Pathology notes

Lecture 1: Cell responses to stress and toxic insults

1. Cellular responses
a. Hypertrophy: increase in size of cells, increase in mitochondria
i. Due to increase in stimuli, muscle growth, uterine growth
ii. Barbiturates hypertrophy smooth ER in hepatocytes
b. Hyperplasia: increase in number of cells
i. Compensatory- liver regenerates after resection
ii. Hormonal- increase functional capacity of tissue when needed
1. Breast growth in puberty
iii. Pathologic hyperplasia can lead to cancer
iv. Benign prostatic hyperplasia- hyperplasia of prostate due to response from
androgens
v. Worts
c. Atrophy: decrease in size and metabolic activity of cells
i. Normal part of development
ii. Pathologic atrophy occurs from decreased workload, bedrest, cast,
denervation, ischemia, inadequate nutrition, loss of hormone regulation in
reproductive tissues, tissue compression
iii. Mechanism: decreased protein synthesis, reduced metabolic activity
iv. Increased autophagy, increase in autophagic vacuoles
v. Autophagic vacuoles
1. Membrane bound vacuoles that contain cell fragments, appear as
brown vacuoles, Lipofuscin granules( brown atrophy)
d. Metaplasia: change in cell phenotype
i. Reversible change
ii. Reprogramming of STEM cells
iii. Cells of one type are replaced by cells of another type
iv. In smoker, columnar respiratory cells replaced by squamous cells because
of chronic irritation, can lead to cancer
v. Barrett esophagus: squamous to columnar
vi. Connective tissue metaplasia
1. Myositis ossificans
2. Cellular responses are reversible to a certain point but will result in cell death and
irreversible injury if stimulus persists
3. Cell death results from: Ischemia, infection, toxins

Lecture 2: Cellular Responses to stress

1. Hypoxia: deficiency of oxygen, caused by reduced blood flow(ischemia) or inadequate
oxygenation of the blood, Anemia, CO poisoning, severe blood loss
2. Necrosis is caused by ischemia, apoptosis is programmed cell death
3. Reversible injury:

a. Generalized swelling of the cell and organelles, Blebbing of plasma membrane,

detachment of ribosomes from ER, clumping of chromatin
b. Decreased ATP, loss of cell membrane, DNA damage, cytoskeletal damage
c. Cellular swelling and Fatty change are main features of reversible injury
d. Cellular swelling is from failure of ion pumps in plasma membrane
e. Fatty change occurs in liver and myocardial cells via hypoxic injury
f. Small clear cytoplasmic vacuoles seen under microscope, increased eosinophil
staining
4. Irreversible cell injury: causes Necrosis or Apoptosis
5. Necrosis: irreversible membrane injury, increased H&E staining, many vacuoles in
cytoplasm
a. Dead cells are replaced by large whorled phospholipid masses that are derived
from damaged cells
b. Karylosis: fading of the basophila of the chromatin
c. Pyknosis-rasinoid: nuclear shrinkage, chromatin condenses into solid shrinken
basophilic mass
d. Karyorrhexis: pyknotic nucleus undergoes fragmentation, nucleus disappears in 12 days

e. Coagulative necrosis: architecture of the dead tissues remains for a few days after
cellular death
i. Ex: ischemia by obstruction of a vessel
ii. Infarct: area will not have nuclei

Chapter 2 notes from book:

there are myriads of factors that cause disease, they can all be grouped into two classes: genetic
(e.g., inherited mutations and disease-associated gene variants, or polymorphisms) and acquired
(e.g., infectious, nutritional, chemical, physical)

Virtually all forms of disease start with molecular or structural alterations in cells.

The adaptive response may consist of an increase in the size of cells (hypertrophy) and
functional activity, an increase in their number (hyperplasia), a decrease in the size and metabolic
activity of cells (atrophy), or a change in the phenotype of cells

(metaplasia).

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

There are two principal pathways of cell death, necrosis and apoptosis.

Calcium is often deposited at sites of cell death, resulting in pathologic calcification.

Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or
functions of cells in response to changes in their environment

Hypertrophy refers to an increase in the size of cells, that results in an 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

Hypertrophy can be physiologic or pathologic; the former is caused by increased functional

demand or by stimulation by hormones and growth factors

The most common stimulus for hypertrophy of muscle is increased workload.

