) :
 Hemorrhages
 Hemolysis
 Heart
Pericarditis
Toxic myocarditis
Acute bacterial endocarditis
 Hydropic degeneration & fatty changes in the
parenchymatous organs.
 Hyperplastic bone marrow (leucoblastic reaction)
 Symtomps of toxemia: fever, rigors, headache, malaise and
tachycardia.
 Splenic swelling (acute splenic swelling)
 Serofibrinous inflammation of the serous membranes.
 Shock may occur.
 Pyaemia
• Definition: circulation and impaction
of septic emboli producing multiple
abscesses in different organs in the
body.
• Highly virulent organism is usually
responsible.
• Septic thrombophlebitis leads to
thrombus fragmentation and
circulation in the blood to produce
septic infarctions which changes
into abscesses.
• Types:
• Systemic pyaemia: where pyaemic abscesses occurs in
areas supplied by the systemic circulation (lung, brain,
kidney etc..)
• Causes:
Acute suppurative osteomyelitis
Puerperal sepsis
Infective endocarditis
Septic thrombosis of
the cavernous sinus
Suppurative otitis media
As a complication of portal pyaemia
• Portal pyaemia:
• Pyaemic abscesses in the liver,
resulting from suppurative foci
drained by portal ciculation.
• Causes:
Acute suppurative appendicitis
Suppurative cholecystitis
Infected thrombosed piles
Septic ulceration of the intestine
 Pyaemia

• Characters of pyaemic abscesses:

 Multiple
 Small
 Nearly equal in size and similar in shape
 Surrounded by a zone of congestion & hemorrhage
 No fibrosis (usually rapidly fatal condition)