CHAPTER 2

Cellular Responses to Stress and Toxic Insults: Adaptation,

Injury, and Death
Patholo
gy
● Study of the structural, biochemical, and functional changes in cells, tissues, and organs that underlie
disease
○ By the use of molecular, microbiologic, immunologic, and morphologic techniques,
pathology attempts to explain the whys and wherefores of the signs and symptoms
manifested by patients while providing a rational basis for clinical care and therapy
● Divided into general pathology and systemic pathology
➔ General pathology: common reactions of cells and tissues to injurious stimuli
◆ acute inflammation in response to bacterial infections produces a very similar
reaction in most tissues
➔ Systemic pathology: alterations and underlying mechanisms in organ specific diseases
◆ ischemic heart disease
● Four aspects of a disease process that form the core of pathology:
❖ Cause (Etiology)
○ Factors that cause the disease
○ Genetic or acquired
■ Genetic: inherited mutations and disease-associated gene variants, or
polymorphisms that will cause the disease.
■ Acquired: infectious, nutritional, chemical, physical factors (INC-PF)
❖ Biochemical and molecular mechanisms of its development (Pathogenesis)
○ Sequence of cellular, biochemical, and molecular events that follow the exposure
of cells or tissues to an injurious agent
○ Remains one of the main domains of pathology
❖ Structural alterations induced in the cells and organs of the body (Morphologic
Changes)
○ Structural alterations in cells or tissues that are either characteristic of a
disease or diagnostic of an etiologic process
❖ Functional consequences of these changes (Clinical Manifestations)
○ The end results of genetic, biochemical, and structural changes in cells and tissues
are functional abnormalities, which lead to the clinical manifestations (symptoms
and signs) of disease, as well as its progress (clinical course and outcome)

CELLULAR RESPONSES TO STRESS AND TOXIC INSULTS: CELLULAR RESPONSES TO STRESS AND NOXIOUS
STIMULI

The normal cell maintains a steady state called

homeostasis so when there is stress they can adapt.
Adaptations are reversible functional and structural
responses to changes in physiologic states (e.g., pregnancy)
and some pathologic stimuli, during which new but altered
steady states are achieved, allowing the cell to survive and
continue to function. (When stress is eliminated, the cell can
go back to its normal state or homeostasis)

If the limits of adaptive responses are exceeded or if cells are

exposed to injurious agents or stress, deprived of
essential nutrients, or become compromised by mutations
that affect essential cellular constituents, a sequence of
events follows that is termed cell injury. Cell injury is
reversible up to a certain point, but if the stimulus persists or
is severe enough from the beginning, the cell suffers
irreversible injury and ultimately undergoes cell death
(necrosis or apoptosis). Adaptation, reversible injury, and
cell death may be stages of progressive impairment following
different types of insults.
ADAPTATIONS OF CELLULAR GROWTH AND DIFFERENTIATION
➔ Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or
functions of cells in
response to changes in their environment.

Hypertrophy
➔ Increase in the size of cells: increase in the size of the affected organ
◆ The hypertrophied organ has no new cells, just larger cells. The increased size of the
cells is due to the
synthesis and assembly of additional intracellular structural components.
➔ Physiologic: increased functional demand or by stimulation by hormones and growth factors
◆ (eg., pregnancy: uterus will enlarge to accommodate the baby and postpartum it will shrink
or go back to its normal size)
➔ Pathologic: left ventricular hypertrophy or enlargement of left ventricle of the heart because of
hypertension
➔ Mechanism: increased production of cellular proteins (increase synthesis)

Hyperplasia
➔ Increase in the number of cells in an organ or tissue in response to a stimulus
◆ Although hyperplasia and hypertrophy are distinct processes, they frequently occur together,
and may be
triggered by the same external stimulus.
◆ Hyperplasia can only take place if the tissue contains cells capable of dividing; thus
increasing the number of cells.
➔ Stimulus: hormonal or compensatory
➔ Physiologic: action of hormones or growth factors when there is a need to increase
functional capacity of hormone sensitive organs; when there is need for compensatory increase
after damage or resection.
◆ Hormonal hyperplasia: proliferation of the glandular epithelium of the female breast
at puberty and during pregnancy, usually accompanied by enlargement (hypertrophy) of
the glandular epithelial cells
◆ Compensatory hyperplasia comes from the study of liver regeneration
◆ Marrow is remarkable in its capacity to undergo rapid hyperplasia in response to a
deficiency of terminally differentiated blood cells
➔ Pathologic: excessive or inappropriate actions of hormones or growth factors acting on target
cell
◆ Endometrial hyperplasia is an example of abnormal hormone-induced hyperplasia
● Hormones stimulate endometrium to produce more cells thus there will be
abnormal uterine bleeding.
● One of the risk factors for a woman to acquire endometrial cancer.
➔ Mechanism: growth factor-driven proliferation of mature cells and, in some cases, by increased
output of new cells from tissue stem cells
➔ A fertile ground for cancer to occur or develop

Atrophy
➔ Reduction in the size of an organ or tissue due to a decrease in cell size and number
➔ Mechanism: decreased protein synthesis and increased protein degradation in cells
◆ Protein synthesis decreases because of reduced metabolic activity.
◆ The degradation of cellular proteins occurs mainly by the ubiquitin-proteasome pathway.
➔ Physiologic: normal development
◆ Some embryonic structures, such as the notochord and thyroglossal duct, undergo
atrophy during fetal development.
◆ The decrease in the size of the uterus that occurs shortly after parturition is another form
of physiologic atrophy (postpartum- it will go back to normal size)
➔ Pathologic: several causes; local or generalized
➔ Common causes of atrophy:
◆ Decreased workload (atrophy of disuse)
● a fractured bone is immobilized in a plaster cast or when a patient is restricted to
complete bed rest, skeletal muscle atrophy rapidly ensues. The initial decrease in
cell size is reversible once activity is resumed.
 ● With more prolonged disuse, skeletal muscle fibers decrease in number (due to
apoptosis) as well as in size; muscle atrophy can be accompanied by increased
bone resorption, leading to osteoporosis of disuse. However if activity is resumed,
decrease in cell size can be reversible
◆ Loss of innervation (denervation atrophy)
● The normal metabolism and function of skeletal muscle are dependent on its nerve
supply.
● Damage to the nerves leads to atrophy of the muscle fibers supplied by those nerves
◆ Diminished blood supply
● A gradual decrease in blood supply (ischemia) to a tissue as a result of slowly
developing arterial occlusive disease results in atrophy of the tissue. (blood vessels
are narrowed as we age)
● In late adult life, the brain may undergo progressive atrophy, mainly because of
reduced blood supply as a result of atherosclerosis. This is called senile (old)
atrophy, which also affects the heart.
◆ Inadequate nutrition
● Profound protein-calorie malnutrition (marasmus) is associated with the
utilization of skeletal muscle proteins as a source of energy after other reserves such
as adipose stores have been depleted. This results in marked muscle wasting
(cachexia)
○ All energy sources like adipose tissue have already been used as fuel to the
cell. With this the muscle becomes the source of energy for the cell
causing cachexia or muscle wasting)
○ Cachexia is also seen in patients with chronic inflammatory diseases and
cancer.
◆ Loss of endocrine stimulation
● Many hormone-responsive tissues, such as the breast and reproductive organs, are
dependent on endocrine stimulation for normal metabolism and function.
● The loss of estrogen stimulation after menopause results in physiologic atrophy of
the endometrium, vaginal epithelium, and breast.
◆ Pressure
● Tissue compression for any length of time can cause atrophy
● An enlarging benign tumor can cause atrophy in the surrounding uninvolved tissues
Metaplasia
➔ A reversible change
➔ One differentiated cell type (epithelial or mesenchymal) is replaced by another cell type
➔ Most common epithelial metaplasia: columnar to squamous (respiratory tract in response to chronic
irritation)
◆ occurs in the respiratory tract in response to chronic irritation. In the habitual cigarette
smoker, the normal ciliated columnar epithelial cells of the trachea and bronchi are often
replaced by stratified squamous epithelial cells
● Columnar epithelium provides another layer of protection such as it secretes
mucus and it has cilia so if it is replaced with stratified squamous the protection is
also gone.
➔ Metaplasia from squamous to columnar type: Barrett esophagus (reflux gastric acid)
◆ esophageal squamous epithelium is replaced by intestinal-like columnar cells under the
influence of refluxed gastric acid.
◆ Cancers may arise in these areas; these are typically glandular (adenocarcinomas)
➔ Connective tissue metaplasia: formation of cartilage, bone, or adipose tissue (mesenchymal
tissues) in tissues that normally do not contain these elements
➔ Mechanism: reprogramming of cells
◆ stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal
cells present in connective tissue.
● (respiratory epithelium: stem cells is supposed to develop into columnar ciliated
epithelium but because of constant stress or constant irritation in the respiratory
tract, stem cell will be reprogram to develop stratified squamous instead of
columnar ciliated epithelium)
➔ Stimulus: stress
CELL INJURY AND CELL DEATH
➔ Cell injury results when cells are stressed so severely that they are no longer able to adapt or
when cells are exposed to inherently damaging agents or suffer from intrinsic abnormalities.
◆ (stress/injurious simulus is still constant which causes cell injury)
➔ Injury may progress through a reversible stage and culminate in cell
death

Reversible Cell Injury

➔ In early stages or mild forms of injury, the functional and morphologic changes are reversible
if the damaging stimulus is removed.