Reversible cell injury: Cellular swelling, fatty change, plasma membrane

blebbing and loss of microvilli, mitochondrial swelling, dilation of the ER,
eosinophilia (due to decreased cytoplasmic RNA)

Necrosis: Increased eosinophilia; nuclear shrinkage, fragmentation, and

dissolution; breakdown of plasma membrane and organellar membranes;
abundant myelin figures; leakage and enzymatic digestion of cellular contents

Patterns of tissue necrosis: Under different conditions, necrosis in tissues

may assume specific patterns: coagulative, liquefactive, gangrenous, caseous, fat,
and fibrinoid
Pathologic calcification is the abnormal tissue deposition of calcium salts, together with
smaller amounts of iron, magnesium, and other mineral salts. There are two forms of
pathologic calcification. When the deposition occurs locally in dying tissues it is known as
dystrophic calcification; it occurs despite normal serum levels of calcium and in the absence
of derangements in calcium metabolism. In contrast, the deposition of calcium salts in
otherwise normal tissues is known as metastatic calcification, and it almost always results
from hypercalcemia secondary to some disturbance in calcium metabolism

The massive physiologic growth of the uterus during pregnancy is a good ple of hormoneinduced enlargement an organ that results mainly from hypertrophy of muscle fibers

Hypertrophy is the result of increased production of cellular proteins.

Mechanical sensors appear to be the major triggers for physiologic hypertrophy

Hyperplasia is defined as an increase in the number of cells in an organ or tissue in

response to a stimulus.

Hyperplasia can only take place if the tissue contains cells capable of dividing; thus increasing
the number of cells. It can be physiologic or pathologic.

Physiologic hyperplasia due to the action of hormones or growth factors occurs in several
circumstances: 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 is well illustrated by the proliferation of the glandular epithelium of the
female breast

The classic illustration of compensatory hyperplasia comes from the study of liver regeneration

Most forms of pathologic hyperplasia are caused by excessive or inappropriate actions of

hormones or growth factors acting on target

Hyperplasia is a characteristic response to certain viral infections, such as papillomaviruses,

which cause skin warts and several mucosal lesions composed of masses of hyperplastic
epithelium.

Hyperplasia is the result of growth factor-driven proliferation of mature cells and, in some
cases, by increased output of new cells from tissue stem cells.

Atrophy is defined as a reduction in the size of an organ or tissue due to a decrease in cell
size and number. Atrophy can be physiologic or pathologic. Physiologic atrophy is common
during 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.

Pathologic atrophy has several causes and it can be local or generalized

Decreased workload (atrophy of disuse)

Loss of innervation (denervation atrophy)

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.

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

Loss of endocrine stimulation

Pressure. Tissue compression for any length of time can cause atrophy

The fundamental cellular changes associated with atrophy are identical in all of these settings.
The initial response is a decrease in cell size and organelles, which may reduce the metabolic
needs of the cell sufficiently to permit its survival. In atrophic muscle, the cells contain fewer
mitochondria and myofilaments and a reduced amount of rough endoplasmic reticulum (RER

Early in the process atrophic cells and tissues have diminished function, but cell death is
minimal.

Atrophy results from 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.

atrophy is also accompanied by increased autophagy, marked by the appearance of increased

numbers of autophagic vacuoles. Autophagy (self-eating) is the process in which the starved
cell eats its own components in an attempt to reduce nutrient demand to match the supply

Some of the cell debris within the autophagic vacuoles may resist digestion and persist in the
cytoplasm as membrane-bound residual bodies. An ple of residual bodies is lipofuscin granules,

discussed later in the chapter. When present in sufficient amounts, they impart a brown
discoloration to the tissue (brown atrophy)

Metaplasia is a reversible change in which one differentiated cell type (epithelial or

mesenchymal) is replaced by another cell type

habitual cigarette smoker, the normal ciliated columnar epithelial cells of the trachea and bronchi
are often replaced by stratified squamous epithelial cells

he influences that predispose to metaplasia, if persistent, can initiate malignant transformation

in metaplastic epithelium

Metaplasia from squamous to columnar type may also occur, as in Barrett esophagus

Connective tissue metaplasia is the formation of cartilage, bone, or adipose tissue (mesenchymal
tissues) in tissues that normally do not contain these elements

Metaplasia does not result from a change in the phenotype of an already differentiated cell
type; instead it is the result of a reprogramming of stem cells that are known to exist in
normal tissues, or of undifferentiated mesenchymal cells present in connective tissue.

