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Pathology Lecture 2 Core Batch
Introduction to Pathology
Notes
❖ Pathology is the study of suffering “scientific study of diseases” involving the Greek pathos:
processing of the disease and the structural and functional changes in tissues and suffering , logos:
organs cause or are caused by a disease. study
❖ It is a bridge -link between preclinical sciences (anatomy, physiology…) and the courses in clinical medicine.
❖ Uses molecular, microbiologic, immunologic, and morphologic techniques trying to reach a diagnosis and
Explaining clinical signs noted in the patient
Classification of Pathology
❖ Pathology could be classified into two main type:
i. General pathology: (general reactions of disease)
 Cellular and tissue responses to pathologic stimuli
 Cellular injury and cellular death
 Cellular adaptations of cellular growth and differentiation
 Homeostasis, hemodynamic disorders, genetic disorders and thrombosis
 Inflammation and repair
 Diseases of immunity
 infectious disease and environmental diseases.
 Neoplasia
ii. Systemic pathology: (specific process or reaction)
 Alterations in specialized organs and tissues in diseased status.
Core of pathology
❖ Etiology: refers to the underlying causes and modifying factors that are responsible for the initiation and
progression of disease and has 2 major classes:
i. Intrinsic(genetic): inherited defect in genetic material (chromosomes and genes)
 Examples: most common diseases, such as hypertension, diabetes, and cancer, are caused by a
combination of inherited genetic susceptibility and various environmental triggers.
 Understanding the genetic and environmental factors Notes
underlying diseases is a major theme of modern medicine So etiology refers to why disease
occur and pathogenesis to how
ii. Acquired: infectious, nutritional, chemical, physical disease progress
(environmental factors)
❖ Pathogenesis: refers to the mechanisms of development and progression of disease

 Note: Defining the etiology and pathogenesis of disease not only is essential for understanding a
disease but is providing the basis for developing treatments - Thus, by explaining the causes and
development of disease, pathology provides the scientific foundation for the practice of
medicine
❖ Disease: Accumulation of various defects, abnormalities, excesses, deficiencies and injuries occurring at
the cell and tissue level which ultimately result in clinically apparent dysfunction.
❖ Morphologic changes: structural alterations in cells and organs due to disease

❖ Clinical significance: distribution and nature of morphologic lesions determines functional changes (clinical
signs, course and prognosis of disease).
 Lesion - Alteration or abnormality in tissue due to disease.
 In the disease state, with rare exceptions, no new structures, cellular functions or new
metabolic pathways are at work. Existing pathways are accentuated, diminished or lost.
Classification of Pathology
i. Anatomical (Morbid anatomy)/surgical pathology (taken during surgery):
❖ Gross examination (naked eyes) and microscopic (under microscope) examination to reach a
diagnosis. (morphology of tissue and cell)
❖ Macroscopic and microscopic levels.
❖ Anatomical pathology: involves the examination of specimens obtained during surgery from a part of
our body such as a breast lump biopsy obtained during mastectomy.
❖ Include specialties:
A. Histopathology:
• Examination of tissues under a microscope (stained)
B. Cytopathology (cytology ”study of cell” +pathology):
• Microscopic evaluation of cells From body fluids, scrappings or aspiration to diagnosis
• Ex: cervical smear, sputum and gastric washing
C. Autopsy (Forensic pathology):
• A systematic external and internal examination of a dead body to determine if any
abnormalities are present (Post morterm examination)
D. Subspecialties:
• neuropathology, dermatopathology (skin diseases), oral pathology
❖ Anatomical pathology can be used for diagnosis through:

A. Biopsies:
1. Excisional: taken the whole tissue
2. Incisional: taken from part of the tissue
B. Smears
 Pap smear: a screening tool used to detect precancerous cervical lesions that may lead to
cervical cancer.
 Cytopathologic tests are sometimes called smear tests
 samples may be smeared across a glass microscope slide for subsequent staining and
microscopic examination.
• How are samples in smear tests collected:
- Exfoliative (surface): not accurately and may be repeated, quick , simple, Ex: from
inside the mouth
- Fine needle aspiration: deeply, collected by needles, can be performed under
palpation guidance on a mass in superficial regions like the neck, thyroid or
breast.
ii. Clinical pathology:

❖ Diagnosis and monitoring of diseases through the examination of blood, body fluids, secretions, and
tissue biopsy specimens for chemical, morphological, microbiological, and immunological
abnormalities.
❖ Hematology, microbiology, immunology , serology and biochemistry.
Specimen identification
❖ Each specimen label must contain:
 Patient name, age, sex and medical record number
 Date and time of collection
 Requesting physician's name, service, physician index number, and pager number.
 Suspected diagnoses, clinical history including previous biopsies, surgeries, prior therapies, and
diagnoses.
 Names of physicians other than the submitting physician who should receive copies of the report.
 Multiple specimens from the same operative procedure are designated as letters "A", "B”.
 Note: specimen label must contain at least: 1) Patient name 2) File number. 3) Physician name. 4)
Request form.
❖ Specimen Labeling:
 Fixation:
• We use formalin to fix the tissue and preserve it.
 Dehydration:
• Washing tissue cassettes in graded ethanol wash (50% --> 100%) to extract natural water
from the tissues.
 Clearing:
• Soaking in Citrosolv bath to make tissues miscible to paraffin in the next steps.
 Infiltration:
• Pressurized paraffin baths to infiltrate paraffin where natural tissue water was previously.
Makes the tissue uniformly the consistency of paraffin for easy sectioning.
 Embedding:
• Allowing infiltrated tissues to harden in a paraffin block.
 Sectioning:
• forming a block that is cut with a microtome into slices 7-8 μm thick for further use.
{paraffin block can be stored for 30 years and the slices (slides) for 10 years.}
 Staining:
• Rehydrate with graded ethanol to restore natural consistency of tissues so stain can
adhere. After staining, dehydrate the tissues by bring them back through the ethanol
gradient and finishing with Citrasolv to preserve the final product. Staining allows tissue
components to be distinguished from one another.
 We will stain the slide with H & E stain (Hematoxylin and Eosin) that will give us blue and pink colors
mainly under the microscope.
 The blue color always indicates for nucleus.
 The pink color always indicates for the cytoplasm.
❖ Which stain (H or E) is a basic dye?

 H
❖ What kind of charge does a basic dye carry on its colored proton?
 Net positive (+) charge
❖ What kind of tissue component is most likely to bind to basic dyes?
 Anionic components (-)
❖ What cellular components are preferentially stained by hematoxylin?
 Hematoxylin stains basophilic (Acidic) things purple. Ex. Nuclei.
❖ What term correctly describes a cell or cellular component that stains with hematoxylin?
 Basophilic.
❖ What term correctly describes a cell or cellular component that stains with eosin?
 Eosinophilic.(acidophilic)
❖ What is the role of eosin in H&E staining?
 Stains proteins red and cytoplasm pink.
Notes
Hematoxylin mnemonic: "Basic Binds Basophilic
Becoming Blue"
Eosin mnemonic: "Acidic Attaches Acidophilic Applying
Auburn"
‫ سند عصام الدويري‬:‫تنسيق ومراجعة‬

Pathology Sheets Lec-2 Core-Batch
Cellular Response
❖ In the basic formation of any living organism, it is mainly composed of the following levels:
Atoms molecules Cells tissues organs systems organism
❖ All normal cells in our body are in continuous homeostasis and are under physiological stress ( ‫) إيش هذول‬
 Homeostasis: The standard environment (balance between Notes

physiologic demand and the metabolic capacity) that the cells Increase, decrease or change in
looks to live in. this stress result in cellular
 Physiological stress: The normal stress associated to response
homeostasis.
Cellular Response to Stress
❖ Cells aim to live in a normal environment to function and survive but may sometimes undergo some
changes in Temp, Electrolytes, Glucose or pH
❖ These changes may lead to cellular responses such as:
i. Adaptation:
 It is a reversible process which includes hypertrophy, hyperplasia, atrophy & metaplasia.
ii. Injury:
 This process could be reversible or an irreversible path Notes
which leads to cell death. Reversible process means, when
iii. Apoptosis: the causative stimulus goes away
 Can occur in a sequence of events that lead to minimal the cell returns back to its normal
complications. state.
iv. Calcification i.e. Intracellular accumulation.
v. Cellular aging.
❖ The type of respond the cell chooses to undergo, depends on 3 important factors:
i. The nature & severity of the stimulus.
ii. The Duration of the stimulus.
iii. The capability of the cell to tolerate.
❖ A normal cell is exposed to a mild, stressful event (increased demand), this leads to Adaptation.
❖ A normal cell is exposed to a severe event (injury causing) (e.g. hypoxia), this leads to cell injury and then
later cell death.
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❖ If a cell is in the adaptation path and loses the capability to adapt -due to a long/severe stimulus-, it will
lead to cell injury. (non-reversible route)
❖ Prolonged, mild stimulus (hypertension) lead to adaptation response of cardiac muscles, which in this case
is hypertrophy. It will increase the thickness of the left ventricular muscle to increase workload for
stronger blood flow.
❖ Prolonged, severe stimulus (blockage of blood vessels) which lead to hypoxia, concludes in cellular injury.
Growth Adaptations
❖ These adaptive responses must always be reversible, if not reversible it's not adaptation
❖ The changes occurring on the cell might be in the size, phenotype, metabolic activity or in the function.
❖ Can be:
a. Physiological. E.g., due to increased demand of estrogen during pregnancy, the uterine size will
increase in size and thickness.
b. Pathological. E.g., Ovarian cancer produces high level of estrogen, which increases the size and
thickness of the uterine, but might lead to malignancy later on
Types of Growth Adaptations
i. Hypertrophy:
 Increasement in the size of cells, which is reflected on organs’ size, due to increased production of
structural proteins, and the size & number of organelles.
 It involves gene activation, protein synthesis and production of organelles.
(in the same cell) Notes
 Causes of hypertrophy: Always remember
A. Increased functional demand (workload) that there’s a limit
B. Stimulation by hormones or growth factors. for hypertrophy.
 Hypertrophy and hyperplasia usually occur together, but If cell can’t divide (non-dividing cells like
cardiac myocytes, skeletal muscle cells or nerve cells) then hypertrophy occurs alone
 As all adaptation responses, it can be physiological or pathological
A. Physiological hypertrophy: Building Muscles in The Gym
B. Pathological Hypertrophy: The enlargement of the cardiac muscles during HTN and Aortic
Valve diseases.
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ii. Hyperplasia:
 Increase number of cells (from stem cells) reflected on organ size.
 This process can only take place in cells that are capable of dividing.
 If we don’t treat hyperplasia , it will go on further to dysplasia which is a fertile soil for malignancy
 Causes:
a. Increased number of hormones.
b. Increased number of growth factors.
 Can be divided to:
A. Physiological hyperplasia (hormonally induced or compensatory)

- Examples:
1. Hormonal: uterus enlargement during pregnancy, breast during puberty & lactation
2. Compensatory: Partial liver resection hyperplasia.
B. Pathological hyperplasia
- Examples:
A. Hyperplasia of the endometrium (excessive hormone stimulation) and prostate hyperplasia.
B. Wound healing (effects of growth factors).
C. Infection by papillomavirus (skin warts).
❖ Hypertrophy and hyperplasia generally occur together -Mixed- (in dividing cells) (e.g. uterus during
pregnancy).
❖ In permanent tissues (non-dividing cells) (e.g. cardiac, skeletal muscles & nervous tissue) undergo
hypertrophy only (Pure hypertrophy). (e.g. hypertrophy in cardiac myocytes)
❖ Pathological hyperplasia (e.g. endometrial hyperplasia) causes dysplasia (pre-cancerous state) and
eventually cancer, except Benign prostatic hyperplasia (BPH), which does not increase the risk for
prostate cancer.
iii. Atrophy :
 Reduced size of cell, tissue or organ as a result from loss of cell substance (organelles) in size &
number, NOT number of cells.
 This process is reversible, although, cell size & function will be diminished BUT the cell is still ALIVE and
can at some point go back to normal status (reversible). So, cell death is not considered as atrophy.
 Causes of atrophy:
1. Physiological: involuting gravid uterus & Embryonic development
2. Pathological:
A. Decreased workload (Disuse atrophy)
B. Loss of innervation (Denervation atrophy)
C. Diminished blood supply
D. Inadequate nutrition
E. Loss of endocrine stimulation
F. Aging
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 Organ atrophy:
- A decrease in stress (e.g. decreased hormonal stimulation, disuse, or decreased nutrients/blood
supply) leads to decrease in organ size.
- Decrease in cell number occurs via apoptosis.
- Example: Brain atrophy
 Atrophy mechanisms:
1. Ubiquitin-proteosome degradation of the cytoskeleton:
- The protein binds organelles and starts sending signals that induce the killing of the cell by decreasing
the number of organelles.
2. Autophagy of cellular components.
- A survival mechanism in which lysosomes start the digestion of the cell's components refers to
lysosomal digestion of the cell’s own components.
3. Decreased protein synthesis & Increased protein degradation.
4. Reduced metabolic activity, which also causes decreased protein synthesis.
iv. Metaplasia:
 A reversible mechanism in which Mature cells are replaced to other types due to stress.
 Most commonly involves change of one type of surface epithelium (squamous, columnar, or urethral)
to another.
 Metaplastic cells (new mature cells) have better ability to handle the new stress.
 Pathological examples:
A. Gastric metaplasia in esophageal mucosa:
- Esophagus is normally lined by nonkeratinizing squamous epithelium (suited to handle friction of a
food bolus)
- Acid reflux (causes heartburn) from the stomach into the esophagus causes metaplasia (change of
epithelium) to non-ciliated, mucin producing columnar cells, which tolerate acidity more.
- This is done by Reprogramming of stem cells → Replacement of one cell type by another that can
adapt to a new stress.
- This example is called Barrett Esophagus. (can progress to dysplasia & adenocarcinoma)
- BUT, persistence of new epitheliums (metaplastic tissues) may lead to progression into malignant
transformation. But, this doesn’t happen in every case of metaplasia i.e. apocrine metaplasia of the
breast is a notable exception. (because it is physiological).
- Remember that metaplasia is a reversible mechanism. So, treatment of Gastroesophageal reflux may
reverse Barret Esophagus
B. Metaplasia in respiratory epithelium: (Smokers)

- Due to inhaled antigens, this might damage the columnar epithelium, and penetrate the alveoli. (can
cause shortness of breath).
- Ciliated simple columnar will transform into Squamous epithelium that withstand stress better.
- As the situation above, there is loss of some function (loss of cilia & mucin production).
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Pathology Lec 3 Core Batch
Cell injury
❖ Cell injury is a type of cellular response which occurs when the stimulus is severe and the cell can’t adapt
more
❖ The cell at homeostasis “stress” adaptation “severe or prolonged stimuli” cell injury or cell at
homeostasis “very severe stimuli” cell injury.
❖ The likelihood of injury depends on the type of stress, its severity, and the type of cell affected, Ex:
➢ Neurons are highly susceptible to ischemic injury; whereas Skeletal muscle is relatively more
resistant.
Types of cell injury
Reversible Cellular Injury:
❖ This response is different from adaption.