The hallmarks of reversible injury are:

➔ Reduced oxidative phosphorylation with resultant depletion of energy stores in the
form of adenosine triphosphate (ATP)
➔ Cellular swelling caused by changes in ion concentrations and water influx
➔ intracellular organelles (mitochondria and the cytoskeleton) may show alterations
➔ With continuing damage the injury becomes irreversible, at which time the cell cannot recover
and it dies (CELL DEATH)

Cell Death
➔ Historically, two principal types of cell death, necrosis and apoptosis, which differ in their
morphology, mechanisms, and roles in physiology and disease

➔ Necrosis
● Accidental and unregulated form of cell death resulting from damage to cell
membranes and loss of ion homeostasis
○ When damage to membranes is severe, lysosomal enzymes enter the cytoplasm
and digest the cell giving rise to a set of morphologic changes described as
necrosis.
○ Cellular contents also leak through the damaged plasma membrane into the
extracellular space, where they elicit a host reaction (inflammation).
● The pathway of cell death in many commonly encountered injuries such as those
resulting from ischemia, exposure to toxins various infections, and trauma was a
pathologic process
○ Pathologic process because it is associated with inflammation
● Serves many normal functions and is not (?) necessarily associated with cell injury
➔ Necroptosis
● Hybrid of necrosis and apoptosis.
● It is a regulated form of cell death
➔ Apoptosis
● Form of cell death that is characterized by nuclear dissolution, fragmentation of the cell
without
complete loss of membrane integrity and rapid removal of the cellular debris
● Highly regulated process driven by a series of genetic pathways
● Programmed cell death
● Serves many normal functions
● Not necessarily associated with cellular injury
○ Because cellular contents do not leak out, unlike in necrosis, there is no inflammatory
reaction.
Cell Injury
➔ Causes:
● Oxygen deprivation: hypoxia
○ Hypoxia is an extremely important and common cause of cell injury and cell death
○ Causes of hypoxia include
■ reduced blood flow (ischemia),
■ inadequate oxygenation of the blood due to cardiorespiratory failure,
■ and decreased oxygen-carrying capacity of the blood,
■ as in anemia or carbon monoxide poisoning (producing a stable
carbon monoxyhemoglobin that blocks oxygen carriage) or after severe
blood loss.
○ Depending on the severity of the hypoxic state, cells may adapt, undergo injury, or die.
 ● Physical agents: mechanical trauma, extremes of temperature, sudden changes in
atmospheric pressure, radiation and electric shock (too much oxygen can be tosic)
● Chemical agents and drugs
○ Simple chemicals such as glucose or salt in hypertonic concentrations may cause
cell injury
directly or by deranging electrolyte balance in cells.
○ Oxygen at high concentrations is toxic.
○ Trace amounts of poisons, such as arsenic, cyanide, or mercuric salts, may
damage su cient numbers of cells within minutes or hours to cause death
● Infectious agents
○ Submicroscopic viruses to tapeworms several feet in length.
○ In between are the rickettsiae, bacteria, fungi, and higher forms of parasites
● Immunologic reactions
○ The immune system serves an essential function in defense against infectious
pathogens, but immune reactions may also cause cell injury.
○ Injurious reactions to endogenous self antigens are responsible for several autoimmune
diseases
○ Immune reactions to many external agents, such as viruses and environmental
substances, are also important causes of cell and tissue injury
● Genetic derangements
○ genetic abnormalities as obvious as an extra chromosome, as in Down syndrome,
○ subtle as a single base pair substitution leading to an amino acid substitution, as
in sickle cell anemia,
● Nutritional imbalances
○ Marasmus: protein-calorie deficiencies cause an appalling number of deaths.

MORPHOLOGIC ALTERATIONS IN CELL INJURY

➔ These morphologic changes are associated with

◆ decreased generation of ATP,
◆ loss of cell membrane integrity,
◆ defects in protein synthesis,
◆ cytoskeletal damage, and DNA damage.
➔ Within limits, the cell can repair these derangements and, if the injurious stimulus
abates, will return to normalcy.
➔ Persistent or excessive injury, however, causes cells to pass the rather nebulous “point of
no return” into irreversible injury and cell death. Different injurious stimuli may induce death
by necrosis or apoptosis.

Reversible Injury
➔ Generalized swelling of the cell and its organelles
➔ Blebbing of the plasma membrane
➔ Detachment of ribosomes from the ER
➔ Clumping of nuclear chromatin
➔ Features of reversible injury recognized under the microscope.
● Cellular swelling
○ First manifestation of almost all forms of injury to the cell
○ Appears whenever cells are incapable of maintaining ionic and fluid homeostasis
○ Result of failure of energy-dependent ion pumps in the plasma membrane
● Fatty change
○ Hypoxic injury and various forms of toxic or metabolic injury
○ Appearance of lipid vacuoles in the cytoplasm
○ Mostly seen in cells that are involved in and dependent on fat metabolism
(hepatocytes and myocardial cells)
■ Obese, chronic alcoholic leads to cirrhosis (irreversible cell injury)
Necrosis
➔ Irreversible injury form of epithelial cells
➔ Morphologic appearance of necrosis as well as necroptosis is the result of
◆ Denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell
● Necrotic cells are unable to maintain membrane integrity and their contents often
leak out, a process that may elicit inflammation in the surrounding tissue (cellular
leakage)
➔ Common morphological features:
● Increased eosinophilia on H&E staining
● More glassy homogeneous appearance (mainly as a result of the loss of glycogen particles)
● Vacuoles (the cytoplasm becomes vacuolated and appears moth-eaten)
● Myelin figures
➔ Nuclear changes:
● Karyolysis: decreased bosophilla of the chromatin
● Pyknosis: nuclear shrinkage and increased basophilia
● Karyorrhexis: fragmentation of the pyknotic nucleus

➔ Patterns of tissue necrosis

● Coagulative necrosis
○ Architecture of the dead tissue is preserved (acidophilic tombstone)
○ Ischemia: obstruction in a vessel that may lead to coagulative necrosis
■ Ischemia caused by obstruction in a vessel may lead to coagulative
necrosis of the supplied tissue in all organs except the brain
○ Infarct: localized area of coagulative necrosis
■ A wedge-shaped kidney infarct (pic)
● Liquefactive necrosis
○ contrast to coagulative necrosis
○ Digestion of the dead cells resulting in transformation of the tissue into a liquid
viscous mass (pus)
■ Pus: frequently creamy yellow because of the presence of dead leukocyte
○ Bacterial or fungal infections
○ Ischemic necrosis in the brain
● Gangrenous necrosis
○ Not a specific pattern of cell death
○ Ischemic coagulative necrosis of the limb (lower leg)
■ .It is usually applied to a limb, generally the lower leg, that has lost its
blood supply and has undergone necrosis (typically coagulative necrosis)
○ Superimposed bacterial infection:
■ Liquefactive necrosis: wet gangrene
● Caseous necrosis
○ Cheese-like: friable white appearance of the area of the necrosis
○ Tuberculous infection
○ Architecture is not preserved
○ Also known as granuloma
■ necrotic area appears as a structureless collection of fragmented or
lysed cells and amorphous granular debris enclosed within a distinctive
inflammatory border
● Fat necrosis
○ Refers to a focal area of fat destruction
■ typically resulting from release of activated pancreatic lipases into the
substance of the pancreas and the peritoneal cavity
 ○ Acute pancreatitis
■ Pancreatic enzymes leak out of acinar cells and liquefy the membranes of
fat cells in the peritoneum.
■ The released lipases split the triglyceride esters contained within fat cells.
■ The fatty acids, so derived, combine with calcium to produce grossly visible
chalky-white areas (fat saponification) causes the identification of lesions
○ Fatty acids+Calcium= fat saponification (chalky-white areas)
● Fibrinoid necrosis
○ special form of necrosis usually seen in immune reactions involving blood vessels
○ Immune reactions involving blood vessels Antigen-antibody complexes are
deposited in the walls of the arteries
■ Deposits of these “immune complexes,” together with fibrin that has leaked
out of vessels, result in a bright pink and amorphous appearance in H&E
stains, called “fibrinoid” (fibrin-like)
○ Vasculitis syndromes (tachyaseous (?), giant cell, small cell arteritis)
Apoptosi
s
➔ Death by apoptosis is a normal phenomenon
◆ occurs during development and towards adulthood
◆ serves to remove unwanted, aged, or potentially harmful cells
➔ It is also a pathologic event when diseased cells become damaged beyond repair and are eliminated.
➔ Eliminates cells that are no longer needed
➔ Maintains a steady number of various cell populations in tissues
➔ Apoptosis in Physiological Situations:
● Destruction of cell during embryogenesis
● Involution of hormone-dependent-tissues upon hormone withdrawal
○ endometrial cell breakdown during the menstrual cycle,
○ ovarian follicular atresia in menopause,
○ the regression of the lactating breast after weaning,
○ and prostatic atrophy after castration
● Cell loss in proliferating cell populations
○ immature lymphocytes in the bone marrow and thymus
○ B lymphocytes in germinal centers that fail to express useful antigen receptors
● Elimination of potentially harmful self-reactive lymphocytes either before or after they
have completed their maturation
○ Auto-immune diseases (it has to be removed)
● Death of host cells that have served their useful purpose
○ neutrophils in an acute inflammatory response
○ lymphocytes at the end of an immune response
➔ Apoptosis in Pathologic Conditions:
● DNA damage
○ Radiation, cytotoxic anticancer drugs, and hypoxia can damage DNA, either directly
or via production of free radicals.
○ If repair mechanisms cannot cope with the injury, the cell triggers intrinsic
mechanisms that induce apoptosis
● Accumulation of misfolded proteins
○ mutations in the genes encoding these proteins or because of extrinsic factors,
such as damage caused by free radicals.
○ Excessive accumulation of these proteins in the ER leads to a condition called ER
stress, which culminates in apoptotic cell death
● Cell death in certain infections
○ particularly viral infections, in which loss of infected cells is largely due to apoptosis
that may be induced by the virus (as in adenovirus and HIV infections) or by the host
immune response (as in viral hepatitis
● Pathologic atrophy in parenchymal organs after duct obstruction
○ occurs in the pancreas, parotid gland, and kidney
 ➔ Morphologic and biochemical changes in Apoptosis
● Cell shrinkage
○ smaller in size, the cytoplasm is dense, and the organelles, although relatively
normal, are more tightly packed
● Chromatin condensation
○ most characteristic feature of apoptosis
○ chromatin aggregates peripherally, under the nuclear membrane, into dense
masses of various shapes and sizes
● Formation of cytoplasmic blebs and apoptotic bodies
○ extensive surface blebbing, then undergoes fragmentation into membrane-
bound apoptotic bodies
● Phagocytosis of apoptotic cells or cell bodies
○ rapidly ingested by phagocytes and degraded by the phagocyte’s lysosomal enzymes.