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), and cellular swelling caused by changes in ion
concentrations and water influx

Necrosis has been considered an accidental and unregulated form of cell death resulting
from damage to cell membranes and loss of ion homeostas

Necrosis is the pathway of cell death in many commonly encountered injuries, such as those
resulting from ischemia, exposure to toxins, various infections, and trauma.

In contrast to necrosis, when the cells DNA or proteins are damaged beyond repair, the
cell kills itself by apoptosis, a 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

Whereas necrosis is always a pathologic process, apoptosis serves many normal

functions and is not necessarily associated with cell injury.

Hypoxia is a deficiency of oxygen, which causes cell injury by reducing aerobic oxidative
respiration.

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

Reversible injury is characterized by generalized swelling of the cell and its organelles, blebbing
of the plasma membrane, detachment of ribosomes from the ER, and clumping of nuclear
chromatin

Two features of reversible cell injury can be recognized under the light microscope: cellular
swelling and fatty change

The 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

Coagulative necrosis is a form of necrosis in which the architecture of dead tissues is preserved
for a span of at least some days

A localized area of coagulative necrosis is called an infarct

Liquefactive necrosis, in contrast to coagulative necrosis, is characterized by digestion of the

dead cells, resulting in transformation of the tissue into a liquid viscous mass

hypoxic death of cells within the central nervous system often manifests as liquefactive necrosis

Gangrenous necrosis is not a specific pattern of cell death, but the term is commonly used in
clinical practice. It is usually applied to a limb, generally the lower leg, that has lost its blood
supply and has undergone necrosis (typically coagulative necrosis)

Caseous necrosis is encountered most often in foci of tuberculous infection (Chapter 8). The
term caseous (cheeselike) is derived from the friable white appearance of the area of necrosis

Fibrinoid necrosis is a special form of necrosis usually seen in immune reactions involving
blood vessels. This pattern of necrosis typically occurs when complexes of antigens and
antibodies are deposited in the walls of 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)

Reduction in ATP levels is fundamental cause of necrotic cell death.

Mitochondria are critical players in cell injury and cell death by all pathways. This should
be expected because they supply life-sustaining energy by producing ATP. Mitochondria can be
damaged by increases of cytosolic Ca2+, reactive oxygen species (discussed later), and oxygen
deprivation, and so they are sensitive to virtually all types of injurious stimuli, including hypoxia
and toxins.

The mitochondria sequester between their outer and inner membranes several proteins
that are capable of activating apoptotic pathways; these include cytochrome c and proteins that
indirectly activate apoptosis-inducing enzymes called caspases

The accumulation of Ca2+ in mitochondria results in opening of the mitochondrial

permeability transition pore and, as described earlier, failure of ATP generation

Cell injury induced by free radicals, particularly reactive oxygen species, is an important
mechanism of cell damage in many pathologic conditions, such as chemical and radiation
injury, ischemia-reperfusion injury (induced by restoration of blood flow in ischemic tissue),
cellular aging, and microbial killing by phagocytes

Rapid bursts of ROS are produced in activated leukocytes during inflammation.

Lipid peroxidation in membranes. In the presence of O2, free radicals may cause
peroxidation of lipids within plasma and organellar membranes. Oxidative damage is initiated
when the double bonds in unsaturated fatty acids of membrane lipids are attacked by O2-derived
free radicals, particularly by OH. The lipid-free radical interactions yield peroxides, which are
themselves unstable and reactive, and an autocatalytic chain reaction ensues

Oxidative modification of proteins. Free radicals promote oxidation of amino acid side
chains, formation of covalent protein-protein cross-lins (e.g., disulfide bonds), and oxidation of
the protein backbone. Oxidative modification of proteins may damage the active sites of
enzymes, disrupt the conformation of structural proteins, and enhance proteasomal degradation
of unfolded or misfolded proteins, raising havoc throughout the cell.

Lesions in DNA. Free radicals are capable of causing single- and double-strand breaks in
DNA, cross-linking of DNA strands, and formation of adducts

The traditional thinking about free radicals was that they cause cell injury and death by necrosis,
and, in fact, the production of ROS is a frequent prelude to necrosis. However, it is now clear
that free radicals can trigger apoptosis as well

Early loss of selective membrane permeability, leading ultimately to overt membrane

damage, is a consistent feature of most forms of cell injury (except apoptosis).