❖ No Damage take place to cell membrane nor to the chromatin material.
❖ In this case, if the stimulus causing response disappears the cell will go back to its normal state
❖ Most cases are pathological.
Irreversible Cellular Injury:
❖ Here, Cell membrane and chromatin material are damaged so even if the stimulus disappears, the cell
won’t be able to go back to its normal state.
❖ All of cases the undergo irreversible cellular injury are pathological.
Causes of cell injury
Hypoxia:
❖ Hypoxia is the deprivation of oxygen, so the delivery of Oxygen to tissues is decreased.

❖ Low oxygen delivery to tissue; important and most common cause of cellular injury.
1. Oxygen is the final electron acceptor in the electron transport chain of oxidative
phosphorylation.
2. Decreased oxygen impairs oxidative phosphorylation, resulting in decreased ATP production
3. Lack of ATP (essential energy source) leads to cellular injury. 1
❖ Causes of hypoxia include: ischemia, hypoxemia and decreased O2- carrying capacity of blood.
❖ The most common cause of hypoxia is ischemia (Decreased blood supply) which takes place due to:
1. Decreased arterial perfusion (e.g., atherosclerosis)
2. Decreased venous drainage (e.g., Budd-Chiari syndrome)
3. Shock-generalized hypotension resulting in poor tissue perfusion (e.g., cardiogenic,
hypovolemic [gunshot], septic...)
❖ Other causes of hypoxia include

1. Hypoxemia: is a low partial pressure of oxygen in the blood (PaO2<60 mm Hg, SaO2<90%),
Arises with:
• High altitude
• Hypoventilation
• Diffusion defect
• V/Q mismatch
2. Decreased 02-carrying capacity arises with

hemoglobin loss or dysfunction.
• Examples include:
I. Anemia (decrease in RBC mass)
II. Carbon monoxide poisoning: PaO2 is normal and the SaO2 is decreased, CO
bind more avidly to Hb than Oxygen (200x more affinity), Classic finding
is Cherry-red appearance of skin, Early sign of CO exposure is Headache;
significant exposure leads to coma and death
III. Methemoglobinemia:
• Iron in heme is oxidized to Fe3+, which cannot bind oxygen-Pao2

normal; Sao2 decreased
• Seen with oxidant stress (e.g., sulfa and nitrate drugs) or in newborns
• Classic finding is cyanosis with chocolate-colored blood.
• Treatment is intravenous methylene blue, which helps reduce Fe3+ back to

Fe2+ state
Physical agents:
❖ Mechanical trauma from an external force such as a laceration, gunshot wound, or fall.
❖ Extremes of temperature such as burns and frostbite
❖ Change in atmospheric pressure
❖ Radiation
❖ Electric shock
2
Chemical agents and drugs:
❖ Glucose (hyperglycemia in DM), salt ❖ Pollutants, insecticides, herbicides, asbestos

(electrolytes) ❖ Alcohol
❖ Arsenic compounds ❖ smoking
❖ cynaide ❖ Therapeutic drugs
Infectious agents:
❖ Viruses ❖ Fungi
❖ Bacteria ❖ Parasites
Injurious immunological reactions:
❖ When the immune system overreacts (allergic reactions against environmental substances), in other
words: hypersensitivity
❖ Excessive or chronic immune responses to microbes
❖ Attacks the own body's cells causing cell injury and creating a disease (autoimmune disease such as
RA)
Genetic derangement (create mutations):
❖ Chromosomal anomalies
❖ Gene alteration
❖ Simple amino acid alteration (Sickle cell anemia)
Nutritional imbalance:
❖ Protein calorie deficiencies, vitamin deficiencies
❖ Excess food intake (obesity, atherosclerosis, DM type2, even cancer☺)
❖ Psychiatric disorders (anorexia nervosa)
Aging:
❖ Decreased replicative and repair abilities.
Note: Changes (cell injury) can be detected by
❖ Histochemical
❖ Ultrastructural techniques
❖ Microscopy
3
❖ Grossly
Morphological alterations (changes) in reversible cell injury
1. Accumulation of fluids (cell swelling)

❖ This process is also called hydropic change or vacuolar degeneration.
❖ It is the first manifestation (change) where defection in plasma membrane ion pumps takes place
which will lead to disturbances in ionic and fluid homeostasis.
❖ Sodium ions will stay inside allowing water to follow it and accumulate inside the cell, which leads to
swelling and increase in size.
❖ Fatty change: accumulation of fat increases the size of cell, especially with cell involved or dependent
on fat metabolism. Such cells include: hepatocytes and cardiomyocytes
2. Plasma membrane changes
❖ Plasma membrane remains intact here but there will be

A. Membrane blebs
B. Blunting or loss of microvilli
C. loosening of intercellular attachments.
3. Mitochondrial changes
❖ Swelling
❖ appearance of small phospholipid-rich amorphous densities.
4. Dilatation of ER results in:
❖ detachment of polysomes (ribosomes)

❖ decreased protein synthesis
❖ possibility of myelin figure formation in the cytoplasm.
5. Nuclear alterations
❖ nuclear chromatin clumping (Why? To use the minimal amount of O2 and to avoid a death)
4
Morphologic alterations in irreversible cell injury (Necrosis)
❖ Result from:
➢ Denaturation of intracellular proteins.

➢ Enzymatic digestion of cells.
❖ Here the plasma membrane loses integrity (Its Function) leading to leakage, so the digestive enzymes will
be recruited form the cell itself or form leukocytes, resulting in:
➢ An inflammatory response will take ➢ Plasma and organelle membrane

place. discontinuities.
➢ Structural changes (need time to ➢ Appearance of myelin figures:
develop).
✓ aggregates of damaged cell
membranes (phospholipids).
➢ Increased eosinophilia in H&E stain.
✓ either phagocytosed further
degraded into fatty acids bind
➢ Vacuolation due to digestion of
calcium salts and calcify.
cytoplasmic organelles.
❖ Marked dilatation of mitochondria and appearance of large densities.

❖ Nuclear changes: nonspecific breakdown of DNA and chromatin, through:
A. Pyknosis:
➢ nuclear shrinkage and increased basophilia (darkening)
B. Karyolysis:
➢ loss of DNA because of enzymatic degradation by endonucleases (DNases), fade of basophilia
(nothing of the nucleus is visible except a purple haze)
C. Karyorrhexis:
➢ pyknotic nucleus undergoes fragmentation into nuclear dust
‫ سند عصام الدويري‬: ‫مراجعة و تنسيق‬
5
Pathology Lec - 4 Core Batch
Overview of Necrosis
 The process of irreversible cell injury on cells is called cell death, but when it happens at the level of
tissues it is called necrosis. And it Always pathological.
 The main cause of cell death in irreversible cell injury is that there is permanent damage for the plasma
membrane and the nuclear material.
 If we have plasma membrane damage and we don’t have fast regeneration of the plasma membrane,
we will end up with leakage of contents and cell death. This happens because of the denaturation of
proteins.
 Since we have enzymes in the organelles inside the cell, sometimes those enzymes will be released and
start digesting the cell from the inside; they will digest the nuclear membrane, plasma membrane and
organelles.
Pattern Tissue Necrosis

i. Coagulative necrosis:
 It is a form of necrosis in which the dead tissue architecture is preserved

for some days.
 Ischemia in any organ will lead to coagulative necrosis, except for

ischemia in brain which leads to liquefactive necrosis.
 The main cause here is denaturation of structural proteins and enzymes, which leads to digestion of the internal
contents of the cell, but will prevent plasma membrane digestion.
 The end result will be Eosinophilic anucleate cells (no nucleus because the enzymes digest the nuclear material).
 Everything inside in the cell will be in an eosinophilic color.
 The plasma membrane is partially attacked until inflammatory leukocytes and neutrophils start releasing
interleukin and cytokines, they will start digestion of the plasma membrane from the outside and they would
lead to Total resolution or total necrosis of cell.
ii. Liquefactive necrosis:
 Happens in cases of focal bacterial or fungal infections and in

hypoxic death in the central nervous system (brain mainly).
 There will be total digestion of the dead cells and the end result will
be a fluid material or busy material (accumulation of leukocytes that
give creamy yellow color) because there will not be denaturation of
the enzymes that will it prevent digestion of the cell membrane
(liquefaction).
iii. Gangrenous necrosis:
 It is not a distinctive pattern (it is like a combination between Liquefactive and

Coagulative necrosis).
 Example: necrosis that happens in diabetics. There will be a

decrease in the blood supply to the organs.
 It is usually applied to a limb mostly the lower limb, that has

lost its blood supply (ischemia) and has undergone
coagulative necrosis (dry gangrene) > because those
diabetics patients are immunocompromised and ischemia of
tissue will lead to more decrease in their immunity. They are
at higher risk to bacterial infections.
 Once infected by bacteria it becomes Liquefactive necrosis (wet gangrene).
 Another example is what happens in the intestine here we have a necrotic

intestine for the patient who developed ischemia with super added infection is in
this location.
iv. Caseous necrosis:
 White Cheese-like friable necrosis. Example: tuberculosis
 Collection of fragmented or lysed cells and amorphous

granular debris.
 Surrounded by histiocytes (macrophages) this

appearance is characteristic of an inflammation known as
a granuloma.
 Characteristic of granulomatous inflammation due to

tuberculous infection
 Under microscope, you will see eosinophilic materials

surrounded by macrophages which we called caseating
granuloma. One of the features of TB in tissues.
v. Fat necrosis:
 A clinical term and it is not a specific type (destruction of fats)
 Examples: fat necrosis of breast tissue because of trauma
 Another example: pancreatic enzymes (lipases) leakage that will

lead to fat necrosis in the abdomen in acute pancreatitis.
 in acute pancreatitis there will be stagnation (accumulation) of the pancreatic enzymes in the
pancreatic duct for a long time because of stones.
 They will start to digest the pancreatic tissue then they will go outside and start to digest the fatty
tissue. The fatty acids result from the breakdown of fat. Fatty acids will combine with calcium
leading to the formation of white chalky areas (Fat Saponification).
vi. Fibrinoid necrosis:
 Seen in immune reactions involving blood vessels where

there are complexes of antigens and antibodies are
deposited in the walls of arteries in most of cases.
 Deposits of these "immune complexes," together with fibrin

that result in a bright pink and amorphous appearance in
H&E stains.
 Example: vasculitis
 The very dense eosinophilic material is called Fibrin material.
Apoptosis
 Apoptosis is a non inflammatory programmed death of cells that could be physiological or pathological and
affect single cells.
 A pathway of cell death in which cells activate enzymes that: degrade the cell's own nuclear DNA and nuclear
and cytoplasmic proteins.
 Pathway of cell death induced by a “suicide” program in which activation of degrading enzymes takes place.
 Pathological V.s Physiological
Pathological Physiological
DNA damage due to accumulation of misfolded Involution of hormone-dependent tissue upon
proteins. hormonal withdrawl.
Certain viral infections Embryogenesis.
Morphologic appearance of apoptotic cells under the

microscope
 Cell will decrease in the size, resulting in dense cytoplasm, tightly packed organelles.
 There will be chromatin condensation peripherally under the nuclear membrane.
 Formation of cytoplasmic blebs and apoptotic bodies.
 Phagocytosis of apoptotic cells or bodies by macrophages
 On H&E stain apoptotic cell appears intensely eosinophilic or shrunken basophilic fragment surrounded by
halo.
Pathways of Apoptosis
 The process of apoptosis results from the activation of special enzymes known as caspases -which are
proteases-. This activation depends on a tuned balance between two types of proteins (pro-apoptotic
& anti-apoptotic proteins)
 The increase in levels of pro-apoptotic proteins will result in the induction of apoptosis, while the
increase in the levels of anti-apoptotic proteins, helps in the prevention of
apoptosis. Notes
Anti-apoptotic
 There are two types of caspases functioning in apoptosis:
proteins are a
A. Initiators: Caspase 8 & 9 BCL-2, BCL-X,
MCL-1
B. Executioners: Caspase 3 & 6
 Apoptotic cells are broken into fragments known as apoptotic bodies that contain portions of the cell
cytoplasm and nucleus, these bodies will later be targets for macrophages
 So apoptosis has two phases an initiating phase (happens in two ways) and an execution phase (same
way).
 Lets go into details….