Mechanism of APOPTOSIS
◆ Apoptosis results from the activation of enzymes called caspases
● Caspases
○ cysteine proteases that cleave proteins after aspartic residues
○ exist as inactive proenzymes, or zymogens, and must undergo enzymatic
cleavage to become active
➔ Activation of caspases
● Two phases
○ Initiation phase (caspases become catalytically active)
○ Execution (caspases trigger the degradation of critical cellular components)
➔ Two pathways: (although different they can converge)
○ Intrinsic (Mitochondrial)
■ major mechanism of apoptosis in all mammalian cells
■ results from increased permeability of the mitochondrial outer membrane
with consequent release of death-inducing molecules from the mitochondrial
intermembrane space into the cytoplasm
○ Extrinsic (Death receptor)
■ initiated by engagement of plasma membrane death receptors on a variety of
cells
Necroptosis
➔ Form of cell death
➔ Hybrid that shares aspects of both necrosis and apoptosis
● Resembles necrosis
○ Loss of ATP
○ Swelling of cell and organelles
○ Generation of ROS (reactive oxygen species)
○ Release of lysosomal enzymes
○ Rupture of the plasma membrane
● Resembles apoptosis
○ Triggered by genetically programmed signal transduction events that culminate in cell
death
➔ Sometimes called programmed necrosis
In sharp contrast to apoptosis
➔ “Caspase-independent” programmed cell death
○ genetic program that drives necroptosis does not result in caspase activation
Autophagy
➔ Process in which a cell eats its own contents ((Greek: auto, self; phagy, eating)
➔ Delivery of cytoplasmic materials to the lysosome for degradation
➔ Three types depending on how the material is delivered:
● Chaperone-mediated autophagy
○ direct translocation across the lysosomal membrane by chaperone proteins
● Microautophagy
○ inward invagination of lysosomal membrane for delivery
 ● Macroautophagy
○ Major form of autophagy
○ Involves in the sequestration and transportation of portions of cytosol in a double
membrane bound autophagic vacuole (autophagosome)
➔ Function: Survival mechanism under various stress conditions, maintaining the integrity of cells
by recycling essential metabolites and clearing of cellular debris
➔ Prominent in atrophic cells which are exposed to severe nutrient deprivation
➔ Involved in the turnover of organelles
➔ Clearance of intracellular aggregates that accumulate during aging, stress, and various other disease
states
➔ Implicated in
● Physiologic states
○ Aging
○ Exercise
● Pathologic states
➔ Steps:
● Formation of an isolation membrane (also called phagophore, and its nucleation; the
isolation membrane is believed to be derived from the ER)
● Elongation of the vesicle
● Maturation of the autophagosome

INTRACELLULAR ACCUMULATIONS
➔ One of the manifestations of metabolic derangements in cells is the intracellular
accumulation of abnormal amounts of various substances that may be harmless or associated
with varying degrees of injury
➔ The substance may be located in the cytoplasm, within organelles (typically lysosomes), or in
the nucleus, and it may be synthesized by the affected cells or may be produced elsewhere

Main pathways of abnormal intracellular accumulations

● Inadequate removal of a normal substance secondary to defects in mechanisms of packaging and

transport
○ as in fatty change (steatosis) in the liver
● Accumulation of an abnormal endogenous substance as a result of genetic or acquired defects
○ in its folding, packaging, transport, or secretion, as with certain mutated forms of α1-antitrypsin
● Failure to degrade a metabolite due to inherited enzyme deficiencies
○ The resulting disorders are called storage diseases
● Depositions and accumulation of an abnormal exogenous substance
○ The cell has neither the enzymatic machinery to degrade the substance nor the ability
to transport it to other sites.
○ Accumulation of carbon or silica particles is an example of this type of alteration
○ In many cases, if the overload can be controlled or stopped, the accumulation is reversible
Lipids
● All major classes of lipids can accumulate in cells: triglycerides,
cholesterol/cholesterol esters, and phospholipids.
● Phospholipids are components of the myelin figures found in necrotic cells.
➔ Steatosis (Fatty change)
● Abnormal accumulations of triglycerides within the parenchymal cells,
● Liver (MC), heart, muscle, and kidney
● Causes: toxins, protein malnutrition (marasmus), DM, obesity, and anorexia
○ Lipid vacuoles in the cytoplasm of cells
➔ Cholesterol and Cholesterol Esters
◆ Most cells use cholesterol for the synthesis of cell membranes without intracellular
accumulation of cholesterol or cholesterol esters.
● Atherosclerosis
○ Blood vessels
 ● Xanthomas
○ Accumulation within macrophages that is characteristic of acquired and
hereditary hyperlipidemic states
○ Clusters of foamy cells are found in the subepithelial connective tissue of the skin and
in tendons, producing tumorous masses known as xanthoma
● Cholesterolosis
○ Macrophages in the lamina propria of the gallbladder
○ The mechanism of accumulation is unknown.
● Niemann-Pick disease Type C
○ lysosomal storage disease
■ mutations affecting an enzyme involved in cholesterol tra cking,
resulting in cholesterol accumulation in multiple organs
Protei
ns
➔ Appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm
➔ Amorphous, fibrillar, or crystalline in appearance
➔ In some disorders, such as certain forms of amyloidosis, abnormal proteins deposit primarily in
extracellular spaces
➔ Mechanisms:
● Reabsorption droplets in proximal renal tubules: nephrotic syndrome
● Renal diseases associated with protein loss in the urine (proteinuria)
● heavy protein leakage across the glomerular filter there is increased reabsorption
of the protein into vesicles, and the protein appears as pink hyaline droplets within
the cytoplasm of the tubular cell
● The process is reversible; if the proteinuria diminishes, the protein droplets are
metabolized and disappear
● Production of excessive amounts of normally-secreted proteins: multiple myeloma (Russell
bodies)
● produced in excessive amounts, as occurs in certain plasma cells engaged in
active synthesis of immunoglobulins.
● The ER becomes hugely distended, producing large, homogeneous eosinophilic
inclusions called Russell bodies
● Detective intracellular transport and secretion of critical proteins: α1-antitrypsin deficiency
● mutations in the protein significantly slow folding, resulting in the buildup of
partially folded intermediates, which aggregate in the ER of the liver and are not
secreted.
● Accumulation of cytoskeletal proteins: Alzheimer's disease (neurofibrillary Tangles)
● Accumulations of keratin filaments and neurofilaments are associated with certain
types of cell injury.
● Aggregation of abnormal proteins: Amyloidosis
● These disorders are sometimes called proteinopathies or protein-aggregation diseases.
Hyaline Change
➔ Alteration within cells or in the extracellular space
➔ Homogenous, glassy, pink appearance in H&E
➔ Produced by a variety of alterations and does not represent a specific pattern of accumulation
➔ Intracellular hyaline
● Reabsorption droplets (nephrotic syndrome)
● Russell bodies
● Alcoholic hyaline
➔ Extracellular hyaline
● Hyaline atherosclerosis in hypertension and DM
○ Collagenous fibrous tissue in old scars may appear hyalinized
Glycogen
➔ Patients with abnormality in either glucose or glycogen metabolism
➔ Appear as clear vacuoles within the cytoplasm
➔ Stains best with Best carmine or PAS (periodic acid sheet staining) : rose to violet color to the glycogen
➔ Diabetes mellitus (primary example of glucose metabolism)
 ➔ Glycogen can be found in renal tubular epithelial cells, as well as within liver cells, β cells of
the islets of Langerhans, and heart muscle cells.
➔ Glycogen storage diseases or Glycogenoses
● Accumulation of glycogen due to defects in synthesis or breakdown of glycogen, causing cell
injury and cell death
○ Glycogen accumulates within the cells in a group of related genetic disorders
PIGMENTS
➔ Pigments are colored substances, some of which are normal constituents of cells (e.g., melanin),
whereas others are abnormal and accumulate in cells only under special circumstances.
➔ Pigments can be
◆ exogenous, coming from outside the body,
◆ endogenous, synthesized within the body itself.