The most important sites of membrane damage during cell injury are the mitochondrial
membrane, the plasma membrane, and membranes of lysosomes

Two phenomena consistently characterize irreversibilitythe inability to reverse mitochondrial

dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the
original injury, and profound disturbances in membrane function.

Ischemia is the most common type of cell injury in clinical medicine and it results from
hypoxia induced by reduced blood flow, most commonly due to a mechanical arterial
obstruction.

in ischemic tissues, not only is aerobic metabolism compromised but anaerobic energy
generation also stops after glycolytic substrates are exhausted, or glycolysis is inhibited by the
accumulation of metabolites that would otherwise be washed out by flowing blood. For this
reason, ischemia tends to cause more rapid and severe cell and tissue injury than does hypoxia
in the absence of ischemia

If ischemia persists, irreversible injury and necrosis ensue

Irreversible injury is associated morphologically with severe swelling of mitochondria, extensive

damage to plasma membranes (giving rise to myelin figures) and swelling of lysosomes (Fig. 210C). Large, flocculent, amorphous densities develop in the mitochondrial matrix

The best-defined of these is induction of a transcription factor called hypoxia-inducible factor-1,

which promotes new blood vessel formation

The strategy that is perhaps the most useful in ischemic (and traumatic) brain and spinal cord
injury is the transient induction of hypothermia (reducing the core body temperature to 92F).
This treatment reduces the metabolic demands of the stressed cells, decreases cell swelling,
suppresses the formation of free radicals, and inhibits the host inflammatory response

Restoration of blood flow to ischemic tissues can promote recovery of cells if they are
reversibly injured, but can also paradoxically exacerbate the injury and cause cell death

How does reperfusion injury occur?

Oxidative stress. New damage may be initiated during reoxygenation by increased

generation of reactive oxygen and nitrogen species

ntracellular calcium overload. As mentioned earlier, intracellular and mitochondrial calcium

overload begins during acute ischemia; it is exacerbated during reperfusion due to influx of
calcium resulting from cell membrane damage and ROS mediated injury to sarcoplasmic
reticulum. Calcium overload favors opening of the mitochondrial permeability

Inflammation. Ischemic injury is associated with inflammation as a result of dangers

signals released from dead cells, cytokines secreted by resident immune cells such as
macrophages, and increased expression of adhesion molecules by hypoxic parenchymal and
endothelial cells, all of which act to recruit circulating neutrophils to reperfused tissue. The
inflammation causes additional tissue injury

Activation of the complement system may contribute to ischemia-reperfusion injury.

Some IgM antibodies have a propensity to deposit in ischemic tissues

Most toxic chemicals are not biologically active in their native form but must be converted to
reactive toxic metabolites, which then act on target molecules. This modification is usually
accomplished by the cytochrome P-450 mixed-function oxidases in the smooth ER of the liver
and other organs

CCl4, which was once widely used in the dry cleaning industry, is converted by cytochrome P450 to the highly reactive free radical CCl3, which causes lipid peroxidation and damages many
cellular structures. Acetaminophen, an analgesic drug, is also converted to a toxic product during
detoxification in the liver, leading to cell injury.

Mild Ischemia: Reduced oxidative phosphorylation .reduced ATP generation failure

of Na pump influx of sodium and water organelle and cellular swelling (reversible)

Severe/prolonged ischemia: severe swelling of mitochondria, calcium influx into

mitochondria and into the cell with rupture of lysosomes and plasma membrane. Death by
necrosis and apoptosis due the release of cytochrome c from mitochondria

Reperfusions injury follows blood flow into ischemic area is caused by oxidative stress
due to release of free radicals from leukocytes and endothelial cells. Blood brings calcium that
overloads reversibly injured cells with consequent mitochondrial injury. Influx of leukocytes
generates free radicals and cytokines. Local activation of complement by IgM antibodies
deposited in ischemic tissues.

Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program
in which cells destined to die activate intrinsic enzymes that degrade the cells' own nuclear
DNA and nuclear and cytoplasmic proteins

Apoptotic cells break up into fragments, called apoptotic bodies, which contain portions of the
cytoplasm and nucleus. The plasma membrane of the apoptotic cell and bodies remains intact,
but its structure is altered in such a way that these become tasty targets for phagocytes.

cell death by this pathway does not elicit an inflammatory reaction in the host.