A- Initiating Phase:
1. Mitochondrial (intrinsic) pathway:
 Normal cells are always reciveing energy, hormones and

growth factors that maintain levels of anti-apoptotic proteins.
 Abnormal cells will undergo an imbalance, leading to the

increase of pro-apoptotic proteins, which will ultimately start
the below story:
 This increase leads to defects in mitochondrial

preservation of cytochrome C, thus its released
through bax/bak channels .
 Cytochrome C will then bind to certain proteins known

as APAF – 1 which forms an apoptosome that binds to caspase 9 which is the critical initiator caspase.
2. The Death Receptor (Extrinsic) pathway:
 This process is initiated when TNF death receptors – Specific receptors on membrane- receive specific
signals.
 These receptors have specific cytoplasmic structures that are involved in the process of protein interaction
that are important for the delivery of apoptotic signals.
 TNF-1 receptor is related with a specific protein called Fas ( CD95), and this complex is expressed on surfaces
of many cells.
 The specific ligand of this complex is known as FasL and it is expressed in the surface of T-cells, when it sends
signals to the cell, this will lead to the activation of caspases without passing through the mitochondria
B- Execution phase:
 Initiators will activate executioners
(caspase 3&6).
 Activation of DNase
 Degradation of structural
components of nuclear matrix
(fragmentation of nuclei).
 Caspases will be activated in both intrinsic and extrinsic pathways lead to Membrane alterations and
recognition:
 Membrane alterations and recognition:

changes making cells recognizable by
phagocytes.
 Movement of some phospholipids

(phosphatidylserine) from the inner leaflet
to the outer leaflet of the membrane which
are able to bind to receptors on phagocytes.
‫ سند عصام الدويري‬:‫مراجعة و تنسيق‬

Mechanisms of cell injury

 The cellular response to injurious stimuli depends on the nature of the injury, its duration and its
severity.
 low doses of toxin or brief duration of ischemia may lead to reversible cell injury whereas large
toxin doses or longer ischemic duration result in irreversible cell injury and cell death.
 The consequences of injurious stimuli depend on the type, status, genetic makeup and adaptability of
the injured cell
 striated skeletal muscle in the leg can accommodate complete ischemia for two to three hours
without irreversible cell injury whereas cardiac muscle dies after only 20 to 30 min
 when two people exposed to the same dose of a toxin for individuals that have different genes
encoding cytochrome p-450 may catabolise the toxin at different rates leading to a different
outcome.
 Cell injury results from different biochemical mechanisms acting on several essential cellular
components (mitochondria, calcium homeostasis, plasma membranes and DNA) all play role in
mechanisim of cell injury.
 Any injurious stimulus may simultaneously trigger multiple interconnected mechanisms that damage
cells.
Biochemical mechanisms
i. Depletion of ATP
 This process takes place usually in hypoxic injuries and chemical injuries.
 ATP is the main source of energy and it is formed by oxidative phosphorylation of ADP during reduction
of oxygen in the electron-transport system of mitochondria ,and Glycolytic pathway using Glucose.
 The major causes of ATP depletion are reduced supply of oxygen and nutrients, mitochondrial damage
and the actions of some toxins (Cyanide).
 Tissues with a greater glycolytic capacity (such in the liver) are more able to survive loss of oxygen and
decreased oxidative phosphorylation better than tissues with limited capacity for glycolysis (for Ex the
brain).
A. The decrease of ATP will decrease

the activity of Na+ which will lead to
the accumulation of Na+ & Ca+2 and
the efflux of K+ which will then lead
to the accumulation of fluid and
cellular swelling thus dilation of ER,
loss of microvilli & formation of
blebs.
B. A compensatory mechanism which

leads to Anaerobic glycolysis in an
attempt to maintain the cells energy
sources as consequence the glycogen
stores are rapidly reduced leading to
lactic acid accumulation thus a
decrease in the PH which leads to inhibition of some enzymes to induce chromatin clumping.
Notes
Low oxygen situation results in
C. Depletion of ATP causes structural disruption of the protein misfolding of proteins which trigger
synthetic apparatus manifested as detachment of ribosomes a cellular response called the
in the RER and dissociation of polyribosomes into unfolded protein response that may
monosomes which leads to deficiency in protein synthesis ( lead to cell death (Activation of
apoptosis).
thus there is irreversible damage of mitochondria and
lysosomal membrane) ,this deficiency will lead to lipid deposition which is irreversible cell injury
that leads to necrosis.
ii. Mitochondrial damage
 As far as we know that the mitochondria is the major source of ATP that provides energy to the cell.
 Mitochondria is by (causes)Calcium influx, reactive oxygen species, radiation, oxygen deprivation,
toxins and mutations in mitochondrial genes.
 Know what is the Consequences of mitochondrial damage?
1. Formation of mitochondrial permeability transition pore

which leads to loss of membrane potential, failure of
phosphorylation and ATP depletion and then necrosis.
2. Release of cytochrome c into the cytosol that activate

apoptosis (death).
3. Failure of oxidative phosphorylation leads to ATP depletion
and formation of ROS
iii. Influx of calcium and loss of calcium homeostasis:
 we need to know that Depleting

extracellular Ca delays the cell death
after hypoxia and some toxins
exposures.
 Cytosolic Ca concentration is very low

(maintained by ATP dependent ca
transporters at concentrations as
much as 10000 times lower than
extracellular one ),it is present
intracellularly in mitochondria and ER.
 Ischemia and certain toxins causes an
increase in Cytosolic Ca concentration
initially because of release of Ca from the intracellular stores and influx to the plasma membrane.
 This increase leads to:
1. Opening of mitochondrial permeability transition pore, and activation of a number of enzymes

A. Phospholipases: cause membrane damage.
B. Proteases: which brake down the plasma membrane and the cytoskeleton.
C. Endonucleases: which are responsible for DNA and chromatin fragmentation & ATPases which
cause Depletion of ATP ).
2. Also it induces apoptosis by direct activation of caspases and increasing mitochondrial permeability.
Accumulation of oxygen derived free radicals

 Free radicals are chemical species that have a single unpaired electron in the outer orbital
 They are unstable atoms that react with inorganic and organic chemicals (proteins, lipids,
carbohydrates), to initiates autocatalytic reactions that will do Creation of more radicals (propagation).
Notes
autocatalytic reactions mean that one of the reaction products is a catalyst for the same reaction.
 Free radicals are important in:
1. chemical and radiation injuries.

2. ischemia-reperfusion injury (we will talk about this in future lectures ).
3. cellular aging and microbial killing by phagocytosis.
this image shows some of the formation of free radicals in life

and their sources are:
1. smoking
2. UV light
3. Metabolism of mitochondria.
4. Inflammation
5. Air pollution
6. Ionizing radiation
Reactive oxygen species (ROS)

 It is One of the oxygen derived free radicals where it is Produced
normally in small amounts and removed by defence mechanisms. Notes
 Once the ROS amount increases this will lead to what so called ROS are produced by
leukocytes and macrophages
oxidative stress which will lead to cell injury, cancer, aging and
in inflammation.
some degenerative diseases like Alzheimer.
 Generation of free radicals
1. Reduction oxidation reactions:

A. Normal mitochondrial respiration:
 molecular Oxygen is reduced by reacting with H2 to generate two water molecules to
produce:
1. superoxide anion.
2. hydrogen peroxide (H2O2)
3. hydroxyl ions (OH).
2. Absorption of radiant energy:

 in this type it uses UV light and X-rays to Hydrolyse water into OH & H free radicals.
3. Production by leukocytes:
 her the Plasma membrane multiprotein complex using NADPH oxidase, the Intracellular
oxidases such as xanthine oxidase generate superoxide anion.
4. Enzymatic metabolism of exogenous chemicals or drugs:

 they are not ROS but similar
 Ex: Carbon tetrachloride (CCL4) and Carbon trichloride (CCL3).
5. Transition metals:
 Iron and copper for example donate or accepts electrons during intracellular reaction and
catalyse free radical formation as in the Fenton reaction (H2O2+Fe²⁺ Fe³⁺+OH•+OH⁻)
 Because of intracellular free iron is in the Ferric state it should be reduced to ferrous iron to
participate in Fenton reaction. This reaction is enhanced by superoxide anion and so sources
of iron and superoxides may participate in oxidative cell damage.
6. Nitric oxide (NO) :

 it is important chemical mediator and it is generated by :
1. Endothelial cells .
2. Macrophages.
3. Neurons.
4. other cell types.
 Can act as a free radical and can also be converted to highly reactive peroxynitrite anion as well
as NO2 and NO3.
Removal of free radicals
 Free radicals are unstable and generally Decay spontaneously.

 The rate of superoxide decaying significantly increases by the action of the Superoxide dismutase
found in many cell types.
 Substances help in removal of free radicals:
Antioxidants Enzymes
Vitamin E Catalase-----H2O2 ----- O2 and H2O.
Vitamin A Superoxide dismutase.
ascorbic acid superoxide anion.
glutathione in the cytosol. Glutathione peroxidase. (Important for cell safety)
Pathological effects of free radicals

reactive oxygen species cause a cell injury by three main reactions :
1. Lipid peroxidation in membranes.

 Oxidative damage of the double bonds in the polyunsaturated fatty acids resulting in
formation of peroxides which are unstable and lead to membrane damage.
 The lipid-radical interaction yield peroxidase which is unstable and reactive and auto
catalytic chain reaction induced.
2. Oxidative modification of proteins.

 Damage the active sites on enzymes, change the structures of proteins and enhance
proteasomal degradation of unfolded proteins.
3. Lesions in DNA.
 Single and double strand breaks in DNA. Oxidative DNA damage has been implicated in cell
aging and in malignant transformation of cells.
 Please note that Radicals

are involved in both
necrosis and apoptosis
not only necrosis or in
only apoptosis but both.
‫ سند عصام الدويري‬:‫مراجعة و تنسيق‬

Clinical Applications of cellular injury

Defects in membrane permeability:
❖ Defects in plasma membrane will lead to leakage if intracellular components of the cell, and this process
happens in all types of injury except apoptosis. (Only Fragmentation)
❖ The defect in the membrane is Caused by:
A. Ischemia:
i. ATP depletion
ii. Calcium mediated activation of phospholipases
B. Direct damage:
i. Bacterial toxins
ii. Viral proteins
iii. Lytic complement components
iv. Physical and chemical agents).
❖ What is the mechanism of membrane damage ?

 We know that ROS cause lipid peroxidation, which will decrease the synthesis of phospholipids
in the membrane, and these ROS will start destroying the original phospholipids in the
membrane.
 This increased phospholipid breakdown will increase cytosolic Ca+2, and this will activate the
endogenous phospholipase aiding in more breakdown.
 The product of phospholipids (unesterified free fatty acids, acyl carnitine and lysophospholipids,
have an effect of inducing alteration in the permeability and electrophysiology of the
membrane (conc. Of ions)
 The high levels of Ca+2 leads to the activation of proteases which will lead to the damage in the
elements of cytoskeleton.
❖ Most important sites of membrane damage:

Notes
 Mitochondria
Misfolded
 Plasma membrane
proteins will
 Lysosome
trigger apoptosis
❖ Lysosomes contain many degrading enzymes like:

 RNases
 DNases
 Proteases
❖ Cells usually have mechanisms to repair DNA damage but if the damage is severe the cells initiate a
suicide program results in cell death by Apoptosis, but if apoptosis is not triggered this leads to cancer.
❖ The identification of factors that determine when reversible injury becomes irreversible and progresses to
cell death would be very useful so we may be able to identify strategies to prevent permanent
consequences of cell injury.
❖ Leakage of intracellular proteins into blood through damaged membranes provides a means of detecting
tissue damage :
A. High level of Creatine Kinase and troponin indicate Notes
Myocardial Infarction.
In order to reach a good
B. High level of ALT, AST and ALK indicate liver tissue damage.
diagnosis, we have to make
correlation between clinical and
pathological results.
Ischemic and hypoxic injury

❖ Most common type of injury in clinical medicine.
❖ Ischemia is more damaging than hypoxia, because in ischemia there will be less blood supply, therefore
less nutrients.
❖ While hypoxia is only reduction in oxygen and in this case anaerobic glycolysis can compensate a little for
the oxygen deprivation
❖ There are two ways:
A. Reversible:
 Here, there will be decrease in O2 leading to loss of oxidative phosphorylation and decreased
generation of ATP will results in a failure in Na+ / K+ & Ca+2 pumps which ends up in cellular
swelling due to fluid accumulation.
 Next there will be progressive loss of glycogen and decreased protein synthesis. (Compensatory
Mechanism.)
 Now there will be increase in cytosolic Ca+2, which will lead to loss function, cytoskeleton
abnormalities such as blebs and loss of villi, though the cell is not yet dead
 Last Step is formation of myelin figures and swollen organelles.
B. Irreversible:
 Severe swelling to the mitochondria associated with extensive damage to the plasma
membranes, myelin figures formation and swelling of lysosomes.
 Then large densities develop in the mitochondria.
 Next there will be massive influx of Ca⁺² especially if the ischemic area is reperfused.
 Death is mainly by necrosis but apoptosis also takes place-rare-
 Dead cells may become replaced by large masses of myelin figures which are either
phagocytosed or degraded more into fatty acids and may become calcified.
Ischemia-reperfusion injury
❖ Restoration of blood flow to ischemic tissues can promote recovery if they are reversibly injured.
❖ In certain situations, reperfusion paradoxically exacerbates injury (more dead cells in addition to the
already irreversibly injured cells).
❖ Mechanisms:
A. Reoxygenation:
 increased regeneration of reactive oxygen and nitrogen species from parenchymal and
endothelial cells and leukocytes. Ca⁺² influx.
B. Inflammation response:
 mediated by cytokines which recruits more leukocytes and more injury.
- Applying of Anti-cytokines might aid in decreasing the unwanted effects of inflammation.
C. Activation of the complement system:
 Some IgM antibodies are deposited in ischemic tissues for unknown reasons and once the
blood is restored complement proteins bind to those antibodies and lead to their activation
and so more injury.
Chemical injury
❖ Here the major problem leading to chemical injury is drugs
❖ Liver is a major site of drug metabolism is a target for drug toxicity.
❖ Mechanisms:
A. Directly by combining with critical molecular component. Example:
 mercuric chloride poisoning bind to the sulfhydryl groups of cell membrane proteins causing
increased permeability. More in GIT and kidney.
 Cyanide poisons mitochondrial cytochrome oxidase and inhibits oxidative phosphorylation
B. Most chemicals are not biologically active and need to be Notes

converted into active forms (toxic metabolites). Acetaminophen
 This usually takes place in liver (cytochrome P-450 (paracetamol) converted to
mixed-function oxidases). toxic products in liver
 Free radical formation and lipid peroxidation. leading to injury.
 CCl4 is converted to CCl3
 This causes lipid peroxidation and decrease export of lipids (Fatty change).
‫ سند عصام الدويري‬: ‫تنسيق و مراجعة‬

Intracellular Accumulation
❖ Intracellular accumulations are one of the manifestations(appearance) of metabolic derangements in cells

is of abnormal amounts of various substances.
❖ These substances could be transient or permanent, they also can be harmless or toxic.
❖ They accumulate in two main places:
A. Cytoplasm within the organelles.
B. Nucleus
❖ There are two main types of intracellular accumulation: Notes
A. Normal cellular components: Intracellular accumulation

 These are water, lipids, proteins and carbohydrates that accumulate could be reversible or
in excess amounts. progressive and lead to cell
death.
B. Abnormal substances:
1. Exogenous such as minerals or products of infectious agents
2. Endogenous such as a product of abnormal synthesis or metabolism
Mechanisms of intracellular accumulation
i. Inadequate removal of normal endogenous substance:

 Here there will be certain defects in packaging and transport.
 Example: fatty change in the liver.
 Fatty change most usually happens in the liver (causing a Fatty Liver) as the liver is the main site of
metabolism of lipids
 So when we have abnormal metabolism of lipids in the liver, it’ll lead to inadequate removal &
accumulation of lipids
ii. Accumulation of abnormal endogenous substance:

 Due to defects in:
1. Folding 3. Transport
2. Packaging 4. Secretion
 Example: Antitrypsin Deficiency & CNS Degenerative Disorders
• Antitrypsin deficiency usually happens in the lungs & liver, due to a defect in the folding of
antitrypsin protein leading to its accumulation.
• CNS degenerative disorder, we’ll have accumulation of proteins in brain tissue, like in diseases such
ch as Alzheimer’s disease.
iii. Normal endogenous substance accumulation

 A Normal endogenous substance will accumulate due to defects or lack in metabolic (degrading)
enzymes that are required for this substance metabolism. (can be inherited or acquired)
 Example on inherited one is Glycogen Storage Disease
• Seen in new born babies as a result of the lack of an enzymes that metabolize glycogen, therefore
glycogen will accumulate in the hepatocytes
iv. Abnormal exogenous substance accumulation

 Happens due to ingestion of indigestible materials, the cell won’t be able to degrade or transport
them.
 Examples:
• Accumulation of Carbon & Silica. As in inhaling carbon particles and so accumulation of them in the
lungs inside the lymphatic cells.
Accumulation of specific substances
1. Lipids
❖ All 4 major classes of lipids can accumulate in our body.
❖ Most common ex. Steatosis. also known as fatty change.
❖ Steatosis is the accumulation of triglycerides in the parenchymal cells, it mainly happens in the liver ,
but can also happen , in the heart, kidney and muscle .
❖ Causes: Obesity, alcohol abuse (mainly in western countries), diabetes mellitus, anoxia& protein
malnutrition (starvation).
Metabolism of fatty acids in the liver:
 when free fatty acids to the liver they are:
 catabolized to give cholesterol esters and phospholipids.