EXOGENOUS Pigments
Carbon (Coal dust)
● Most common exogenous pigment
● When inhaled it is picked up by macrophages within the alveoli and is then
transported through lymphatic channels to the regional lymph nodes in the
tracheobronchial region.
● Ubiquitous air pollutant in urban areas
● Anthracosis: lungs
● Accumulations of this pigment blacken the tissues of the lungs (anthracosis) and
the involved lymph nodes.
● Coal worker's pneumoconiosis
● In coal miners the aggregates of carbon dust may induce a fibroblastic
reaction or even emphysema and thus cause a serious lung disease known as
coal worker’s pneumoconiosis
Tattooi
ng ● form of localized, exogenous pigmentation of the skin.
● The pigments inoculated are phagocytosed by dermal macrophages, in which they
reside for the remainder of the life of the embellished
● The pigments do not usually evoke any inflammatory response.

ENDOGENOUS Pigments
Lipofuscin ( insoluble
pigment)
➔ Also known as Lipochrome or wear and tear pigment
➔ Importance : Sign of free radical injury and lipid peroxidation
➔ Yellow brown, finely granular cytoplasmic/often perinuclear pigment
➔ term is derived from the Latin ( fuscus, brown), referring to brown lipid
➔ It is seen in cells undergoing slow, regressive changes and is particularly prominent in the liver and
heart of aging patients or patients with severe malnutrition and cancer cachexia.
Melanin
➔ Endogenous, brown black pigment
➔ Formed from the oxidation of tyrosine (catalyzes the oxidation of tyrosine to
dihydroxyphenylalanine in melanocytes)
➔ For practical purposes melanin is the only endogenous brown-black pigment
Homogentisic acid
➔ a black pigment that occurs in patients with alkaptonuria
➔ Alkaptonuria: rare metabolic disease
➔ Pigment is deposited in the skin, connective tissue, and cartilage
➔ Pigmentation: ochronosis
➔ Occurs around the mouth
Hemosiderin
➔ Hemoglobin derived
➔ Golden yellow-to-brown, granular or crystalline pigment
➔ In cells, it is stored in association with a protein, apoferritin, to form ferritin micelles
 ➔ When there is a local or systemic excess of iron, ferritin forms hemosiderin granules,
which are easily seen with the light microscope.
➔ Hemosiderin pigment represents aggregates of ferritin micelles
➔ One of the major storage forms of iron

Local or systemic excesses of iron cause hemosiderin to accumulate within cells.

➔ Local excess: bruise (best example of localized hemosiderosis)
➔ Local excesses result from hemorrhages in tissues
➔ Hemosiderosis: (systemic overload of iron) deposition of hemosiderin in organs and tissues

PATHOLOGIC CALCIFICATION
➔ abnormal tissue deposition of calcium salts, together with smaller amounts of iron,
magnesium, and other mineral salts

Dystrophic Calcification
➔ Encountered in areas of necrosis
➔ Can be a telltale sign of previous cell injury, it is often a cause of organ dysfunction.
➔ Deposition occurs in dying tissues
➔ Normal serum calcium levels
➔ No derangements in calcium metabolism
➔ Calcification present: Atheromas of advanced atherosclerosis
➔ Commonly develop: Aging or damaged heart valves (further hampering their function)
➔ white deposits in heart valves are dystrophic
➔ Macroscopically (calcium salts): fine, white granules or clumps often felt as gritty deposits
➔ Histology:
● Basophilic. amorphous granular, sometimes clumped appearance (B-AG-C)
● Psammoma bodies
◆ Concentric circle, most commonly seen in thyroid

Metastatic Calcification
➔ Deposition of calcium salts in normal tissues (whenever there is hypercalcemia)
➔ Hypercalcemia also accentuates dystrophic calcification
➔ Hypercalcemia secondary to a disturbance in calcium metabolism
➔ Four principal causes of hypercalcemia
● Increased secretion of parathyroid hormone with subsequent bone resorption
○ in hyperparathyroidism due to parathyroid tumors, and ectopic secretion of
PTH-related protein by malignant tumors
● Resorption of bone tissues
○ secondary to primary tumors of bone marrow (e.g., multiple myeloma, leukemia)
○ diffuse skeletal metastasis (e.g., breast cancer),
○ accelerated bone turnover (e.g., Paget disease),
○ immobilization;
● Vitamin-D related disorders
○ including vitamin D intoxication,
○ sarcoidosis (in which macrophages activate a vitamin D precursor),
○ idiopathic hypercalcemia of infancy (Williams syndrome), characterized by
abnormal sensitivity to vitamin D
● Renal failure
○ which causes retention of phosphate, leading to secondary hyperparathyroidism
● Less common causes include:
○ aluminum intoxication, which occurs in patients on chronic renal dialysis,
○ milk-alkali syndrome, which is due to excessive ingestion of calcium and
absorbable antacids such as milk or calcium carbonate.
➔ Metastatic calcification may occur widely throughout the body but principally affects the interstitial
tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins.
 CHAPTER 3
Inflammation and
Repair
INFLAMMATIO
N

● Response of vascularized tissues to infections and damaged tissues that brings cells and
molecules of host defense from the circulation to the sites where they are needed, in order to
eliminate the offending agents.
● It is actually a protective response that is essential for survival.
● It serves to rid the host of both the initial cause of cell injury (e.g., microbes, toxins) and the
consequences of such injury (e.g., necrotic cells and tissues)
● Mediators:
➔ Phagocytic leukocytes
➔ Antibodies
➔ Complement proteins
● The process of inflammation delivers these cells and proteins to damaged or necrotic tissues
and foreign invaders, such as microbes, and activates the recruited cells and molecules, which
then function to get rid of the harmful or unwanted substances

General steps:
➔ Recognition of the injurious agent
➔ Recruitment of leukocytes.
➔ Activation of leukocytes and proteins and elimination of the agent
➔ Regulation (control) of the response
➔ Resolution (repair)

Fundamental properties
➔ Components of the inflammatory response
● Blood vessels
● Leukocytes
○ Blood vessels dilate to slow down blood flow, and by increasing their
permeability, they enable selected circulating proteins to enter the site of
infection or tissue damage. Characteristics of the endothelium lining blood
vessels also change, such that circulating leukocytes first come to a halt and
then migrate into the tissues. Leukocytes, once recruited, are activated
and acquire the ability to ingest and destroy microbes and dead cells, as
well as foreign bodies and other unwanted materials in the tissues
➔ Harmful consequences of inflammation
● Local tissue damage and its associated signs and symptoms
○ (e.g., pain and functional impairment)
○ However, these harmful consequences are self-limited and resolve as the
inflammation abates, leaving little or no permanent damage. In contrast,
there are many diseases in which the inflammatory reaction is misdirected
(e.g., against self tissues in autoimmune diseases), occurs against normally
harmless environmental substances (e.g., in allergies), or is inadequately
controlled. In these cases, the normally protective inflammatory reaction
becomes the cause of the disease, and the damage it causes is the
dominant feature.
➔ Local and systemic Inflammation
● Although even such local reactions can have some systemic manifestations
(e.g., fever in the setting of bacterial or viral pharyngitis), the reaction is
largely confined to the site of infection or damage.
➔ Mediators of inflammation
● The vascular and cellular reactions of inflammation are triggered by soluble
factors that are produced by various cells or derived from plasma proteins
and are generated or activated in response to the inflammatory stimulus.
◆ Trigger the elaboration of inflammatory mediators and thus elicit inflammation
○ Soluble factors
 ○ Microbes
○ Necrotic cells
○ Hypoxia
➔ Termination of inflammation and initiation of tissue repair
● Elimination of offending agent; activation of anti-inflammatory mechanisms
○ Inflammation is terminated when the offending agent is eliminated. The
reaction resolves because mediators are broken down and dissipated, and
leukocytes have short lifespans in tissues. In addition, antiinflammatory
mechanisms are activated, serving to control the response and prevent it
from causing excessive damage to the host.
○ Once inflammation has achieved its goal of eliminating the offending
agents, it also sets into motion the process of tissue repair.
○ Repair consists of a series of events that heal damaged tissue.
■ The injured tissue is replaced through regeneration of surviving cells
and filling of residual defects with connective tissue (scarring).
Acute and chronic inflammation
Acute Inflammation Chronic Inflammation
(Cannot clear out inflammation)
Initial, rapid response to infections Longer duration
Develops within minutes to hours, lasting for More tissue destruction
several hours or a few days
Short duration Main cells: Lymphocytes and macrophages
Main characteristics: edema (exudation of fluid and proliferation of blood vessels, and the deposition
plasma proteins) and emigration of leukocytes of connective tissue
(polymorphonuclear cells)
Innate immunity Adaptive immunity