Before discussing the mechanisms of apoptosis, the morphologic and biochemical characteristics
of this process are described

Cell shrinkage

Chromatin condensation

Formation of cytoplasmic blebs and apoptotic bodies.

Phagocytosis of apoptotic cells or cell bodies, usually by macrophages

the apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm with
fragments of dense nuclear chromatin

apoptosisin contrast to necrosisdoes not elicit inflammation, making it more difficult to

detect histologically.

Apoptosis results from the activation of enzymes called caspases (so named because they
are cysteine proteases that cleave proteins after aspartic residues)

Two distinct pathways converge on caspase activation: the mitochondrial pathway and the
death receptor pathway

The mitochondrial pathway is the major mechanism of apoptosis in all mammalian cells. It
results from increased permeability of the mitochondrial outer membrane

If, however, unfolded or misfolded proteins accumulate in the ER because of inherited mutations
or stresses, they trigger a number of cellular responses, collectively called the unfolded protein
response.

Autophagy is a process in which a cell eats its own contents

Autophagy is an adaptive response that is enhanced during nutrient deprivation, allowing

the cell to cannibalize itself to survive.

The terms steatosis and fatty change describe abnormal accumulations of triglycerides
within parenchymal cells. Fatty change is often seen in the liver because it is the major organ
involved in fat metabolism

Xanthomas. Intracellular accumulation of cholesterol within macrophages is also

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 xanthomas.

The term hyaline usually refers to an alteration within cells or in the extracellular space
that gives a homogeneous, glassy, pink appearance in routine histologic sections stained
with hematoxylin and eosin.

he most common exogenous pigment is carbon (coal dust), a ubiquitous air pollutant in
urban areas. 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. Accumulations of this pigment blacken the tissues of the lungs (anthracosis) and the
involved lymph nodes

Metastatic calcification may occur in normal tissues whenever there is hypercalcemia.

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.

Cellular aging is the result of a progressive decline in cellular function and viability caused
by genetic abnormalities and the accumulation of cellular and molecular damage due to the
effects of exposure to exogenous influences

All normal cells have a limited capacity for replication, and after a fixed number of
divisions cells become arrested in a terminally nondividing state, known as replicative
senescence

One mechanism of replicative senescence involves progressive shortening of telomeres,

which ultimately results in cell cycle arrest. Telomeres are short repeated sequences of DNA
present at the ends of linear chromosomes that are important for ensuring the complete
replication of chromosome ends

as most somatic cells age, their telomeres become shorter and they exit the cell cycle, resulting
in an inability to generate new cells to replace damaged ones. Conversely, in immortalized
cancer cells, telomerase is usually reactivated and telomere length is stabilized, allowing the cells
to proliferate indefinitely

Lecture 4: Acute Inflammation

1. Define inflammation and discuss its fundamental properties.
a. (1) recognition of the injurious agent
b. (2) recruitment of leukocytes
c. (3) removal of the agent
d. (4) regulation (control) of the response
e. (5) resolution (repair)
2. Be familiar with the five cardinal signs of inflammation.
a. Rubor (redness)

b. Tumor (swelling)
c. Calor (heat)
d. Dolor (pain)
e. Loss of function
3. List and describe the stimuli involved in inflammatory reactions.
a. Foreign bodies
b. Immune reactions
c. Infections (bacterial, viral, fungal, parasitic) and microbial toxins
d. necrosis
4. Discuss the cellular receptors and circulating proteins that aid in the recognition of
offending agents.
a. Histamine, NO = vasodilation
b. Chemoattractants, exogenous and endogenous(cytokines, complement, arachodic
acid)
c. Offending agents
5. Define acute inflammation and describe the three major components of acute
inflammation.
a. Rapid in onset (minutes)
b. Short duration (hours or a few days)
c. Exudation of fluid and plasma proteins (edema)
d. Emigration of leukocytes (neutrophils)
e. Three major components
i. Alterations in vascular caliber
ii. Structural changes in the microvasculature
iii. Emigration of the leukocytes
6. Be familiar with the series of changes to a blood vessel during periods of inflammation,
including the discussion of exudate and transudate.
a. Exudate
i. Inflammatory extravascular fluid
ii. High protein concentration