 Oxidized to give ketone bodies&CO2.
 Esterified by α-Glycerophosphate to give triglycerides,
these triglycerides can't be eliminated into the blood
unless they are transformed into lipoproteins by
apoproteins.
Any defects in these steps will lead to lipid accumulation.
Risk Factors for Lipd Accumulation

1) Alcohol increases synthesis and decreases breakdown of lipids.
2) Protein malnutrition & CCL4 reduce synthesis of apoproteins.
3) Hypoxia inhibits fatty acid oxidation (less ketone bodies – more triglycerides).
4) Starvation increases fatty acid mobilization from peripheral stores of fats, (more fatty acids enter the
liver, more synthesis of triglycerides)
5) Increased fat intake will lead to the ingestion of large fat quantities, thus the cell won’t be able to
degrade all of them
This picture shows the power detail of fatty change (Steatosis)

of the liver.
The white vacuoles represents the triglycerides (lipids) . And
some of the hepatocytes their nuclei are displaced at the
periphery due to the compression from the triglycerides.
2. Cholesterol and Cholesteryl Esters:

❖ Cellular cholesterol metabolism is tightly regulated to ensure normal generation of cell membranes
without significant intracellular accumulation.
❖ However, phagocytic cells may become overloaded with lipid (triglycerides, cholesterol, and cholesteryl
esters) in several different pathologic processes. Examples:
i. Atherosclerosis:
 Accumulation of cholesterol & cholesterol ester on the intima (walls of blood vessels), leading to
narrowing of the wall.
 Then the formation of Atherosclerotic Plaque, which reduces blood flow significantly and may later on
detach and form a thrombus which will lead to infarction or occlusion.
ii. Xanthomas:
 Accumulation of cholesterol & cholesterol ester in macrophages, which forms special foamy cells
known as xanthomas.
 Could be Hereditary or Sporadic.
iii. Cholesterolosis:
 Accumulation of cholesterol & cholesterol laden macrophages in the lamina propria of the gallbladder
3. Proteins
❖ Appears as small rounded eosinophilic droplets , vacuoles or aggregates.

❖ It is less common than lipid accumulation.
A. Accumulation of proteins the renal tubules:

 Like in some renal diseases such as Glomerulonephritis; high
abnormal filtration of protein in the glomerulus leads to a
high rate of accumulation of proteins tubules.
 This causes proteinuria (high protein in urine).
 These droplets appear as pink hyaline.
B. Excessive production of proteins (accumulation of proteins by accumulation of plasma cells):

 Plasma cells release immunoglobulins (Ig) from their surface, when the immunoglobulin accumulate,
we call them Russel Bodies (globules of proteins)
 So, the presence of Russel bodies means excessive production
of Ig in the plasma cells. (Sign of tumor of plasma cell)
 Examples:
 In Plasmacytosis (a kind of tumor).
 During Chronic inflammation.
C. Defective intracellular transport and secretion of critical proteins. Antitrypsin
deficiency
 Accumulation of mutated proteins like “α 1antitrypsin” in the liver, due to a
defect in transport & secretion mechanisms of the protein.
D. Mallory Bodies (Alcoholic Hyaline)

 Accumulation of cytoskeletal proteins like the intermediate filaments, such
as: (Keratin – Desmin – Glial – Vimentin – Neurofilaments)
 Mallory bodies are eosinophilic hyaline material, mostly seen in alcoholic
patients’ hepatocytes, in a condition called steatohepatitis.
E. Neurofibrillary Tangles in the brain tissue; as in the Alzheimer
4. Glycogen
 Accumulation of glycogen takes place due to the absence of enzymes
responsible for its digestion.
 There are two examples of glycogen accumulation:
A. Glycogen storage diseases: here Glycogen accumulates within cells in a group of related genetic
disorders.
B. DM: here glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of the
islets of Langerhans.
5. Pigments
 Pigments are colored substances that has two types:
A. Exogenous:
• The most common exogenous pigment is carbon it's an example of coal dust and air pollutant of
urban life.
• The carbon pigments are 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).
B. Endogenous:
• synthesized within the body itself, an example of endogenous pigment is :
1. Lipofuscin or “wear-and-tear pigment”

• is an insoluble brownish-yellow granular intracellular material that accumulates in a variety of
tissues (particularly the heart, liver, and brain) with aging or atrophy.
• Lipofuscin represents complexes of lipid and protein that are produced by the free radical–
catalyzed peroxidation of polyunsaturated lipids of subcellular membranes.
• The brown pigment when present in large amounts, imparts an appearance to the tissue that is
called brown atrophy.
2. Melanin:
• Synthesized by melanocytes in the skin, it accumulates due to excessive melanocytes. Appear brown-
yellow or black-yellow.
• Example: Freckles.
3. Hemosiderin:
• Hemoglobin derived pigment.
• it’s an accumulation of iron, appears golden yellow to brown.
• Excessive deposition of hemosiderin is called “Hemosiderosis” & can be found in the liver of patients
who undergo blood transfusions frequently (as people with thalassemia).
• Morphologically, it’s hard to differentiate between lipofuscin and Hemosiderin, so we use a specific
stain called “Prussian-Blue stain” and gives IRON a blue color.
Pathologic calcification
❖ It is an abnormal deposition of calcium, and it could be of two types:

A. Dystrophic:
 Calcification of dying and necrotic tissues, in the presence of normal calcium serum levels. It occurs
usually in irreversible cell injury cases.
 Pathogenesis:
• Initiation (nucleation) and propagation then formation of crystalline calcium phosphate,
Calcium is concentrated in membrane bound vesicles.
• Calcium concentrated in vesicles due to its affinity to membrane phospholipids.
• Phosphates accumulate due to phosphatases
• Over time and with the increase in accumulation of calcium, heterotopic bone may be
formed.
• Heterotopic bone may develop around collection of calcium called“Psammoma bodies”
B. Metastatic:
 Occurs in normal tissue, with high serum levels of calcium “Hypercalcemia”
 Affects tissues throughout the body.
 Mainly affects the interstitial tissues of gastric mucosa – kidneys – lungs – systemic arteries –
pulmonary veins.
 Hypercalcemia happens because of: -
1. Hyperparathyroidism
2. Destruction of the bone (Paget's disease)
3. Vitamin D related disorders
4. Renal failure
Cellular Aging
❖ Is a progressive decline in the proliferative capacity and life span of cells, and is told to be as the effect of
continuous exposure to exogenous factors that cause accumulation of cellular and molecular damage.
❖ Mechanism of cellular aging:
A. DNA damage:
 Accumulation of damaged DNA, as some aging syndromes are associated with defects in DNA
repair mechanisms.
B. Decreased cellular replication:
 With age, there will be replicative senescence (a limitation in the number of times that cells can
divide.
C. Telomeres shortening:
 As the telomeres become shortened, the end of chromosomes cannot be protected, and will be
seen as broken DNA, which signals cell cycle arrest. causing defective protein homeostasis and
the accumulation of metabolic damage and free radicals
Ways to counteract/prevent cellular aging:

1. Calorie restriction and environmental stresses alter signaling pathways that influence aging.
2. Decreased insulin/GF signaling, reduced activation of kinases and promotion of Sir counteracts aging.
Pathology Inflammation -1 Core Batch
Inflammation
❖ Inflammation is dynamic process of chemical and cytological reactions in vascularized tissue as
response to infections and tissue damage.
❖ This response brings cells and molecules of host defense from the circulation to the sites where they
are needed to eliminate the offending agents.
❖ So, inflammation will lead to the following things:
A. Accumulation of leukocytes at the site of inflammation, and fluid in extravascular tissue.
B. Systemic effects through the chemical mediators or the cytokines.
Pros & Cons of inflammation

❖ Although inflammation suggests a harmful reaction, it is actually a protective response that is
essential for survival.
❖ The main goal of inflammation is to protect our body through:
1. Eliminating the cause of cell injury to stop the ongoing process of inflammation.
2. Eliminating the necrotic cells and tissue to pave the way for repair .
❖ Without inflammation, infections would go unchecked, wounds would never heal, and injured tissues
might remain permanent festering sores.
❖ In some situations, the excessive inflammatory reaction becomes the cause of disease such cases are:
1. Autoimmune Process (Misdirected inflammation) where leukocytes will be stimulated to
recognize and attack your own cells as a foreign cells .
2. The immunological & hypersensitivity reactions (allergies) .
3. Prolonged inflammation might result because microbes would resist eradication.
❖ Anti-inflammatory drugs would control the harmful sequelae of inflammation rather than interfering
with its beneficial effects.
❖ Defective inflammation where there is too little inflammation induced by the body in reaction to an
offending agent or stimulus or infectious agent. This kind of defective inflammation is also responsible
for serious illnesses as seen in cancer and immunocompromised patients.
Causes of inflammation
1. Microbial infections (most important one) such as bacteria, Notes
viruses, fungi, parasites
In terminology there are
2. Immunologic causes may lead to inflammation such as
certain words added before
hypersensitivity (contact with some substances), autoimmune the main root word know as
reactions prefix, while words added
3. Physical agents such as trauma, heat, cold, ionizing radiation, after are known as suffix.
etc For inflammation we add the
4. Chemical agents such as acids, alkali, bacterial toxins, metals, suffix itis
etc
5. Foreign material such as sutures, dirt, etc
6. Tissue necrosis such as ischemic necrosis
Participants of inflammation
i. White blood cells and platelets
 Neutrophils, lymphocytes, monocytes eosinophils, basophils
ii. Plasma proteins

 Coagulation / fibrinolytic system, kinin system and complement system.
 Groups of proteins that are synthesized in the liver, they are found in the plasma in inactive
forms
 once we have inflammation they will be activated, and they will give byproducts each one
has a role in the inflammation
iii. Endothelial cells and smooth muscles of vessels

 They secrete chemical mediators that have an influence on the inflammatory response.
iv. Extracellular matrix and stromal cells

 Mast cells, fibroblasts, macrophages & lymphocytes.
 Structural fibrous proteins, adhesive glycoproteins, proteoglycans, basement membrane
 All of them function late in the process of inflammation, mostly in healing and repair.
Types of Inflammation
Steps of a typical inflammatory reactions

❖ Offending agents (in extravascular tissues), are recognized by host cells, macrophages and other
sentinel cells in tissue which might be dendritic or mast cells, initiating inflammation.
❖ Certain Mediators are released (amines, cytokines), then Leukocytes and plasma proteins are recruited
from inside the blood vessels to the site where the offending agent is located.
• This Step needs vasodilation and increase the vascular permeability to facilitate the extravasation of
these WBCs to extracellular tissue or matrix and this may lead to edema.
❖ Leukocytes and proteins are activated and work together to eliminate offending agents by cytokines
and the growth factor which are released mainly by macrophages and other WBCs.
❖ The reaction is controlled and terminated.
❖ The damaged tissue is repaired by fibroblasts and the matrix proteins and the cells.
Acute inflammation
❖ It is an early response of the vascularized tissue toward the injury which is orchestrated by release of
chemical mediators.
❖ It aims on recruiting neutrophils (first 3 days) and then macrophages or monocytes (after day 3).
❖ Macrophages and monocytes function is to clear the cause of injury and remove necrotic cells
(phagocytosis) they also help in the healing and repair process.
❖ Acute inflammation also aims to deliver plasma proteins: antibodies, complement, others.
Local manifestations of acute inflammation

Notes
1. When there is inflammation the first manifestation is:
Capillary bed Is where the smallest
 increase blood flow because of vasodilation.
arterioles and the smallest venules
 Expansion of the capillary bed as a result of increased are anastomosing
blood flow and vasodilation and the stasis this will lead to
increase vascular permeability
2. Deposition of fibrin and other plasma proteins in the extracellular matrix and fluid , and this will lead
to EDEMA which will expand that extracellular matrix.
3. neutrophils emigration from inside the circulation to outside
The Two Components of Acute Inflammation:
A. Cellular Events
B. Vascular changes:
1. Vasodilatation:
 Vasodilation takes place under the action of histamine on vascular smooth muscle which results in
more blood coming to the area, because of cytokine release.
 Weakens the junctions in the interepithelial space to allow cells and plasma proteins to get into the
interstatium.
 It is the most important step in vascular changes.
2. Increased vascular permeability:

 Movement of fluid from inside to outside the blood vessel (extravasation).
 This is increased by the endothelial contraction of blood vessels.
 This step also helps neutrophils and leukocytes to reach the extravascular space.
3. Stasis:
 Is a process when the blood flow is reduced due to (slowly moving red cells) in order to allow
chemical mediators and inflammatory cells to respond.
 Seen histologically as vascular congestion and externally as localized redness (erythema) of the
involved tissue.
 How is stasis initiated?