When acute inflammation achieves its desired goal of eliminating the offenders, the reaction subsides, but if
the response fails to clear the stimulus, the reaction can progress to a protracted phase that is called
chronic inflammation

HISTORICAL HIGHLIGHTS
➔ Celsus (1ª century AD)
○ Roman writer, first listed the 4 cardinal signs of inflammation
● Heat (calor)
● Pain (dolor)
● Redness (rubor)
● Swelling (tumor)
➔ John Hunter (1793) (Scottish surgeon)
○ Inflammation is not a disease but a response
■ inflammation is not a disease but a stereotypic response that has a salutary effect on its
host
➔ Elle Metchnikoff (1800s) (Russian biologist)
○ Process of phagocytosis
■ observing the ingestion of rose thorns by amebocytes of starfish larvae and of
bacteria by mammalian leukocytes
■ The purpose of inflammation was to bring phagocytic cells to the injured area to
engulf invading bacteria
● satirized by George Bernard Shaw in his play “The Doctor’s Dilemma,” in
which one physician’s cure-all is to “stimulate the phagocytes!”
➔ Rudolf Virchow (19th century)
○ 5th clinical sign of inflammation
■ Loss of function (functio laesa)
➔ Sir Thomas Lewis
○ Studied the inflammatory response in the skin; established chemical substances such
as histamine (produced locally in response to injury) mediate the vascular changes of
epithelium
Cause
s:
○ Infections and microbial toxins
■ (bacterial, viral, fungal, parasitic) and microbial toxins are among the most
common and medically important causes of inflammation.
■ Different infectious pathogens elicit varied inflammatory responses to the host
○ Tissue necrosis
■ elicits inflammation regardless of the cause of cell death, which may
include
● ischemia (reduced blood flow, the cause of myocardial infarction), t
● trauma, and physical and chemical injury (e.g., thermal injury, as in burns
or frostbite; irradiation; exposure to some environmental chemicals).
■ Several molecules released from necrotic cells are known to trigger inflammation;
○ Foreign bodies:
● Splinters, Dirt, Sutures
● may elicit inflammation by themselves or because they cause traumatic tissue
injury or carry microbes
○ Immune reactions
● Also known as Hypersensitivity
○ reactions in which the normally protective immune system damages the
individual’s own tissues (Autoimmune diseases)
○ The injurious immune responses may be directed against self antigens,
causing autoimmune diseases
● Allergies
○ inappropriate reactions against environmental substances or against microbes
○ Asthma, allergic rhinitis, and Hay fever

ACUTE INFLAMMATION

● Three major components:

○ Dilatation of small vessels (leading to an increase in blood flow)
○ Increased permeability of the microvasculature (enabling plasma proteins and
leukocytes to leave the circulation)
○ Emigration of the leukocytes from the microcirculation (their accumulation in the
focus of injury, and their activation to eliminate the offending agent)
● Reactions of blood vessels in acute inflammation
○ Vascular reactions of acute inflammation consist of
■ Changes in blood flow
■ Permeability of the blood vessel
● both designed to maximize the movement of plasma proteins and
leukocytes out of the circulation and into the site of infection or injury
○ Exudation: escape of fluid, proteins, and blood cells from the
vascular system into the interstitial tissue or body cavities
○ An exudate is an extravascular fluid that has a high protein
concentration and contains cellular debris.
○ A transudate is a fluid with low protein content (most of which is
albumin), little or no cellular material, and low specific gravity
● Changes in vascular flow and caliber
○ Vasodilation (induced by the action of several mediators)
■ One of the earliest manifestation of acute inflammation
■ Histamine
● Most notable mediator on vascular smooth muscle
■ First involves the arterioles and then leads to opening of new Capillary beds
■ The result in vasodilation is increased blood flow, which is the cause of heat
and redness (erythema) at the site of inflammation.
● Heat and erythema
○ Increased permeability of the microvasculature, with the outpouring of protein-rich
fluid into the extravascular tissues
 ○ Stasis (engorgement of small vessels with slowly moving red cells)
■ loss of fluid and increased vessel diameter lead to slower blood flow, concentration of
red cells in small vessels, and increased viscosity of the blood
■ seen as vascular congestion and localized redness of the involved tissue
○ Migration of leukocytes
■ As stasis develops, blood leukocytes, principally neutrophils, accumulate along the
vascular endothelium.
■ At the same time endothelial cells are activated by mediators produced at sites of
infection and tissue damage, and express increased levels of adhesion molecules.
■ Leukocytes then adhere to the endothelium, and soon afterward they migrate
through the vascular wall into the interstitial tissue,

VASODILATION-INCREASE PERMEABILITY-STASIS (CONGESTION OF BLOOD VESSELS RESULTING IN INCREASE IN

PROTEIN, RBC, ETC.)- AS IT STASIS (RBC), LEUKOCYTES ARE PUSHED TO THE PERIPHERY TOWARDS THE
ENDOTHELIUM OF BLOOD VESSEL.-ONCE ADHERE TO THE ENDOTHELIUM AND INTERSTITIAL TISSUE

● Increased vascular permeability (vascular leakage)

■ Several mechanisms are responsible for the increased permeability of
postcapillary venules, a hallmark of acute inflammation
○ Contraction of endothelial cells (resulting in increased interendothelial spaces is the most
common mechanism of vascular leakage)
■ It is elicited by histamine, bradykinin, leukotrienes, and other chemical mediators.
It is called the immediate transient response because it occurs rapidly after
exposure to the mediator and is usually short-lived (15 to 30 minutes)
○ Endothelial injury (resulting in endothelial cell necrosis and detachment)
■ Direct damage to the endothelium is encountered in severe injuries, for example,
in burns, or is induced by the actions of microbes and microbial toxins that target
endothelial cells. Neutrophils that adhere to the endothelium during inflammation
may also injure the endothelial cells and thus amplify the reaction. In most
instances leakage starts immediately after injury and is sustained for several
hours until the damaged vessels are thrombosed or repaired.
○ Transcytosis
■ Increased transport of fluids and proteins through the endothelial cell
■ This process may involve intracellular channels that may be stimulated by certain
factors, such as vascular endothelial growth factor (VEGF), that promote vascular
leakage.
● Responses of lymphatic vessels and lymph nodes
■ The system of lymphatics and lymph nodes filters and polices the extravascular
fluids. Lymphatics normally drain the small amount of extravascular fluid that has
seeped out of capillaries. In inflammation, lymph flow is increased and helps drain
edema fluid that accumulates because of increased vascular permeability. In addition
to fluid, leukocytes and cell debris, as well as microbes, may find their way into lymph.
Lymphatic vessels, like blood vessels, proliferate during inflammatory reactions to
handle the increased load of blood flow.
○ Filter and police the extravascular fluids
○ Proliferate
● Recruitment of leukocytes to sites of inflammation
■ The changes in blood flow and vascular permeability are quickly followed by an
influx of leukocytes into the tissue
■ It is a must that the leukocyte goes to the site of inflammation to perform its
function which is to eliminate the offending agent.
■ The most important leukocytes in typical inflammatory reactions are the ones
capable of phagocytosis, namely neutrophils and macrophages
○ The journey of leukocytes from the vessel lumen to the tissue is a multistep process that is
■ Mediated and controlled by adhesion molecules and cytokines (chemokines)
■ Steps: for leukocytes to enter the injury
● Margination
○ process of leukocyte redistribution, more peripheral location
● Rolling
 ● Adhesion
● Transmigration (Diapedesis)
○ migration of the leukocytes through the endothelium
● Migration in the tissues towards the chemotactic stimulus
○ leukocytes move in the tissues toward the site of injury
○ locomotion along a chemical gradient
● Termination of the acute inflammatory response
○ inflammation declines after the offending agents are removed because the mediators of
inflammation are produced in rapid bursts, only as long as the stimulus persists, have
short half-lives, and are degraded after their release.
■ Neutrophils also have short half-lives in tissues and die by apoptosis within a few
hours after leaving the blood.
○ As inflammation develops, the process itself triggers: Production of stop signals that
actively terminate the reaction

Margination, Rolling and Adhesion:

❖ Because blood flow slows early in inflammation (stasis), hemodynamic conditions change (wall
shear stress decreases), and more white cells assume a peripheral position along the
endothelial surface. This process of leukocyte redistribution is called margination. Subsequently,
leukocytes adhere transiently to the endothelium, detach and bind again, thus rolling on the
vessel wall. The cells finally come to rest at some point where they adhere firmly (resembling
pebbles over which a stream runs without disturbing them).