iii. Specific gravity > 1.020

iv. Usually due to permeability
b. Transudate
i. Fluid with low protein concentration (albumin)
ii. Specific gravity < 1.012
iii. Permeability usually not increased (due to a pressure response)
c. Edema
i. Excess interstitial fluid
ii. Can be either an exudate or transudate
d. Pus
i. Purulent exudate, Leukocytes (neutrophils)
ii. Debris of dead cells, Microbes

e.
7. Discuss the changes in vascular flow and caliber following injury.
a. Vasodilation
i. Earliest manifestations of acute inflammation
ii. Follows a transient constriction of arterioles
iii. Lasts a few seconds
iv. First involves the arterioles
v. Leads to opening of new capillary beds
vi. Result is increased blood flow: Cause of heat and redness (erythema) at
the site of inflammation

vii. Histamine and nitric oxide

8. Describe the mechanisms responsible for increased vascular permeability.
a. Loss of fluid and increased vessel diameter
b. Leads to slower blood flow, concentration of red cells in small vessels, and
increased viscosity of the blood: stasis
c. Changes result in dilation of small vessels
d. As stasis progresses.
e. Leukocytes (neutrophils) accumulate along the vascular endothelium
f. Endothelial cells are activated by mediators produced at sites of infection and
tissue damage
g. Express increased levels of adhesion molecules
h. Leukocytes then adhere to the endothelium
i. Migrate through the vascular wall into the interstitial tissue
j. Hallmark of acute inflammation
i. Increased vascular permeability
1. Leads to the escape of a protein-rich exudate into the extravascular
tissue
2. Causes edema
3. Mechanisms
4. Contraction of endothelial cells
a. Results in increased interendothelial spaces
b. Most common mechanism of vascular leakage
c. Elicited by histamine, bradykinin, leukotrienes, the
neuropeptide substance P, and many other mediators
d. Called the immediate transient response
e. Occurs rapidly after exposure to the mediator
f. Usually short-lived (15-30 minutes)
5. Endothelial injury
a. Results in endothelial cell necrosis and detachment
b. Direct damage to the endothelium

6. Transcytosis
a. Increased transport of fluids and proteins through the
endothelial cell
9. Be familiar with the responses of lymphatic vessels to inflammation.
a. Lymph flow is increased and helps drain edema fluid
i. Accumulates due to increased vascular permeability
ii. Lymphatic vessels proliferate during inflammatory reactions
iii. Lymphatics may become secondarily inflamed (lymphangitis)
iv. Draining lymph nodes may become inflamed (lymphadenitis)
1. Hyperplasia of the lymphoid follicles
2. Increased numbers of lymphocytes and macrophages
10. Explain the processes of leukocyte recruitment to sites of infection and injury.
a. Extravasation: Journey of leukocytes
i. Vessel lumen to the interstitial tissue
b. Lumen: Margination(leaving the blood stream, going to side of blood vessels),
rolling, and adhesion to endothelium
c. Migration across endothelium and vessel wall
d. Migration in the tissues toward a chemotactic stimulus

11. Discuss the other responses of activated leukocytes.

a. Stimulate the proliferation of endothelial cells and fibroblasts
b. Stimulate the synthesis of collagen
c. Stimulate enzymes that remodel connective tissues
d. Drive the process of repair after tissue injury
e. phagocytosis
12. Briefly describe the clinical diseases associated with defects in leukocyte function (use
Table 3-3 as a guide).
a. Chdiak-Higashi syndrome
i. Autosomal recessive condition
ii. Defective fusion of phagosomes and lysosomes in phagocytes
iii. Causing susceptibility to infections
iv. Abnormalities in melanocytes (leading to albinism)
v. Cells of the nervous system (associated with nerve defects)
vi. Platelets (causing bleeding disorders)
vii. Leukocyte abnormalities: Neutropenia (decreased numbers of neutrophils)
viii. Defective degranulation

ix. Delayed microbial killing

b. Chronic granulomatous disease
i. Defects in bacterial killing
ii. Render patients susceptible to recurrent bacterial infection
iii. Inherited defects in the genes encoding components of phagocyte oxidase
iv. Initial neutrophil defense is inadequate
1. Collections of activated macrophages that wall off the microbes
2. Aggregates called granulomas
c. Bone marrow suppression
i. Decreased production of leukocytes
ii. Seen following therapies for cancer, Radiation and chemotherapy
iii. Marrow space is compromised by tumors
iv. Leukemias, Metastatic from other sites
13. Chronic inflammation:
a. Can follow acute inflammation, longer duration, presence of lymphocytes and
macrophages, angiogenis and fibrosis