• We already knew that the first manifestation of acute inflammation is vasodilation which may be later
on preceded by transient vasoconstriction as an initial response.
• Vasodilation first involves the arterioles and then leads to openings of new capillary beds in the area
and increased blood flow, which is the cause of heat and redness (erythema) at the site of
inflammation.
• Vasodilatation is followed by increased permeability which will aid in outpouring of an exudate (a
protein rich fluid).
• The loss of this fluid and increased vessel diameter leads to lower blood flow and increased viscosity of
the blood. These changes result in stasis. Stasis will allow leukocytes to migrate to site of inflammation.
Mechanisms of increase vascular permeability ( vascular leakage )
1. Endothelial cell retraction:

 Reversible process leading to opening of inter-endothelial
spaces.
 Immediate transient response with short life (15-30 minutes).
 Induced by histamine, bradykinin, leukotrienes, neuropeptide
substance p.
 Occurs mostly in post capillary venules.
2. Direct endothelial injury:

 Occur in severe injury (burns or microbial toxins).
 Endothelial cell necrosis and detachment
 Immediate sustained response
 All microvessels can be affected by this kind of injury.
3. Increased transport of fluid and proteins:

 intracytosis through the endothelial cells, which is usually
stimulated by vascular endothelial growth factor (VEGF)
4. Delayed prolonged response:

Begins after delay (2-12 hours), lasts for hours or days.
Caused by thermal injury , ultraviolet(UV) radiation , bacterial toxins.
5. Leukocyte-dependent endothelial injury .

6. Leakage from newly formed blood vessels.
Cellular events:
Selectins.
❖ These events happen with the help of CAMS family, and
❖ Transmembrane glycoprotein receptors
they are:
that mediate the initial weak interactions
between leukocytes& endothelium.
1. Leukocyte adhesion to endothelium ❖ Expressed on the surface of endothelial
A. Margination: cells and surface of leukocytes, they bind
 When blood flows from capillaries into post-capillary selected sugars only.
venules, the circulating cells will be pushed towards the ❖ The need calcium to bind a ligand.
vessel wall. ❖ 3 types:
i. E-selectin (CD62E) → Endothelial cells.
 RBC being smaller, thus faster, will be confined to the
 expressed in very low level in normal
center of the flow, while WBC, will be pushed towards the
situations, and then upregulated after
wall of the vessel. the stimulation of cytokines and
 But the high blood flow will prevent them from attaching other mediators(IL-1 & TNF).
to the endothelium.
 Now, stasis causes, some hemodynamic ( wall shear stress ii. P-selectin (CD62P) → Platelets and
decreases). endothelial cells.
 In result, more WBC take a peripheral position close to the  functions as a cell adhesion molecule
endothelial wall. on the surfaces of activated
 This process of redistribution of leukocytes is margination. endothelial cells and platelets.
 In inactivated endothelial cells it’s
stored in the cytoplasm in a complex
B. Rolling: called Weibel-Palade bodies.
 When leukocytes are now close to the wall , they start  In minutes, After exposure to certain
detecting the changes in the endothelial wall. mediators like Thrombin and
 When the endothelial cells are activated through cytokines histamine , P-selectin will be
and mediators, they express adhesion molecules to which distributed on the surface of the cells.
leukocytes attach loosely.
 These cells then start binding and attaching, thus begin to iii. L-selectin (CD62L) → Leukocytes.
 Since these are present only on
tumble on the wall, a process called rolling.
leukocytes, this means that they will
 This process takes place by selectin (located on the
have specific ligands on the surface of
endothelial cell surface) which interacts with sialyl-Lewis the endothelial surface.
X (on neutrophils) to achieve weak adhesion (rolling).  These ligands are stimulated by the
means of IL-1 & TNF (Tumor necrosis
C. Firm Adhesion: factor) to facilitate the process of
 Chemokines( IL-8 ) are chemoattractant cytokines released adhesion between the leukocytes and
by many cells at the inflammation site. the endothelial surfaces.
 When the rolling leukocytes encounter these chemokines ,

they are activated . Ig-SF:
 The integrins will undergo specific changes thus converting  These are specific ligand present
into high affinity form. on EC for integrins that help
 On the other side IL-1 & TNF will start activating the IG-SF mediate firm adhesion.
on the endothelial cells.  They are activated by IL-1 & TNF
 Ig-SF will increase their expression of ligands for integrins,  EX:ICAM-1///VCAM-1.
THUS:
✓ ICAM-1 BINDS LFA-1//Mac-1
✓ VCAM-1 BINDS VLA-4
2. Transmigration of leukocytes (Diapedesis):

 When leukocytes are arrested on the endothelial
surface, they migrate by squeezing between cells
at the intercellular junctions.
 This extravasation is called transmigration.
 Further movement of leukocytes is done by:
• Chemokines produced in extravascular tissue
which stimulate leukocytes to travel along a
chemical gradient.
• PECAM-1 (IG-SF) is expressed on leukocytes and EC, mediates the binding events that
leukocytes need to transverse the endothelium.
3. Chemotaxis of leukocytes:
 The migration of cells after existing circulation along a chemical gradient by the help of chemotactic
factors released at the area of injury to attract neutrophils to that area.
 These chemotactic factors have several effects on leukocytes:
1) Stimulate locomotion.
2) Degranulation of lysosomal enzymes.
3) Production of arachidonic acid (AA) metabolites
4) Modulation of the numbers and affinity of leukocyte adhesion molecules.
 They also participate in the following:

1) increasing the induction of adhesion molecules on Endothelial Cells.
2) Opening of integrins on Leukocytes.
4. Phagocytosis:
 It is the process of ingestion and digestion by cells of solid substances done by neutrophils after they reach
the site if inflammation through chemotaxis. (injurious agents e.g.: other cells,bacteria, necrotic tissue or
foreign material).
 Phagocytosis undergoes many steps:
i. Recognition of the foreign bodies.
• There are many methods of recognition:
A. Opsonization:
- Immune system coats microorganism with an opsonin that facilitates the process of
recognition, e.g: (IgG, C3b, collectins) .
- Leukocytes have certain receptors that recognized opsonin upon binding, which will help them
to engulf the foreign body and form phagocytic vacuoles around them.
- These vacuoles fuse with lysosomes forming phagolysosomes resulting in degradation of the
Microorganism.
E. Cytokine receptors. B. Toll-like receptors which act as

F. Mannose receptor bind to terminal microbial sensor.
mannose residues on microbes cell C. IL-1.
wall D. Scavenger receptors: oxidized LDL,
and microbes.
G. Inflammasome: a multiprotein cytoplasmic complex that recognizes product of dead cells such as uric
acid→ activation of caspases-1 →that will lead to secretion of the biologically active
ii. Engulfing and putting them in

phagocytic vacuoles
iii. Fusion of phagocytic vacuoles with
lysosomes.
iv. Killing or degradation of ingested

material:
 The process of killing is done by
several ways:
c. Lysosomes a. Major basic protein (eosinophils)

d. Defensins especially in helminthic infections.
e. Lactoferrin. b. Bactericidal permeability increasing
protein.
f. Neutrophilic Extracellular Traps (NETs):

• An extracellular fibrillar network where neutrophils sacrifice themselves and the nucleus is
degraded to form a network (framework) of nuclear chromatin with granule protein.
• This network traps foreign microbes and provides a high concentration of antimicrobial
substances.
• In this process the nuclei of neutrophils are lost.
g. Oxygen burst products:

• It is a rapid release of ROS species from different type of cells.
• The H2O2-MPO-halide is the most efficient bactericidal system, and if anyone has
inefficiency in this system (deficiency in NADPH oxidase, dismutase, myeloperoxidase), they
become more susceptible to recurrent infections.
• Oxygen derived species have different effects:
1- At High levels:
- Endothelial damage & thrombosis
- Protease activation & inhibition of antiproteases
- Direct damage to other cells
2- At low levels:
- Increase in Chemokines, Cytokines, Adhesion molecules

h. Granule Enzymes and Other Proteins

• Neutrophils and monocytes contain granules packed with enzymes and anti-microbial
proteins that degrade microbes and dead tissues and may contribute to tissue damage.
• Types:
1- Specific (or secondary) granules
- lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase,
and alkaline phosphatase.
2- Larger azurophil (or primary) granules
- MPO, bactericidal factors (such as defensins), acid hydrolases, and a variety of
neutral proteases (elastase, cathepsin G, nonspecific collagenases, proteinase 3).
Lysosomal Content leakage
❖ The contents of lysosomes that digest phagosomes are released in specific situations such as:
A. After cell death
B. Leakage upon formation of phagocytic vacuoles
C. Frustrated phagocytosis (fixed on flat surfaces)
D. After phagocytosis of membranolytic substance, e.g. urate..
❖ Minimizing the damaging effects of proteases is accomplished by antiproteases:

A. Alpha 2 macroglobulin
B. Alpha 1 antitrypsin
Fluid in Inflammation
❖ Edema is an excess of fluid in the interstitial tissues or serous cavity which could be either exudate or
transudate.
Edema type Transudate Exudate
Mechanism Hydrostatic pressure imbalance Alteration in normal permeability of
across vascular endothelium small blood vessels in area of injury
Fluid component Fluid of low protein content (ultra Fluid of high protein content
filtrate of blood plasma) (>3g/dl) & increased cellular debris
Specific gravity <1.012 >1.020
❖ Pus is a purulent exudate rich in neutrophils, debris of cells, and microbes.
Role of lymphatic system in inflammatory reactions
❖ The system of lymphatics and lymph nodes filters and polices the extravascular fluids.
❖ In inflammation, lymph flow is increased to help drain edema fluid that accumulates because of
increased vascular permeability so lymphatic activity will increase.
❖ leukocytes and cell debris, as well as microbes, may find their way into lymph.
❖ Lymphatic vessels, like blood vessels, proliferate during inflammatory reactions to handle the increased
amount of fluid.
❖ The local inflammatory reaction may fail in containing the injurious agent
❖ The lymphatic system is considered a part of the Secondary line of defense through two main parts:
A. Lymphatic system:
 Lymphatic vessels drain offending agent, edema fluid & cellular debris, and may become
inflamed (LYMPHANGITIS).
 Draining Lymph nodes may become inflamed (LYMPHADENITIS).
 Secondary lines of defense may contain infection, or may be overwhelmed resulting in
BACTEREMIA.
B. Macrophage phagocytic system (MPS):

 This is a system of phagocytic cells found in the spleen, liver & Bone Marrow
Miscellaneous Notes
❖ Historical background of inflammation:
 Egyptian Papyrus 3000 BC: people first knew
inflammation during this era.
 Roman Celsus 100 AD: he was the first to
put the 4 cardinal signs of inflammation
 German Virchow 19th Century: a
pathologist, he added the 5th sign of
inflammation.
 Scottish Hunter 1793: he said that
inflammation is not a disease, and he even
wrote about the beneficial aspects of
inflammation.
 Russian Metchnikoff 1880: he was the first
to describe phagocytosis.
 Thomas Lewis 20th Century: he was the first
to describe the role of histamine as
inflammatory mediator.
❖ Cardinal Signs of inflammation:

A. Heat for the Latin calor
B. Redness for the Latin rubor
C. Swelling for the Latin tumor
D. Pain for the Latin dolor
E. Loss of function for the Latin functio laesa, it was added by Virchow.
❖ Cholecystitis is the inflammation of gallbladder
T A B L E 3.4 Endothelial and Leukocyte Adhesion Molecules
❖ The most important leukocytes in typical inflammatory reactions Family Molecule Distribution Ligand
Neutrophils, monocytes
are the ones capable of phagocytosis and chemotaxis, namely, L-selectin
T cells (naïve and central
memory)
Sialyl-Lewis X/PNAd on GlyCAM-1,
CD34, MAdCAM-1, others; expressed
(CD62L) B cells (naïve) on endothelium (HEV)
neutrophils and macrophages Sialyl-Lewis X (e.g., CLA) on
glycoproteins; expressed on
❖ Macrophages also produce growth factors that aid in repair E-selectin

(CD62E)
Endothelium activated by
cytokines (TNF, IL-1)
neutrophils, monocytes, T cells
(effector, memory)
❖ Nobel prize in physiology sas awarded jointly to William G. P-selectin

Endothelium activated by
cytokines (TNF, IL-1),
histamine, or thrombin;
Sialyl-Lewis X on PSGL-1 and other
glycoproteins; expressed on
neutrophils, monocytes, T cells
Selectin (CD62P) platelets (effector, memory)
Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza "for their ICAM-1 (CD54), ICAM-2 (CD102);
Neutrophils, monocytes, T expressed on endothelium
discoveries of how cells sense and adapt to oxygen availability. LFA-1
(CD11aCD18)
cells (naïve, effector,
memory)
(upregulated on activated
endothelium)
ICAM-1 (CD54), ICAM-2 (CD102);
expressed on endothelium
MAC-1 (upregulated on activated
(CD11bCD18) Monocytes, DCs endothelium)
Monocytes VCAM-1 (CD106); expressed on
VLA-4 T cells (naïve, effector, endothelium (upregulated on
(CD49aCD29) memory) activated endothelium)
Monocytes VCAM-1 (CD106), MAdCAM-1;
α4β7 T cells (gut homing naïve expressed on endothelium in gut and
Integrin (CD49DCD29) effector, memory) gut-associated lymphoid tissues
Ig CD31 Endothelial cells, leukocytes CD31 (homotypic interaction)
Pathology Inflammation - 2 Core Batch
Chemical Mediators of Inflammation

❖ Recruiting leukocytes to the site of infection or inflammation is eliminates the offending agent and this
is regulated by chemical mediators.
❖ Chemical mediators are substances that initiate and regulate the inflammatory response, Example:
Adhesion molecules and cytokines
❖ Understanding these chemical mediators and their MOA helps in designing Anti – Inflammatory drugs,
like aspirin, acetaminophen (paracetamol), and ibuprofen.
General Characteristics
❖ They Bind to specific cellular receptors, or have some enzymatic activity to stimulate target cells in
order to release secondary mediators with similar or opposing functions (depending on the stage of
inflammation).
❖ May have limited targets, or wide spread activities (especially if they are produced through enzymatic
activity) like: IL-1.
❖ They have short lived function due to protective mechanisms like:

A. Short half-life (AA metabolites).
B. inactivation by enzymes (bradykinin is inhibited by kininase)
C. Elimination (antioxidants on O2 species)
D. Inhibition (complement inhibitory proteins): each mediator has a specific inhibiting
mechanism that will inhibit it after the function is achieved.
❖ It’s very important to have check points that inhibit them → if unchecked, they cause harm (they will
start destroying normal cells).
Sources of Chemical Mediators

❖ Chemical mediators may be produced locally into the site of inflammation by inflammatory cells or may
be derived from other inactive precursors of cells
❖ Ways of producing Chemical mediators:

1. Circulating plasma proteins (Plasma Derived factors):

 Activated upon stimulation (inflammation) at the site of infection.
A. Kinins B. Complement B. Coagulation / fibrinolytic

factors.
2. Cell/tissue derived:
 There are two types of cell-derived chemical mediators:
A. Formed elements:
• Normally sequestered in granules (always inside the cells)
• Vasoactive amines (serotonin and histamine)
B. Newly synthesized in response to stimulation:

• Prostaglandins (PGs), leukotrienes (LT), ROS, nitric oxide (NO), Cytokines, platelets
activating factors (PAF).
Vasoactive amines
❖ They are cell derived chemical mediators found inside granules that burst upon stimulation and were
named so due to their important function on blood vessels.
❖ There are two main types of vasoactive amines:
A. Serotonin:
 It is a neurotransmitter in the GIT, and it is stored in platelets mainly.
 Serotonin Release is mainly induced by Platelet aggregation & PAF.
B. Histamine:
 Histamine is mainly stored in basophils, mast cells and platelets.
 Cause arteriolar dilatation and increased vascular permeability (principal mediators of
Immediate transient phase of increased vascular permeability)
 Induce endothelial cell contraction in venules.
 Release of histamine is induced by:

1. Physical injury (including trauma and heat)
2. Binding of IgE to Fc receptors
3. Anaphylatoxins: C3a, C5a binding, they play a great roll in anaphylactic shock.
4. Histamine binding proteins derived from PMNs
5. Neuropeptides (Substance P)
6. Cytokines (IL-1, IL-8)
 Histamine binds to H1 receptor (receptors present on microvascular endothelial cells)

 Inactivated by histaminase.
 Antihistamine drugs are medications against histamine and serotonin release, they reduce
mast cell production. They are H1 receptor antagonists.
 Examples of these drugs include allerfin, histal, lortadine, and telfast.
 H2 receptors are found in the stomach.
Arachidonic Acid metabolites

❖ Arachidonic acid is a 20-carbon polyunsaturated fatty acid present in the membrane and it is obtained
from dietary sources or by conversion from the essential fatty acid linoleic acid.
❖ Mechanical, chemical, and physical stimuli or other mediators (e.g., C5a) trigger the release of
arachidonic acid from membranes by activating cellular phospholipases, mainly phospholipase A2
(PLA2) which converts them into bioactive mediators.
❖ These mediators (known as eicosanoids) are synthesized by two major classes of Notes
enzymes: PGI2 is both a
prostaglandin
1. Cyclooxygenases and prostacyclin
 works on the arachidonic acid, produces PGG2, PGH2 and further on Prostacyclin (PGI2),
Thromboxane A2 (TXA2), PGE2 and PGD2, along with PGF2. All these products are called
prostaglandins
• PGI2 vasodilation and inhibits platelet aggregation
• TXA2 vasoconstriction and promotes platelet aggregation
• PGD2, PGE2, PDF2 vasodilation and increases vascular permeability (Edema)
• PGE2 pain induction, in addition to making the skin hypersensitive to painful stimuli and
causes fever during infections
2. Lipoxygenases
 This enzyme produces leukotrienes and lipoxins, by the help of two main enzymes that
mediate this pathway.
 These enzymes are:
A. The 5-lipooxygenase:
• This enzyme gives 5 HETE (from 5 -HPETE)which aids in chemotaxis.
• It also gives leukotrienes LTA4, LTC4, LTD4, LTE4 which are involved in vascular and
smooth muscle reactions
- LTC4, LTD4, and LTE4 cause bronchospasm, vasodilation, increased vascular
permeability, thus inducing inflammation
• LTA4 gives rise to a special leukotriene known as LTB4 which is a chemotactic factor
along with 5 HETE.
B. 12-lipooxygenase:
• gives lipoxin A4 (LXA4) and lipoxin B4 (LXB4) which work as anti-inflammatory
mediators.
• They inhibit neutrophils adhesion & chemotaxis --they start their work at the very end
of inflammations.
Notes:
Anti-inflammatory drugs work basically on the first step affecting phospholipase to inhibit AA secretions
steroids, considered as magical drugs inhibits phospholipase
NSAIDS are COX-1 & COX-2 inhibitors, in which they block PG's synthesis, thus prescribed for fever and
pain. Ex: Aspirin, ibuprofen, indomethacin.
It is much better to prescribe COX-2 selective drugs, because they are gastric protective, unlike COX-1
inhibitors which will alter the stomach functionality.
Montelukast is a LT receptor antagonist which is prescribed for patients of hypersensitivity and

asthmatic patients to relax bronchial muscles.
Platelet-activating factor
❖ Produced together with the arachidonic acid metabolites synthesis, generated from membranes
phospholipids by Phospholipase A2.
❖ Function:
 Aggregates and degranulates platelets.
 Potent vasodilator and bronchoconstrictor(like leukotrienes) and Increased vascular permeability
❖ Effects on leukocytes
 Increase adhesion to endothelial cells
 Chemotactic
 Degranulation (of lysosomal enzymes and granules i.e. serotonin)
 Oxygen burst (production of ROS)
Cytokines
❖ These are proteins that regulate and mediate immune & inflammatory reactionsand are secreted by
many types of cells:
4. endothelial 1. activated lymphocytes

5. epithelial 2. macrophages,
6. connective tissue 3. dendritic cells
❖ Cytokines participating in inflammation are hormone-like polypeptides produced by cells, involved in

cell - cell communication.
❖ Features:
A. Pleiotropic effects (have many effects).
B. Secretion is transient (for a short period of time)
C. Effects: autocrine (same cell), paracrine (neighbor cell), endocrine (distant cell).
❖ Classes of Cytokines:
Lymphocyte function Chemotactics Hematopoietic growth Primary responders to
regulators factors injury(innate immunity)
IL-2 Stimulates IL-8 IL-3 & GM-CSF help Major role in

proliferation regenerate leuckocytes inflammation
TGFβ inhibits lymphocytes IL-1 & TNF
growth
IL-1 & TNF:

These are secreted from macrophages, upon the stimulation of bacterial products, immune complexes,
endotoxins, physical injury, other cytokines
Effects :
1) Systemic Acute phase response:
❖ Acute-phase proteins; some proteins that's level increases in the serum which are indicative of acute
inflammation, for example (C reactive protein).
❖ Sometimes if the inflammatory was very severe it could lead to a shock, like the anaphylactic shock
❖ Responsible for neutrophilia (increases neutrophils in peripheral blood)
2) In the blood vessels

❖ It induces the endothelial cell to secrete even more of IL-1 and IL-8, IL-6 and PDGF.
3) Proliferation of fibroblasts
❖ TNF antagonists have been remarkably effective in the treatment of chronic inflammatory diseases,
particularly rheumatoid arthritis, psoriasis, and some types of inflammatory bowel disease One complication
of this therapy is increased susceptibility to mycobacterial infection, resulting from reduced ability of
macrophages to kill intracellular microbes.
Chemokines
❖ These are related chemotactic polypeptides, all of which have 4 cysteine residues.
❖ Chemokines are a family of small (8–10 kD) proteins that act primarily as chemo-attractants for specific
types of leukocytes.
❖ About 40 different chemokines and 20 different receptors for chemokines have been identified.
❖ Chemokines regulate adhesion, chemotaxis and activation of leukocytes.
❖ Important for proper targeting of leukocytes to infection sites. Chemokines mediate their activities by
binding to seven-transmembrane G protein–coupled receptors.
❖ They have two main functions:
1. In Acute inflammation (inflammatory chemokines)
2. Maintenance of tissue architecture (homeostatic chemokines), Produced constitutively by
stromal cells in tissues.
❖ Classification of chemokines:
- They are classified into four major groups, according to the arrangement of cysteine (C)
residues in the proteins.
- The largest family consists of CC chemokines, so named because the first 2 of the 4 cysteine
residues are adjacent to each other.
- We have another family called CXC and they have one amino acid residue separating the
first two of the four conserved cysteines. These chemokines act primarily on neutrophils.
❖ Examples of CC chemokines:
 CCL2: Monocyte chemoattractant protein 1 (MCP-1)
 CCL3 & CCL4: Macrophage inflammatory protein 1 (MIP-1a & 1b).
 CCL5: RANTES (regulated and normal T-cell expressed and secreted).
 CCL11: Exotoxin.
❖ Examples of CXC chemokines: Notes
 CXCL8: IL-8, neutrophil chemotactic. Although the role of chemokines in
inflammation is well established, it
has proved difficult to develop
chemokine antagonists that
suppress inflammation, perhaps
because of the functional
redundancy of these proteins.
Nitric oxide
❖ Produced from arginine by the effect of the enzyme nitric oxide synthase (NOS)
❖ NOS has 3 different isoforms (depending on its site): nNOS(neuronal), iNOS (inducible, - inside
macrophages-), eNOS (endothelial cell)
❖ Role in inflammation:
1. Vasodilator (smooth muscle relaxant).
2. Antagonist (against)of platelets adhesion, aggregation and stimulation.
3. Reduces leukocytes adhesion and recruitment.
4. Microbiocidal in activated macrophages.
❖ eNOS (in the blood vessel), it reduces leukocytes adhesion and inhibits platelet aggregation
❖ eNOS and nNOS are constitutively expressed at low levels, and the NO they generate acts to maintain
vascular tone and as a neurotransmitter, respectively.
❖ iNOS (inside the macrophage activated by cytokines), it produces ROS (reactive oxygen species) to kill
the microorganism, it also induces the production of NO
Plasma Derived mediators.

❖ These mediators are synthesized in the liver , and they are 4 major clases:
Clotting / fibrinolytic system

❖ In this pathway a protein gets activated and
then leads to the activation of remaining
proteins, so its called cascade.
❖ There are two pathways to stimulate the
clotting / fibrinolytic system:
A. Intrinsic pathway:
 factor 12 is activated with the help of
HMWK and prekallikerin negative
surface
 Activated Fac.12 activates fac.11 , activated fac.11 activates fac.9

 Activated fac.9 with the presence of activated fac.8 activates fac.10
 (after this point is a common pathway between intrinsic & extrinsic)
 Activated Fac.10 turns prothrombin to thrombin and thrombin degrades fibrinogen and turns it into
fibrin.
 Fibrin is usually present in monomers but in the presence of the activated fac.13, they cross link with
each other (to form a blood clot).
B. Extrinsic Pathway:
 starts with fac.7 and with the help of tissue factor (TF) it gets activated, then continues the
common pathway from the step of activating fac.10 and goes along with it.
The fibrinolytic pathway:
 XIIa activates prekallikrein which activates kallikrein.

 Kallikrein promotes the formation of plasmin from plasminogen, and plasmin in turn breaks fibrin
down into split products.
 Also, plasmin could activate other systems --> the complement system, and it can as well activate
factor XII.
Notes :
•Fibrin clot at site of injury helps in containing the cause
•Fibrin clot provides a framework for inflammatory cells
•Xa (activated 10) causes increased vascular permeability and leukocytes emigration.
•Thrombin causes leukocytes adhesion, platelets aggregation, generation of fibrinopeptides (a by-
product when turning fibrinogen into fibrin), and is a chemotactic.
•Fibrinopeptides are chemotactic & induce vasopermeability.
•XIIa (activated 12) also activates the fibrinolytic pathway*** (breaks excess fibrin after
mission is accomplished) to prevent widespread thrombosis.
•Fibrin split products increase vascular permeability.
•Plasmin cleaves C3 to form C3a, which is an anaphylatoxin that causes vasodilatation and increased
permeability (along with C5a & C4a).
• Plasmin activates XIIa amplifying the entire process.
Thrombin as an Inflammatory Mediator:
 Thrombin binds to specific protease-activated receptors (PARs) expressed on platelets, endothelial

cells, smooth muscles leading to:
- P-selectin mobilization.
- Expression of integrin ligands.
- Chemokine production.
- Prostaglandin production by activating cyclooxygenase 2.
- Production of PAF (platelet-activating factor)
- Production of NO (nitric oxide).
Kinin System
❖ These are vasoactive peptides derived from kininogens (plasma proteins), by the action of kallikreins
and the help of HMWK.
❖ Effects of bradykinin
 Increased vascular permeability
 Arteriolar dilatation
 Bronchial smooth muscle contraction (bronchospasm)
 Pain
❖ Bradykinin has a short half-life because they are in activated inactivated by kininases
Complement system
❖ A collection of soluble proteins (More than 20) and their membrane receptors that function mainly in innate
and adaptive immunity against microbes and in pathologic inflammatory reactions.
❖ Several cleavage products of complement proteins are elaborated that cause increased vascular permeability,
chemotaxis, and opsonization.
❖ It has different pathways for its activation

1. alternative pathway
2. lectin pathway
3. plasmin pathway
Classical pathway: Alternative pathway: Lectin

C1 is activated by the presence of a new The presence of a Microbial pathway:
complex that has (IgG, IgM) to form C1a surface molecule
(Polysaccharide, endotoxin, Will be
C1a activates (C2 + C4) to C3 convertase LPS) will trigger the activated
to cleave in C3 to C3a and C3b conversion of C3 to C3b by some
directly. certain
C3b(opsonin) drives the C5 convertase
bacteria
which together with C3 convertase Then with the presence of that has a
cleave in C5 to give C5a and C5b. factor D and factor B it mannose-
turns into C3 convertase binding
C5b will activate the rest C6+C7+C8+C9 and from there to continue lectin
to give MAC (membrane attack complex) normally like in the classical (MBL)
which attacks the membrane of the MO pathway.
causing cell lysis and so killing the MO.
Role of complement in inflammation

C3a and C5a (anaphylatoxins) increased vascular permeability, and cause mast cell to secrete histamine
C5a activates lipoxygenase pathway of AA.
C5a activates leukocytes, increased integrins affinity.
C5a is chemotactic.
C3b and iC3b are opsonins.
Plasmin and proteolytic enzymes split C3 and C5.
Membrane attack complex (C5-9) lyse bacterial membranes.
Defects in complement system

Deficiency of C3 no complement system susceptibility to infections
Deficiency of C2 and C4 susceptibility to SLE
Deficiency of C6, C7, C8, C9 low MAC Neisseria infections.
Inhibitors of C3 and C5 convertase DAF, decay accelerating factor hemolytic anemia (PNH)
C1 inhibitor angioneurotic edema
Morphologic appearance in acute inflammation

❖ Morphologic hallmarks of acute inflammatory reactions are:
A. Dilation of small blood vessels
B. Accumulation of leukocytes
C. Edema (Fluid in the extravascular tissue).
❖ Sometimes there are special morphologic patterns that appear, depending on certain factors:
A. Severity of the reaction
B. Cause of inflammation,
C. Type of tissue
D. Site of tissue
❖ The importance of recognizing distinct gross and microscopic patterns of inflammation is that they
often provide valuable clues about the underlying cause.
Types of morphologic appearances
Catarrhal Serous Fibrinous Suppurative (purulent):

Acute inflammation + Abundant protein-poor fluid Accumulation of thick such as in Acne
mucous with low cellular content exudate rich in fibrin, Pus: Creamy yellow or
hypersecretion (e.g. (transudate), e.g. skin may be resolved by blood stained fluid
common cold) blisters fibrinolysis or consisting of neutrophils,
and body cavities (This type organized into thick proteins , MO
clears away with ease and fibrous tissue (e.g. &tissue debris
without any consequences) acute pericarditis) e.g. acute appendicitis
(Pus is an Exudate).
Abscess: Focal localized
collection of pus
Empyema: Collection of
pus within a hollow
organ
Outcomes of Acute Inflammation.