Transmigration (Diapedesis)

❖ Transmigration of leukocytes occurs mainly in postcapillary venules. Chemokines act on the

adherent leukocytes and stimulate the cells to migrate through interendothelial spaces toward
the chemical concentration gradient, that is, toward the site of injury or infection where the
chemokines are being produced. After traversing the endothelium, leukocytes pierce the
basement membrane, probably by secreting collagenases, and enter the extravascular tissue.
The cells then migrate toward the chemotactic gradient created by chemokines and other
chemoattractants and accumulate in the extravascular site.

Mediators of Inflammation

● Substances that initiate and regulate inflammatory reactions

● Secreted by cells (cell derived) or generated by plasma proteins (plasma derived)
○ Cell-derived mediators are normally sequestered in intracellular granules and can be rapidly
secreted by granule exocytosis (e.g., histamine in mast cell granules) or are synthesized de
novo (e.g., prostaglandins and leukotrienes, cytokines) in response to a stimulus
○ Plasma Derived mediators (e.g., complement proteins) are produced mainly in the liver
and are present in the circulation as inactive precursors that must be activated, usually
by a series of proteolytic cleavages, to acquire their biologic properties.
● Active mediators are produced only in response to various stimuli
○ These stimuli include microbial products and substances released from necrotic cells
● Most of the mediators are short-lived
○ They quickly decay, or are inactivated by enzymes, or they are otherwise scavenged or inhibited
● One mediator can stimulate the release of other mediators

Vasoactive amines:

○ Histamine
■ Mast cells (richest source), basophils, and platelets:
■ Causes dilation of arterioles and increases the permeability of venules
■ Considered to be the principal mediator of the immediate transient phase of
increased vascular permeability, producing interendothelial gaps in venules.
■ Causes contraction of some smooth muscles
■ Both are stored as preformed molecules in cells and are therefore among the first
mediators to be released during inflammation.
 ○ Serotonin
■ Platelets and neuroendocrine cells (GIT); vasoconstrictor
■ Serotonin is a preformed vasoactive mediator present in platelets and certain
neuroendocrine cells, such as in the gastrointestinal tract, and in mast cells in
rodents but not humans.
■ Its primary function is as a neurotransmitter in the gastrointestinal tract.
■ It is also a vasoconstrictor, but the importance of this action in inflammation is unclear.

Arachidonic acid metabolites

➔ The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid (AA)
present in membrane phospholipids, and stimulate vascular and cellular reactions in acute
inflammation

○ Produced from arachidonic acid

○ Prostaglandins
■ Produced by mast cells, macrophages, endothelial cells, and many other cell types
■ Involved in the vascular and systemic reactions of inflammation
○ Leukotrienes
■ Produced by leukocytes and mast cells
■ Involved in vascular and smooth muscle reactions and leukocyte recruitment
○ Lipoxins
■ Generated from arachidonic acid by the lipoxygenase pathway
■ Suppress inflammation by inhibiting the recruitment of leukocytes

Cytokines and Chemokines

○ Cytokines
■ Proteins that are produced by many cell types (activated lymphocytes,
macrophages, and dendritic cells, but also endothelial, epithelial and connective
tissue cells)
■ Mediate and regulate immune and inflammatory reactions
■ Tumor Necrosis Factor (TNF) and Interleukin-1 (L-1)
● serve critical roles in leukocyte recruitment by promoting adhesion of
leukocytes to endothelium and their migration through vessels.
● These cytokines are produced mainly by activated macrophages and dendritic
cells;
● TNF is also produced by T lymphocytes and mast cells, and IL-1 is
produced by some epithelial cells as well.
● The secretion of TNF and IL-1 can be stimulated by microbial products,
immune complexes, foreign bodies, physical injury, and a variety of other
inflammatory stimuli.
○ Chemokines
■ Family of small proteins that act primarily as chemoattractants for specific type of
leukocytes

Complement system

○ Collection of soluble proteins and membrane receptors that function mainly in host
defense against microbes and in pathologic inflammatory reactions
○ 3 pathways depending in the cleavage of C3: classical, alternative, and lectin pathways
○ Functions, inflammation, opsonization and phagocytosis, and cell lysis
○ Anaphylatoxins (C3a, C5a. and C4a): stimulate histamine release from mast cells and
increase vascular permeability and vasodilation

Other mediators:

○ Platelet-activating Factor (PAF)

■ phospholipid-derived mediator that was discovered as a factor that caused platelet
aggregation, but it is now known to have multiple inflammatory effects.
■ causes vasoconstriction and bronchoconstriction, and at low concentrations
it induces vasodilation and increased venular permeability
○ Products of coagulation
■ This concept was supported by the discovery of protease-activated receptors (PARs)
○ Kinins
■ vasoactive peptides derived from plasma proteins, called kininogens, by the
action of specific proteases called kallikreins
■ Bradykinin
● Increases vascular permeability and causes contraction of smooth muscle,
dilatation of blood vessels, and pain
 ○ Neuropeptides
■ secreted by sensory nerves and various leukocytes
■ may play a role in the initiation and regulation of inflammatory responses.
○ Substance P
■ Nerve fibers containing substance P are prominent in the lung and gastrointestinal
tract.
● Lungs
● GIT
■ Many biologic functions, including the transmission of pain signals, regulation of
blood pressure, stimulation of hormone secretion by endocrine cells, and
increasing vascular permeability
○ Neurokinin A
■ (Both Substance P and Neurokinin A) are produced in the central and peripheral nervous
systems.

Morphologic Patterns of ACUTE INFLAMMATION

Hallmark
● Dilatation of small blood vessels and accumulation of leukocytes and fluid in the
extravascular tissue
Patterns:
➔ Serous inflammation,
◆ marked by the exudation of cellpoor fluid into spaces created by cell injury or into body
cavities lined by the peritoneum, pleura, or pericardium.
● May be derived from plasma (as a result of increased vascular permeability)
● Secretions of mesothelial cells (as a result of local irritation)
● Effusion: accumulation in body cavities
● The fluid in serous inflammation is not infected by destructive organisms and does not
contain large numbers of leukocytes

➔ Fibrinous inflammation
● Exudation of fibrinogen and fibrin deposition in extracellular space
● Lining of body cavities: meninges. pericardium, pleura
● May be dissolved by fibrinolysis and cleared by macrophages
● Can lead to scarring
● Histologically, fibrin appears as an eosinophilic meshwork of threads or sometimes as an
amorphous coagulum
➔ Purulent (suppurative) inflammation, abscess:
● characterized by the production of pus consisting of neutrophils, liquified necrotic
debris, and edema fluid
● The most frequent cause of purulent (also called suppurative) inflammation is infection
with bacteria that cause liquefactive tissue necrosis,
○ such as staphylococci; these pathogens are referred to as pyogenic (pus-producing)
bacteria.
■ Staphyloccoci : Pyogenic
● Abscess
○ Localized collections of inflammatory tissues
■ caused by suppuration buried in a tissue, an organ, or a confined space
■ They are produced by seeding of pyogenic bacteria into a tissue
➔ Ulcer
● Excavation on organ surface from the sloughing of inflamed necrotic tissues
● Occurs when tissue necrosis and resultant inflammation exist on or near the surface

Outcomes of ACUTE INFLAMMATION

➔ Complete resolution
● usual outcome when the injury is limited or short-lived or when there has been little
tissue destruction and the damaged parenchymal cells can regenerate.
● Resolution involves removal of cellular debris and microbes by macrophages, and
resorption of edema fluid by lymphatics
➔ Healing by connective tissue replacement (Scarring or Fibrosis)
● occurs after substantial tissue destruction, when the inflammatory injury involves tissues
that are incapable of regeneration, or when there is abundant fibrin exudation in tissue or
in serous cavities (pleura, peritoneum) that cannot be adequately cleared.
➔ Progression to chronic inflammation
● Acute to chronic transition occurs when the acute inflammatory response cannot be resolved,
○ a result of either the persistence of the injurious agent or some interference with
the normal process of healing
CHRONIC INFLAMMATION
● Response of prolonged duration (weeks or months) in which inflammation, tissue injury, and
attempts at repair coexist, in varying combinations.
● It may follow acute inflammation, or may begin insidiously, as a low-grade, smoldering response
without any manifestations of a preceding acute reaction.