Lecture 5: Acute and Chronic inflammation

1. Understand the properties and principles of chemical mediators of inflammation.
a. Mediators are generated either from cells or from plasma proteins
b. Cell-derived mediators
i. Normally sequestered in intracellular granules
ii. Can be rapidly secreted by granule exocytosis
1. Histamine in mast cell granules
iii. Synthesized de novo in response to a stimulus
1. Prostaglandins, cytokines
iv. Cells that produce mediators
1. Platelets, neutrophils, monocytes/macrophages, and mast cells
2. Mesenchymal cells (endothelium, smooth muscle, fibroblasts)

3. Most epithelia
c. Plasma derived mediators
i. Complement, kinins, made in liver

2. List and briefly discuss the source and actions of the major chemical mediators of
inflammation (use Table 3-4 as a guide).

a. Histamine-vasoactive amine
i. In mast cells, basophils, platelet cells
ii. Released: trauma, cold, heat, antibody binding, complement, substance P,
IL-1,IL-8
iii. Causes dilation of arterioles, increases permeability of venules by acting
on endothelial cells
b. Serotonin-vasoactive amine
i. In platelets, GI neuroendocrine cells
ii. Acts like histamine
iii. Platelet coagulation
c. Prostaglandins
i. In mast cells, macrophages, endothelial cells
ii. Inflammation
1. PGE2, PGD2, PGF2, PGI2 (prostacyclin), and TxA2 (thromboxane)
iii. Prostacyclin
1. Vasodilator, inhibitor of platelet aggregation
iv. PGD2
1. in mast cells
2. vasodilation, increases venule perm
3. Neutrophil chemoattractant
4. Seen with PGE2!!!
v. PGF2
1. Contraction of uterine and bronchial SM
vi. PGE2
1. Hyperalgesic: increased pain sensitivity, FEVER
d. Leukotrienes

i. by mast cells, leukocytes

ii. increased permeability, chemotaxis
iii. LTB4
1. Chemotaxis and neutrophil activator
2. ROS generator and releases lysosomal enzymes
iv. LTC4,LTD4,LTE4
1. Intense vasoconstriction, bronchospasm, increased vascular perm
e. Lipoxins
i. Produced by neutrophils and platelets
ii. Inflammation inhibitors, inhibit leukocyte recruitment and inhibit
neutrophil chemotaxis and adhesion of platelets and neutrophils
iii. Opposite of leukotrienes, may play a role in resolution of inflammation
f. Eicosanoid inhibitors
i. COX make prostaglandins
1. NSAIDS block COX1 and COX2
2. Steroids block COX2
ii. Lipoxygenase makes leukotrienes and lipoxygenase
1. Not inhibited by NSAID
2. Zileuton: inhibits leukotriene synthesis(asthma treatment)
3. Montelukast: blocks leukotriene receptors
iii. Corticosteriods: reduce gene transcription for COX2, IL-1, TNF
g. ROS
i. Released from leukocytes, injures endothelial cells and RBCs
h. Nitric Oxide(NO)
i. Released from endothelial cells
ii. Vasodilation, inhibits cellular component of inflammatory response
iii. Reduces platelet aggregation and adhesion
iv. Can be microbicidal
4. Cytokines and chemokines
a. TNF and IL-1
i. Inflammation, FEVER
ii. Produced by activated macrophages
iii. Released when stimulation by immune complex, injury, endotoxin
iv. Sustained production leads to cachexia
b. Chemokines
i. Stimulate leukocyte recruitment, control migration of cells
ii. CXC(alpha)
1. ACTS ON NEUTROPHILS,IL-8
2. Secreted by activated macrophages, endothelial cells
3. Chemotactic for neutrophils ONLY
iii. CC(beta)
1. Attracts monocytes,eosinophils,basophils,lymphocytes but NOT
NEUTROPHILS
iv. C(gamma)
1. Attract lymphocytes
v. CX3C