1. Complete resolution (back to normal)
❖ This is the usual result for acute inflammations, where the tissue goes back to its normal state.
❖ 4 conditions must be met or resolution which are:
A. Injurious Stimuli is cleared

B. Exudate, debris & fibrin are removed . Notes
C. Any changes in the microvasculature is reversed. If one of these conditions aren’t met,
other outcomes will happen (no
D. Parenchymal cells that have been lost during the process
resolution)
are replaced.
2. Healing:
❖ organization by fibrosis (scar) through formation of Granulation tissue
❖ This happens when there is:
A. Substantial tissue destruction (severe inflammation). Notes:

the outcome of acute
B. Tissue cannot regenerate (as in myocardial infarction
inflammation is usually
because myocardiocytes are non-dividing). resolution. But Fibrosis can
C. Extensive fibrinous exudates the fibrinolytic system can’t get happen
rid of the accumulation of fibrinous exudates efficiently in cases of: Abscess
formation (pyogenic
3. Abscess formation (Purulent):
organisms), organization
❖ Takes place in immunocompromised patients. and repair (excessive
destruction) and chronic
4. Progression to chronic inflammation: inflammation (persistence of
injurious agent).
❖ Caused by failure to contain the injurious agent.
Effects of Acute Inflammation:
Beneficial Harmful
Elimination of injurious stimulus & dilution of toxins. Digestion of normal tissues.
Inappropriate inflammatory response &
Delivery of nutrients & oxygen & Drug transport. Swelling.
Stimulation of the immune response & Entry of

antibodies.
Fibrin formation.
Miscellaneous Notes
❖ Studies performed more than 50 years ago suggested that inhibiting coagulation reduced the inflammatory
reaction to some microbes, leading to the idea that coagulation and inflammation are linked processes.
❖ This concept was supported by the discovery of protease-activated receptors (PARs), which are activated by
thrombin (the protease that cleaves fibrinogen to produce a fibrin clot).
 PARs are:
• Expressed on leukocytes, suggesting a role in inflammation.
• Their clearest role is in platelets, in which thrombin activation of a PAR known as the thrombin
receptor is a potent trigger of platelet aggregation during the process of clot formation.
• All forms of tissue injury
that lead to clotting also
induce inflammation,
and inflammation
causes changes in
endothelial cells that
increase the likelihood
of abnormal clotting.
• This mechanism is the
clotting system
Ulcers:
❖ Defects in the surface lining of an organ or tissue.

❖ Foot ulcers: it can happen with Diabetes patients, Ischemic heart disease patients, which will lead
to issues with peripheral vascularization.
❖ Burn blister: an example of serous appearance.
The following tables summarize some of the topics discussed previously:

Chronic Inflammation
❖ Chronic inflammation is a response and inflammation that may start slowly or rapidly and has of
prolonged duration for weeks, months or years.
❖ The main trigger for chronic inflammation is a balance between, the persistent injurious agent &
inability of the host to overcome the injurious agent.
❖ General Characteristics of chronic inflammation:

1. Type of cells that infiltrate during chronic inflammation is mononuclear cells, such as
Lymphocytes, Plasma cells & Macrophages.
2. During chronic inflammation there will be Huge substantial destruction, which means tissue
wont be able to go back to normal state.
3. The destructed tissue is repaired by 2 mechanisms:
A. Neovascularization: Formation of New Blood Vessels.
B. Fibrosis: Formation of fibrous C.T in the tissue, ex: Liver Cirrhosis.
Acute V.s Chronic Inflammation

Acute inflammation Chronic Inflammation
Type of Cells Predominance of neutrophils Predominance of
lymphocytes & macrophages
Type of infiltrate Fluid and plasma protein Vascular proliferation and
exudation fibrosis
Duration Minutes to days Days to years
Histopathology Comparison
❖ The upper slide shows the characteristics of chronic inflammation:
A. Fibrosis.
B. A Lymphoid Follicle, which is collection of chronic inflammatory cells.
C. Destruction in the parenchyma which is replaced by cuboidal epithelium
❖ The Lower slide shows the characteristics of acute inflammation:
A. Vascular congestion.
B. Predominance of neutrophils.
Stimulators (Circumstances) of chronic

inflammation
1. Some may Progress from acute inflammation; Tonsillitis, Notes
osteomyelitis, etc. Silicosis: inflammatory lung disease
2. Repeated & Continous exposure to toxic agent, such as: which results from inhaling silica for a
prolonged period of time
Silicosis, Asbestosis, Hyperlipidemia, etc.
Notes
3. Viral infections:
Hyperlipidemia: high levels of
 some viral infections, start off as a chronic inflammation cholesterol and lipids, these
with chronic infiltrate under the microscope. Ex: hepatitis induce atherosclerosis; which
 The patient may have acute symptoms but it isn’t. is a chronic inflammation
affecting the arterial wall
4. Persistent microbial infections: Mycobacteria (TB), Treponema, Fungi, etc.

5. Autoimmune disorders: Rheumatoid arthritis, Systemic lupus erythematosus (SLE), etc
Macrophages & the Mononuclear Phagocytic

System
❖ Macrophages originate from circulating monocytes, when monocytes enter the tissue, they become
macrophages.
❖ Macrophages have a different names depending on the type of tissue, such as:
A. Kupffer cells (liver)
B. Sinus histiocytes (spleen & Lymph nodes)
C. Alveolar macrophages (lung)
D. Microglia (CNS)
❖ Macrophages are activated by the cytokine IFN- γ ( Secreted from the T-cells) , once this cytokine is
secreted it inducing certain changes on macrophages such as:
 Increased cell size.
 Increased lysosomal enzymes.
 More active metabolism, i.e. greater ability to kill ingested organisms.
 Epithelioid appearance (elongated shape).
Activation Pathways of Macrophages

❖ activated macrophages aid in the destruction of the tissue,
through certain products such as:
1. Toxic oxygen 5. Arachidonic Acid

metabolites (ROS) and Metabolites
NO. 6. IL-1 & TNF.
2. Proteases. 7. Growth factors
3. Neutrophil chemotactic (PDGF, FGF,
factors. TGFβ).
4. Complement and clotting
factors
❖ After the offending agent is gone, healing by fibrosis occurs with these products:
1. Growth factors (PDGF, FGF, TGFβ). 4. Macrophages also cause “Remodeling”

2. Fibrogenic cytokines. collagenesis.
3. Angiogenesis factors (FGF) which leads to
formation of new blood vessels.
The Process of macrophages accumulation:

 Monocytes are recruited from circulation through chemotactic factors : Chemokines, C5a, PDGF, TGFα,
fibrinopeptides, fibronectin, collagen breakdown fragments.
 Proliferation of macrophages at the foci of the inflammation & and then they would remain immobile
Macrophage-lymphocyte interaction
❖ Activated Macrophages present antigens to T cells and produce cytokines (IL-(12,6,23)) which in turn activate T
lymphocytes.
❖ Activated T lymphocytes secrete IFN-γ which activate the Classical macrophage pathway, thus completing the
cycle.
❖ Activated macrophages also Secrete TNF and IL-1 induced inflammation and leukocytes recruitment while
activated T lymphocytes (TH1, TH17) secrete TNF and IL-17, inducing inflammation and leukocytes recruitment.
❖ Activated macrophages ingest debris and promote angiogenesis through secretion of growth factors.
Granulomatous Inflammation.
❖ A distinctive form of chronic inflammation
characterized by collections of epithelioid
macrophages (activated macrophages resembling
epithelial cells.)
❖ In addition to epithelioid macrophages, granuloma
may have one or more of:
A. a surrounding rim lymphocytes & plasma cell.
B. a surrounding rim of fibroblasts & fibrosis.
C. Central Necrosis like: caseating granulomas in TB
D. Giant cells.
 They are formed when multiple histiocytes fuse together, Notes:

producing one big multinucleated giant cell, we have many One of the genetically
types of giant cells, such as: inherited diseases is
1. Giant cells with scattered nuclei (not arranged at the chronic granulomatosis,
periphery) in the case of a foreign body presence. which is manifested by
the formation of multiple
2. Langerhans giant cells (horseshoe shaped), their
granulomas.
nuclei are arranged at the periphery.
Examples of granulomatous inflammation
Bacterial Myobacterium Tuberculosis

Myobacterium Leprae
Trepnema pallidum
Bartonella henslae
Parasitic Schistosomiasis
Fungal Histoplasma Capsutulam
Blastomycosis
Cryptococcus neoformans
Coccidiodes immitis
Inorganic metals Silicosis , Byerlliosis
Foreign Body Suture, other prosthesis, Keratin
Unknown Sarcoidosis
Notes
Caseating Granuloma is most common in TB
We use special stains in granuloma to rule out infections (whether they are fungal or TB) LIKE Acid fast bacillus
stain.
Morphologic Appearance of Chronic Inflammation

❖ Ulceration (Local defect or loss of continuity in surface epithelia).
❖ Chronic abscess cavity.
❖ Indurations (hardness) & fibrosis.
❖ Thickening of the wall of hollow viscous ex: chronic inflammation in the colon.
❖ Caseous necrosis (which appear as granulomatous inflammation) Ex: Tuberculosis
Systemic effects of in inflammation

1. Fever (most prominent manifestation) & Catabolism.
2. Increased slow wave sleep, decreased appetite
3. Hypotension and other hemodynamic changes.
4. Synthesis of acute-phase proteins by liver, e.g. CRP (C-reactive proteins), fibrinogen, serum amyloid A
protein (SAA), which is stimulated by cytokines, especially IL-6.
5. Leukocytosis (increase in the total of white blood cells (leukocytes)) which can be:
A. Neutrophilia: increase in the blood neutrophil count, induced by bacterial infections.
B. Lymphocytosis: increase in numbers of lymphocytes, induced by viral infections.
C. Eosinophilia: increase in number of eosinophils, induced by parasitic infections or reactions.
❖ Leukopenia: decrease in the number of white blood cells (leukocytes).

❖ Increased ESR (erythrocyte sedimentation rate):
 ESR is a blood test that can be checked in labs, but it is nonspecific, and it is only an indication that there is
an inflammation process happening (but not the type or its location).
❖ How Do these Systemic changes take place
 All of these changes happen by the cytokines (IL-1,TNF, IL-6); these mediators will increase the level of
enzymes that make prostaglandins, which is a cyclooxygenase.
 So, increasing in prostaglandins, which act on hypothalamus (responsible of body temperature) and causes
raise on the temperature, to a high-level fever (Panadol).
 These cytokines can also stimulate the pituitary gland to secrete ACTH that will stimulate the adrenal
cortex to secrete corticosteroids (cortisol).
 This will affect the liver to produce acute phase protein, which are (CRP, SAA, Fibrinogen, mannose binding
protein, complement components).
 Secretion of acute-phase proteins from the liver can also happen directly by the cytokines (IL- 1, IL-6, TNF).
 At the same time, they can stimulate the bone marrow to produce more white blood cells (leukocytosis).
Stem Cells
❖ One of the most important things in the body is to regenerate your cells.
❖ This process or regeneration is done by stem cells that share some common features:
A. Self-renewal capacity⟶ they are stable in their numbers; they do not increase or decrease.
B. Asymmetric replication⟶when the stem cell replicates into two cells one of the cells will go and
continue its journey through differentiation and maturation and the other one would go back and
be another stem cell to keep the population of the stem cells stable.
C. Capacity to develop into multiple lineages⟶ to develop into multiple lineages those are what’s
called pluripotential stem cells.
D. Extensive proliferative potential⟶ they can proliferate and they have unstoppable proliferation
activity.
Types of stem cells:

1. Embryonic stem cells:
 Pluripotent cells that can give rise to all tissues of the body which are mesoderm, endoderm
and ectoderm.
 A special type is induced pluripotent stem cells:
• Derived by introducing into mature cells
genes that are characteristic of ES cells.
• iPS cells acquire many characteristics of
stem cells.
• These cells may be used in the process of
treatment and start differentiation by certain
induction factors.
2. Adult stem cells:
 Restricted differentiation capacity (lineage specific) .
Polypeptide Growth Factors
❖ These are the most common chemical mediators affecting cell growth by binding to specific receptors
on the cell surface or intracellularly.
❖ Present in serum or produced locally
❖ Exert pleiotropic effects; proliferation, cell migration, differentiation, tissue remodeling
❖ Regulate growth of cells by controlling expression of genes that regulate cell proliferation (proto-
oncogenes)
Examples of Growth Factors