Causes:
● Persistent infections
○ by microorganisms that are di cult to eradicate, such as mycobacteria and certain
viruses, fungi, and parasites.
○ These organisms often evoke an immune reaction called delayed-type hypersensitivity
○ In other cases, an unresolved acute inflammation may evolve into chronic inflammation, as
may occur in acute bacterial infection of the lung that progresses to a chronic lung
abscess
● Hypersensitivity diseases
○ Chronic inflammation plays an important role in a group of diseases that are caused by
excessive and inappropriate activation of the immune system.
○ Under certain conditions immune reactions develop against the individual’s own
tissues, leading to autoimmune diseases
○ In other cases, chronic inflammation is the result of unregulated immune responses
against microbes, as in inflammatory bowel disease.
● Prolonged exposure to potentially toxic agents either exogenous and endogenous
● An example of an exogenous agent is particulate silica, a nondegradable inanimate material
that, when inhaled for prolonged periods, results in an inflammatory lung disease called silicosis

Morphologic features:
● Infiltration with mononuclear cells
○ Macrophages
○ Lymphocytes
○ Plasma cells
● Tissue destruction
○ induced by the persistent offending agent or by the inflammatory cells
● Attempts at healing by connective tissue replacement of damaged tissue
○ Angiogenesis (proliferation of small blood vessels)
○ Fibrosis (scaring)
● histologic features:
○ (1) collection of chronic inflammatory cells
○ (2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal
epithelium, arrowheads),
○ and (3) replacement by connective tissue (fibrosis)

Cells and Mediators of CHRONIC INFLAMMATION

● The combination of leukocyte infiltration, tissue damage, and fibrosis that characterize chronic
inflammation is the result of the local activation of several cell types and the production of
mediators

➔ Macrophages
● Dominant cells in most chronic inflammatory reactions
● Secrete cytokines and growth factors that can act on various cells, by destroying foreign
invaders and tissues, and by activating other cells (T lymphocytes)
● Tissue cells derived from hematopoietic stem cells in the bone marrow and in the embryonic
yolk sac and fetal liver
● Macrophages are normally diffusely scattered in most connective tissues
● Mononuclear phagocyte system
○ Circulatory system (Monocytes)
○ Liver (Kupffer cells)
○ spleen and lymph nodes (sinus histiocytes)
○ central nervous system (microglial cells)
○ lungs (alveolar macrophages)
➔ Lymphocytes
● Activated lymphocytes (by microbes and environmental antigens) propagate and
amplify chronic inflammation
● May be the dominant population in the chronic inflammation (autoimmune and other
hypersensitivity diseases)
 ● CD4+T lymphocytes: promote inflammation and influence the nature of the inflammatory
reaction
○ By virtue of their ability to secrete cytokines, CD4+ T lymphocytes promote
inflammation and influence the nature of the inflammatory reaction
● Activated B lymphocytes and antibody-producing plasma cells
○ often present at sites of chronic inflammation
➔ Other cells:
● Eosinophils
○ abundant in immune reactions mediated by IgE and in parasitic infections
■ Parasitic infection
■ Allergies
○ Their recruitment is driven by adhesion molecules similar to those used by
neutrophils, and by specific chemokines (e.g., eotaxin) derived from leukocytes
and epithelial cells.
○ Eosinophils have granules that contain major basic protein, a highly cationic protein
that is toxic to parasites but also causes lysis of mammalian epithelial cells.
■
● Mast cells
○ widely distributed in connective tissues and participate in both acute and chronic
inflammatory reactions.
○ allergic reactions to
■ Foods
■ Insect venom
■ Drugs
○ sometimes with catastrophic results
■ Anaphylactic shock
● Neutrophils
○ Although a characteristic of acute inflammation but many forms of chronic
inflammation, lasting for months, continue to show large numbers of neutrophils,
induced either by persistent microbes or by mediators produced by activated
macrophages and T lymphocytes

GRANULOMATOUS INFLAMMATION
● Form of chronic inflammation characterized by collection of activated macrophages often T
lymphocytes and sometimes associated with central necrosis
● Granuloma formation:
○ A cellular attempt to contain an offending agent that is di cult to eradicate
○ In this attempt there is often strong activation of T lymphocytes leading to macrophage
activation, which can cause injury to normal tissues
● Epithelioid cells
○ Activated macrophages that may develop abundant cytoplasm and begin to resemble epithelial
cells
● Multinucleated giant cells
○ Activated macrophages that fuse
● Types:
○ Foreign body granulomas
■ Incited by inert foreign bodies in the absence of T cell–mediated immune responses
■ form around materials such as talc (associated with intravenous drug abuse) ,
sutures, or other fibers that are large enough to preclude phagocytosis by a
macrophage and do not incite any specific inflammatory or immune response
■ Epithelioid cells and giant cells are opposed to the surface of the foreign body. The
foreign material can usually be identified in the center of the granuloma,
particularly if viewed with polarized light, in which it appears refractile
○ Immune granuloma
■ Caused by a variety if agents that are capable of inducing a persistent T-cell
mediated immune response
■ This type of immune response produces granulomas usually when the inciting
agent is di cult to eradicate, such as a persistent microbe or a self antigen
○ Tuberculosis
■ Prototype of a granulomatous disease caused by infection and should always be
excluded as the cause when granulomas are identified
■ The granuloma is referred to as a tubercle.
● Typical tuberculous granuloma showing an area of central necrosis surrounded
by multiple Langhans-type giant cells, epithelioid cells, and lymphocytes
SYSTEMIC EFFECTS OF INFLAMMATION
● Inflammation, even if it is localized, is associated with cytokine-induced systemic
reactions that are collectively called the acute-phase response
● Fever
○ characterized by an elevation of body temperature, usually by 1° to 4°C
○ one of the most prominent manifestations of the acute-phase response, especially when
inflammation is associated with infection
○ Substances that induce fever (pyrogens)
○ Prostaglandins: causes increase in temperature (produced in the vascular and
perivascular cells of the hypothalamus)
○ LPS: exogenous pyrogens
■ stimulate leukocytes to release cytokines such as IL-1 and TNF (called endogenous
pyrogens) that increase the enzymes (cyclooxygenases) that convert AA into
prostaglandins causing an increase in temperature.
○ endogenous pyrogens
■ IL-1
■ Tumor necrosis factor
● Acute-phase proteins 4
○ plasma proteins, mostly synthesized in the liver, whose plasma concentrations may
increase several hundred-fold as part of the response to inflammatory stimuli.
○ Synthesis of these molecules in hepatocytes is stimulated by cytokines, especially IL-6
(for CRP and fibrinogen) and IL-1 or TNF (for SAA). Many acute-phase proteins, such as
CRP and SAA, bind to microbial cell walls, and they may act as opsonins and fix
complement.
○ Best known proteins
■ CRP, Fibrinogen,Serum amyloid A protein
● Leukocytosis
○ common feature of inflammatory reactions, especially those induced by bacterial infections
○ Leukemoid reactions
■ The extreme elevations that are similar to the white cell counts observed in leukemia
and have to be distinguished from leukemia
○ Shift to the left
■ The leukocytosis occurs initially because of accelerated release of cells from the
bone marrow postmitotic reserve pool (caused by cytokines, including TNF and IL-
1) and is therefore associated with a rise in the number of more immature
neutrophils in the blood
● Increased pulse and BP, decreased sweating
○ redirection of blood flow from cutaneous to deep vascular beds, to minimize heat loss through
the skin
■ rigors (shivering), chills. anorexia, somnolence, and malaise
● because of the actions of cytokines on brain cells
● Sepsis
○ Large amounts of bacteria and their products stimulate production of enormous
quantities of cytokines (TNF and IL-1)
○ High levels of cytokines
■ Hypotensive shock
■ Disseminated intravascular coagulation (DIC)
■ Insulin resistance
■ Hyperglycemia
● Septic shock
TISSUE REPAIR
● Repair or healing: refers to restoration of tissue architecture and function after an injury
○ repair is often used for parenchymal
○ connective tissues and healing for surface epithelia
● Types of reactions:
○ Regeneration by proliferation of residual (uninjured) cells and maturation of stem
cells
■ able to replace the damaged components and essentially return to a normal state
■ occurs by proliferation of cells that survive the injury and retain the capacity to proliferate
○ Deposition of connective tissue to form a scar
■ injured tissues are incapable of complete restitution, or if the supporting
structures of the tissue are severely damaged
■ repair occurs by the laying down of connective (fibrous) tissue, a process that may
result in scar formation
● fibrous scar is not normal, it provides enough structural stability that
the injured tissue is usually able to function
 ● fibrosis is most often used to describe the extensive deposition of collagen
that occurs in the lungs, liver, kidney, and other organs as a consequence
of chronic inflammation, or in the myocardium after extensive ischemic
necrosis (infarction).
● If fibrosis develops in a tissue space occupied by an inflammatory exudate,
it is called organization (as in organizing pneumonia affecting the lung).

CELL AND TISSUE REGENERATION

● The ability of tissues to repair themselves is determined, in part, by their intrinsic proliferative capacity
● Labile (continuously dividing) tissues
○ Continuously being lost and replaced by maturation from tissue stem cells and by
proliferation of mature cells
○ Example: Hematopoietic cells, surface epithelium
○ Readily regenerate after injury as long as the pool of stem cells is preserved
● Stable tissues
○ Quiescent (G0 stage of the cell cycle)
○ Minimal proliferative activity in the normal state
○ Capable of dividing in response to injury or loss of tissue mass
○ Parenchyma of most solid tissues (liver, kidney, and pancreas).
○ Also include endothelial cells, fibroblasts, and smooth muscle cells ( proliferation of
these cells is particularly important in wound healing)
○ Limited capacity to regenerate after an injury
● Permanent Tissues
○ Considered to be terminally differentiated and nonproliferative in postnatal life
○ Majority: Neurons and cardiac muscle cells
○ Injury is irreversible and results in a scar
■ neurons and cardiac myocytes cannot regenerate

REPAIR BY CONNECTIVE TISSUE DEPOSITION

➔ If repair cannot be accomplished by regeneration alone it occurs by replacement of the
injured cells with connective tissue, leading to the formation of a scar, or by a
combination of regeneration of some residual cells and scar formation

● Steps in scar formation

○ Angiogenesis
■ Formation of new blood vessels
● supply nutrients and oxygen needed to support the repair process
● leaky because of incomplete interendothelial junctions but GF-VEGF
■ Stimulated by Growth factor: Vascular endothelial growth factor (VEGF)
● drives angiogenesis, increases vascular permeability
● The leakiness accounts in part for the edema that may persist in healing
wounds long after the acute inflammatory response has resolved
○ Formation of granulation tissue
■ Migration and proliferation of fibroblasts and deposition of loose connective tissue,
angiogenesis, and leukocytes
● Granulation tissue
○ Hallmark of repair
○ progressively invades the site of injury; the amount of granulation
tissue that is formed depends on the size of the tissue deficit
created by the wound and the intensity of inflammation
○ derives from its pink, soft, granular gross appearance, such as that
seen beneath the scab of a skin wound
○ Remodeling of connective tissue
■ Maturation and reorganization of connective tissue produce the stable scar

Macrophages play a central role in repair by clearing offending agents and dead tissue, providing
growth factors for the proliferation of various cells, and secreting cytokines that stimulate
fibroblast proliferation and connective tissue synthesis and deposition
FACTORS THAT INFLUENCE TISSUE REPAIR
➔ Tissue repair may be altered by a variety of influences, frequently reducing the quality or
adequacy of the reparative process

● Extrinsic (infections) or intrinsic to the injured tissue, and systemic or local

○ Infection: Clinically one of the most important causes that delay healing
■ It prolongs inflammation and potentially increases the local tissue injury
○ Diabetes mellitus
■ metabolic disease that compromises tissue repair for many reasons
○ Nutritional status
■ profound effects on repair;
● protein deficiency
○ for example: vitamin C deficiency
■ inhibits collagen synthesis and retards healing
○ Glucocorticoids (steroids)
■ well-documented antiinflammatory effects, and their administration may result in
weakness of the scar due to inhibition of TGF-β production and diminished fibrosis
○ Mechanical factor increased local pressure or torsion may cause the wound to pull apart or
dehisce
■ Dehisce: gape or burst open
○ Poor perfusion
■ Due to arteriosclerosis and diabetes or to obstructed venous drainage (e.g., in varicose
veins
○ Foreign bodies
■ fragments of steel, glass, or even bone impede healing
○ Type and extent of tissue injury
■ affects the subsequent repair
○ Location of injury
■ character of the tissue in which the injury occurs are also important
■ Resolution: Subsequent repair may occur by digestion of the exudate, initiated by
the proteolytic enzymes of leukocytes and resorption of the liquefied exudate

ABNORMALITIES IN TISSUE REPAIR

➔ Complications in tissue repair can arise from abnormalities in any of the basic
components of the process, including deficient scar formation, excessive formation of the
repair components, and formation of contractures

● Dehiscence or ulceration
○ Inadequate formation of granulation tissue or formation of scar
● Hypertrophic scars or keloids
○ Excessive formation of the components of the repair process
○ hypertrophic scar: accumulation of excessive amounts of collagen may give rise to a raised
scar
○ keloid: scar tissue grows beyond the boundaries of the original wound and does not regress
● Proud flesh (Exuberant granulation)
○ deviation in wound healing consisting of the formation of excessive amounts of granulation
tissue, which protrudes above the level of the surrounding skin and blocks
reepithelialization
○ Formation of excessive amounts of granulation tissue
■ desmoids, or aggressive fibromatose
● exuberant proliferation of fibroblasts and other connective tissue elements
that may, in fact, recur after excision
● Contraction (in the size of wound)
○ is important part of the normal healing process
○ An exaggeration of this process gives rise to contracture and result
■ Deformities of the wound and the surrounding tissues
○ Contractures are particularly prone to develop on the palms, the soles, and the anterior
aspect of the thorax.
○ Contractures are commonly seen after serious burns and can compromise the movement of
joints
 POST MORTEM
POST MORTEM EXAM
➔ Critical element of epidemiology
➔ Vital role in the basic study of disease processes, therapeutic response and complications,
research, education, genetic counseling, and in audit of medical practice
➔ Determines the cause of death
➔ Remains as the gold standard in evaluating new treatments and diagnostic modalities and in
documenting changing patterns of disease

REASONS FOR PERFORMING A POST MORTEM EXAM

➔ Establish a cause of death
➔ Correlate with premortem diagnosis
➔ Identify unrelated diseases
➔ Confirm or dismiss genetic implications for the family
➔ Audit care and treatment given
➔ Characterize a new disease
➔ Determine the effects of treatment
◆ biopsy
➔ Prevent the spread of communicable disease
➔ Study pathogenesis of disease
➔ Enhance research
➔ Influence health policy.
➔ Assess medicolegal implications
◆ Murders
➔ Benefit and comfort bereaved relatives
➔ Educate medical personnel and students

Decline of Post Mortem Exam

➔ Consent base on cultural attitudes
➔ Religions that inhibit post mortem
◆ Jehovah’s witnesses
➔ Attempt to avoid additional anxiety and grieve for the family of the deceased.

Cause of Post Mortem Exam

➔ Loss of appreciation in both public and medical community
➔ Risk of clinical exposure and possible malpractice lawsuit that could be contributory to decline
postmortem exams

TYPES OF POST MORTEM

The difference between the two is that underlying purpose of examination

➔ At the request of the coroner

◆ Coroner: is the one that will establish whether the death is natural or unnatural or could
have been cause to external influence rather than dealing with disease process
● Can certified death in post mortem or after holding an investigation.
● Most reasons why coroners perform autopsy is because the cause of death is yet
still undecided with certainty, often in a setting of sudden death or with no
suspicious circumstances.
➔ Consented, hospital, or academic post mortems
◆ Mostly, it is suggested in all patients who died in the hospital in order to confirm the
diagnosis as well as to check treatment, identify in consistency and as well as to audit
the quality of patient care.

WHAT TO DO BEFORE POST MORTEM EXAMINATION

➔ Check consent forms
➔ Check the identity of the body
➔ Read all available notes and information (eg., what happens in the ward etc)
➔ Determine the questions being asked (what to really look for)
➔ Identify any special techniques required
➔ Assess risk (to prepare things before autopsy)
➔ General External Inspection
➔ Height and weight
➔ External appearance
● Ethnicity
● Gender
 ● Build
● State of cleanliness
● Skin color
● presence of distinguishing features
○ Scars
○ Tattoos
○ Malformations/deformities
EVISCERATIO
N
➔ Preparation stage
● Preceding organ removal
○ Includes preliminary skin incision and thoracic and abdominal wall dissections to
expose the internal organs
○ Removal of the sternum in order to gain access to the thoracic cavity
○ Evisceration follows a relatively standard approach regardless of the subsequent
manner of organ removal because there are different techniques to remove the
organs.
■ General principle: cut into and reflect the skin in subcutaneous soft tissue
to expose the deeper tissue.
■ Incise in the supra-external notch (chest dapit) then inferiorly (?)
(downward) along the sternum (breast pleat(?)) extend further inferiorly to
the anterior abdominal wall and extend to the pubic.
■ Y shaped incision: straight line of the Y will correspond to CT sternum to
pubis incision and then the core (?) of the Y superiorly to the chest (breast
tissue is not included)

DIFFERENT POST MORTEM EXAMINATION METHODS

➔ En Masse Dissection
● En masse technique (Letulle Technique)
● Described by Letulle
● Removing most it not all of the internal organs at one time
● May be one of the more rapid techniques for removing the organs from the body
● Allows the relationship of various organ system to be adequately access because of removing all
organs
● Considered as the best of the four for observing pathological and anatomical
relationships between structures
● Perinatal autopsies (baby daw, ikaw pa rin ang bebe ko)
● Advantage: leaving all organ and system attachments intact
● Disadvantage: large external incisions, time consuming (esp, inexperience)

➔ The Virchow Method

● Removal of individual organs one by one with subsequent dissection of that isolated organ
● (Good for) Individual organ pathology
● Extremely quick and effective method if the pathological interest is in a single organ
● Disadvantage relationships between organs will often be di cult to interpret or are completely
destroyed
●
➔ En Bloc Removal (Ghon Technique)
● Combines Virchow and Letule
● Most widely used in the United Kingdom
● Developed by Ghon
● Quick but preserves most of the important interiorgan relationships

➔ In Situ Dissection
● Rokitansky
● Rarely performed (rarely useful of speed is
off the set (?))
● Dissecting the organs in situ with little
actual evisceration being performed prior
to dissection
● Method of choice for post mortems on
patients with highly transmissible
diseases
● Most limited risk or threat to anyone
except the prosecutor