A. EGF (epidermal growth factor) & TGF-α
 Binds to its receptor ERB B1
 They exert the function Mitogenic for epithelial cells and fibroblasts also induce migration
of epithelial cells into their usual sites.
B. PDGF (platelet-derived growth factor)

 The function is Migration & proliferation of fibroblast, smooth muscle cell & monocyte also
has chemotactic ability.
C. FGFs (fibroblast growth factors)

 Mitogenic for fibroblast & epithelial cells; angiogenesis; chemotactic for fibroblasts they
recruit the fibroblasts into the sites of injury.
 Important in Wound healing.
D. VEGF (vascular endothelial growth factor)

 Important in Angiogenesis.
 Increased vascular permeability and it is also a pro-inflammatory factor.
E. HGF/scatter factor (hepatocyte growth factor)

 Mitogenic it is induce mitosis of most epithelial cells including hepatocytes.
 Promotes scattering and migration of cells.
F. Transforming Growth Factor Beta (TGF-β):

 One of the important factors
 binds to 2 receptors (types I &II) with serine/threonine kinase activity
 Those Receptors phosphorylate cytoplasmic transcription factors which are called smads.
 Smads enter the nucleus and associate with other DNA binding proteins activating or
inhibiting gene transcription.
 The thing that makes this growth factor different because it Inhibitor of most epithelial
cells and leukocytes. Increases expression of cell cycle inhibitors and prevent the
proliferation of cells like (Cip/Kip, INK4/ARF) which are anti-mitogenic
 Stimulates proliferation of fibroblasts & smooth muscles
 Stimulates fibrosis (fibroblasts chemotaxis, production of ECM, ↓ proteases activity , ↑
protease inhibitors) which means we will not have destruction of the tissue
 Strong anti-inflammatory effect
Intercellular Signaling
1. Autocrine signaling: The cell produce certain factors whether growth factor
or hormone factor and those will wind to the receptor to the same cell.
2. Paracrine signaling (local effect): it will produce this growth factor and it
will exert its function on the adjacent cells.
3. Endocrine signaling: which most hormones in our body work in this type by
production the hormone by the secretory cell into the blood and travel into
target cells which might be distant or nearby
Receptors for Growth Factors

A. Tyrosine kinase receptor:
 These receptors have kinase activities associated with the receptor itself.
 They exert their functions through different pathways, such as PI3 kinase that will phosphorylate
certain factors such as PKB\AKT.
 These phosphorylated factors will go into the nucleus and induce transcription of certain factors.
B. Receptors lacking intrinsic tyrosine kinase activity:

 These recruit special kinases like JAK, that will induce phosphorylation through specific pathways like
JAK\STAT.
 Then they will induce phosphorylation factors such as STAT, that will activate certain transcription
factors.
C. Seven transmembrane G-protein coupled receptors.

 Usually exert their function by CAMP pathway and this will exert multiple effects.
D. Steroid hormone receptors

 Usually present intracellularly and bind to the hormone then enter the nucleus.
Extracellular Matrix
❖ A major component of all tissues, provides the backbone & support. It regulates growth, movement
and differentiation of cells.
A. Basement membrane:
 Type IV collagen
 Adhesive glycoproteins
 Laminin
B. Interstitial matrix:
 The material that are present
between the cells of the tissues
1. Fibrillary and non-fibrillar
collagens
2. Elastin
3. Proteoglycans
4. Fibronectin
Components of the Extracellular Matrix

Collagen: Elastin: Proteoglycans
Adhesive glycoproteins
Most common protein Provides elasticity. Form highly hydrated A. Fibronectin
in animals. gel like material  Multiple Domains bind to
Surrounded by a meshlike
Provides strength collagen, elastin, proteoglycans,
network of fibrillin which Protein core with
The process of etc.
supports elastin many attached long  Bind to integrins via RGD
hydroxylation is deposition. polysaccharides (arginine-glycine-aspartic acid )
mediated by vit c.
Defective fibrillin leads to (glycosaminoglycans) domains
Fibrillar collagens form Marfan syndrome. Act as a reservoir for B. Laminin
most of CT in wounds  Connects cells to collagen and
& scars. Marfan syndrome that bFGF
patients have extensive heparan sulfate
Integral cell membrane
Non-fibrillar (type IV) elasticity in their joints and  Is part of basement membrane it
main component of proteins (e.g.
they have problems in has domain that binds to type 4
BM. syndecan)
heart valves. collagen and it has a domain to
bind to the cell also domain bind
to heparin sulfate or the
proteoglycan site.
Repair
❖ Repair can be done through either of two mechanisms
A. Repair by Regeneration
 Replacing injured tissue by same type of original tissue cells.
 Labile & stable cells
 Involves two tissue components:
1. Cellular proliferation that are regulated by growth factors & growth inhibitors.
2. Extracellular matrix (ECM) & cell-matrix interaction
 An intact basement membrane is essential in repair as it directs epithelial cell polarity.
B. Repair by Connective Tissue

 Severe injury with damage to parenchymal cells and stroma precludes parenchymal regeneration
like ulceration that results in damage of stem cell and basement membrane.
 Repair occurs by CT
 Here the injury is sever that cannot be repaired by regeneration then inflammation happens and
new vascularization formation the granulation tissue and then fibrosis happens and lay down of EM
which result scar formation.
 Components of CT repair:
A. Neovascularization (angiogenesis)
B. Proliferation of fibroblasts
C. Deposition of ECM
D. Remodeling
This is histological appearance of granulation

tissue it’s mainly composed of fibroblasts and a
lot of capillary sites and blood vessels and this
transition tissue that is present at the area of
injury after the injury until the proper repair by
connective tissue happens and lay down EM
happens at the area of injury.
Scar replacement of the tissue at the

injury area by fibrosis& scar tissue.
Granulation tissue a tissue similar to
transition present until C.T is laid and it is
composed of fibroblast, capillaries and blood vessels.
Angiogenesis
The process of formation of new blood vessels known as angiogenesis, is done through two ways:
A. Angiogenesis from Endothelial Precursor Cells (EPCs)
❖ Hemangioblast → Hematopoietic stem cells and angioblasts

Notes
(EPCs)
❖ EPCs are stored in bone marrow VEGF effects on endothelial cells :
❖ EPCs express markers of hematopoietic stem cells and of ↑ migration, ↑ proliferation, ↑
endothelial cells Differentiation, ↑ permeability
❖ EPCs play a role in neovascularization, replacement of Angioipoietins 1 and 2, PDGF, and TGF-β
endothelial cells, re-endothelialization of vascular implants. need to stabilize the newly formed
Sometimes patients need vascular implants in case of sever vessels and prevent them to be
atherosclerosis. damaged or raptured.
B. Angiogenesis from Pre-existing Vessels
❖ A parent vessel sends out capillary sprouts

(start branching) to produce new vessels
❖ Steps involved:
1. Vasodilation in response to NO (nitric
oxide) and increased permeability
induced by VEGF(vascular endothelial
growth factor).
2. Separation of pericytes from the
abluminal surface and breakdown of the
basement membrane to allow
formation of a vessel sprout.
3. Migration of endothelial cells toward the area of tissue injury.
4. Proliferation of endothelial cells (progenitor cells) under growth factors just behind the leading front
(“tip”) of migrating cells.
5. Remodeling into capillary tubes.
6. Recruitment of peri-endothelial cells (pericytes for small capillaries and smooth muscle cells for
larger vessels) to form the mature vessel (maturation).
7. Suppression of endothelial proliferation, migration, and deposition of the basement membrane.
❖ Growth factors involved:

1. Basic fibroblast growth factor (βFGF)
2. Vascular endothelial growth factor (VEGF)
Pathologic Aspects of Repair

Aberrations of growth may occur
A. Exuberant granulation:
 Excessive amount of granulation tissue during wound healing.
 This usually does not have bad sequences, it is temporary can go away after healing the problem.
B. Keloid:
 Excessive collagen accumulation during wound healing resulting in raised tumorous scar
C. Excessive fibrosis:
 this will result from chronic diseases like Cirrhosis, pulmonary fibrosis, rheumatoid arthritis (RA)
D. Tissue damage
Collagen destruction by collagenases in RA and formation of nodules and other rheumatological
conditions.
➢ Histologically you can notice there will be thick rope collagen at the area of keloid.
➢ This appearance of keloid how there was supposed to be scar but continuous growth and fibrosis and
deposition of collagen until it become like tumor
Miscellaneous Notes
Consequences of Defective Inflammation:
❖ Susceptibility to infections (the most important point) Defective innate immunity.

❖ Delayed repair
❖ Delayed clearance of debris and necrotic tissue & Lack of stimuli for repair.
Consequences of Excessive Inflammation:
❖ Allergic reactions (inappropriate type of chronic inflammation)

❖ Autoimmune disorders (inappropriate chronic inflammation).
❖ Atherosclerosis: it happens because of hyperlipidemia (causes chronic inflammation in blood vessels
which causes atheroma).
❖ Ischemic heart disease.
❖ Tissue repair
Impact of Embryonic Stem Cells on Medicine

• Study of specific cell signaling and differentiation steps.
• Production of knockout mice.
• Potentially, generation of specific cell types to regenerate damaged tissue (regenerative medicine)
➢ We have quiescent cells and we have stable cells that they do not divide like cardiac muscle and
the neurons so when the patient have loss in those types of cells they will never regenerate so in
regenerative medicine they are trying to regenerate those cells by production of induced
pluripotent stem cells make them differentiate and implant them in patient's damage cells area.
Examples of Adult Stem Cells Locations
• Bone marrow Hematopoietic stem cell
• Liver Hering canal
• Skeletal muscle Satellite cells
• Intestine Base of crypts

• Skin Hair follicle bulge
Notes
❖ Growth Factors, Receptors, and Signal Transduction Polypeptide growth factors act in autocrine,
paracrine, or endocrine manner.
❖ Growth factors are produced transiently in response to an external stimulus and act by binding to
cellular receptors. Different classes of growth factor receptors include receptors with intrinsic kinase
activity, G protein-coupled receptors and receptors without intrinsic kinase activity.
❖ Growth factors such as epidermal growth factor (EGF) and hepatocyte growth factor (HGF) bind to
receptors with intrinsic kinase activity, triggering a cascade of phosphorylating events through MAP
kinases, which culminate in transcription factor activation and DNA replication.
❖ G protein-coupled receptors produce multiple effects via the cAMP and Ca2+ pathways. Chemokines
utilize such receptors.
❖ Cytokines generally bind to receptors without kinase activity; such receptors interact with
cytoplasmic transcription factors that move into the nucleus.
Most growth factors have multiple effects, such as cell migration, differentiation, stimulation of
angiogenesis, and fibrogenesis, in addition to cell proliferation
Main types of healing:

1. Healing by First Intention: when operation is done open the skin and having only focal disruption
BM and it will result minimal scaring.
2. Healing by Second Intention: here having scar and clot formation then inflammation ,macrophages
,fibroblasts and then fibrous union of the tissue whether epithelialization finally we have large scar
with contraction.

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Pathology Lecture 2 Core Batch

❖ Pathogenesis: refers to the mechanisms of development and progression of disease

❖ Morphologic changes: structural alterations in cells and organs due to disease

❖ Anatomical pathology can be used for diagnosis through:

ii. Clinical pathology:

❖ Which stain (H or E) is a basic dye?

‫ سند عصام الدويري‬:‫تنسيق ومراجعة‬

 Homeostasis: The standard environment (balance between Notes

Cellular Response to Stress

Types of Growth Adaptations

 Can be divided to:

A. Physiological hyperplasia (hormonally induced or compensatory)

B. Metaplasia in respiratory epithelium: (Smokers)

Types of cell injury

Reversible Cellular Injury:

❖ This response is different from adaption.

Irreversible Cellular Injury:

Causes of cell injury

❖ Hypoxia is the deprivation of oxygen, so the delivery of Oxygen to tissues is decreased.

❖ Other causes of hypoxia include

2. Decreased 02-carrying capacity arises with

• Iron in heme is oxidized to Fe3+, which cannot bind oxygen-Pao2

• Treatment is intravenous methylene blue, which helps reduce Fe3+ back to

Chemical agents and drugs:

❖ Glucose (hyperglycemia in DM), salt ❖ Pollutants, insecticides, herbicides, asbestos

Injurious immunological reactions:

Genetic derangement (create mutations):

❖ Decreased replicative and repair abilities.

Note: Changes (cell injury) can be detected by

Morphological alterations (changes) in reversible cell injury

1. Accumulation of fluids (cell swelling)

2. Plasma membrane changes

❖ Plasma membrane remains intact here but there will be

4. Dilatation of ER results in:

❖ detachment of polysomes (ribosomes)

Morphologic alterations in irreversible cell injury (Necrosis)

➢ Denaturation of intracellular proteins.

➢ An inflammatory response will take ➢ Plasma and organelle membrane

❖ Marked dilatation of mitochondria and appearance of large densities.

‫ سند عصام الدويري‬: ‫مراجعة و تنسيق‬

Pattern Tissue Necrosis

 It is a form of necrosis in which the dead tissue architecture is preserved

 Ischemia in any organ will lead to coagulative necrosis, except for

 Everything inside in the cell will be in an eosinophilic color.

ii. Liquefactive necrosis:

 Happens in cases of focal bacterial or fungal infections and in

iii. Gangrenous necrosis:

 It is not a distinctive pattern (it is like a combination between Liquefactive and

 Example: necrosis that happens in diabetics. There will be a

 It is usually applied to a limb mostly the lower limb, that has

 Once infected by bacteria it becomes Liquefactive necrosis (wet gangrene).

 Another example is what happens in the intestine here we have a necrotic

iv. Caseous necrosis:

 White Cheese-like friable necrosis. Example: tuberculosis

 Collection of fragmented or lysed cells and amorphous

 Surrounded by histiocytes (macrophages) this

 Characteristic of granulomatous inflammation due to

 Under microscope, you will see eosinophilic materials

 A clinical term and it is not a specific type (destruction of fats)

 Examples: fat necrosis of breast tissue because of trauma

 Another example: pancreatic enzymes (lipases) leakage that will

vi. Fibrinoid necrosis:

 Seen in immune reactions involving blood vessels where