1. Fractalkine: surface bound and soluble

c. Platelet activating factor
i. Causes platelet aggregation, inflammation, vasoconstriction and
bronchoconstriction
ii. Platelets, basophils, mast cells, neutrophils, macrophages and endothelial
cells
d. Neuropeptides
i. Made in sensory nerves, propagate inflammation
ii. Substance P and neurokinin A
1. Transmit pain, regulate BP, stimulate endocrine cells, increase
vascular permeability
e. Complement
i. Cause increased vascular perm, chemotaxis and opsonization
ii. Inflammation
1. C3a,C5a stimulate histamine release, vasodilation
2. C5a: chemotaxis for neutrophils, monocytes
iii. Phagocytosis
1. C3b for opsonization
iv. Cell lysis
1. MAC cell lysis
v.

f. Kinins
i. Vasoactive peptides derived from plasma proteins
ii. Bradykinin
1. Increases vascular perm, SM contraction, blood vessel dialation
g. Factor XII induces fibrin clot formation and in turn activates the fibrinolytic
system
i. Kallikrein cleaves plasminogen reducing clot size and plasmin

ii. Plasmin lyses fibrin clots, cleaves complement

iii. Activated Hageman factor (factor XIIa) Initiates four systems
(inflammatory response)
iv. Kinin system
1. Produces vasoactive kinins
v. Clotting system
1. Induces formation of thrombin
vi. Fibrinolytic system
1. Produces plasmin
2. Degrades fibrin to produce fibrinopeptides
vii. Complement system
1. Produces anaphylatoxins and other mediators
viii.

5. Neutrophils and monocytes have granules

a. Specific (secondary) granules
i. Have histamine, collagenase
b. Larger azurophil(primary) granules
i. Neutral proteases
Lecture 6: Inflammation lecture 3

1. Acute inflammation: stasis, vasodilation, accumulation of leukocytes and fluid

a.

2. Serous inflammation
a. Outpouring of thin fluid derived from plasma and mesothelial cells into
body cavities

b. Skin blister, edema will occur under the epidermis, separating the
dermis from the epidermis on slide view
Fluid will be clear but straw colored
Serous effusion in pleural cavities is straw colored
Seroanguinous effusion in pleural cavities is bloody
Chylous effusion is milky in color
3. Fibrinous inflammation
a. Fibrinous exudate: lining of meninges, pericardium, pleura
i. Fibrin appears as eosinophilic thread network, appears
ACELLULAR
ii. Looks like bread with butter dropped on floor
iii. Leads to scarring, could happen on pericardium
4. Suppurative inflammation
a. Large amounts of purulent exudate filled with neutrophils and bacteria
b. Will be yellow and pus-like in color
c. Ex. Appendicitis, creamy white meningitis, abscesses
d. Abscesses in lung will have an air fluid line in XRAY
i. Necrotic tissues
ii. Appears histologically as area of dead neutrophils with dilated
vessels around the outside and pink fibroblasts around the
neutrophils

c.
d.
e.
f.

iii.

e. Many neutrophils seen inside alveolar spaces

5. Ulcers
a. Local defect of surface of organ or tissue and produces shedding of
inflamed necrotic tissue

b. Found in stomach, intestines, mouth

c.

6. Acute inflammation outcomes: edema absorbed by lymphatics, macrophages

remove cellular debris

a.
7. Chronic inflammation:
a. Lasts weeks or months
b. Results from infections by microorganisms
c. Macrophages, lymphocytes and plasma cells dominate
d. Tissue destruction, angiogenesis and fibrosis seen
e. Chronic inflammation of the lung: collection of chronic inflammatory
cells, normal alveolar epithelium replaced with cuboidal cells, fibrosis,
alveolar spaces are clear
8. Macrophages
a. Microglia-macrophages in CNS
b. Kupffer cells-in liver
c. Histocytes-lymph nodes
9. Eosinophils
a. Mediated by IgE
10. Granulomatous inflammation
a. Activation of T cells
b. TB, Scarcoiosis
c. Granuloma will be yellow sphere like thing in lung tissue
d. Non-caseating granuloma will have giant cell in the middle
e. Forign body granuloma: foreign body will be at center of granuloma
f. Immune granuloma: caused by agents like TB, reffered to as a
tubercule
i. Giant multinucleated cells will be on the outside of the
granuloma
11. Systemic effects of inflammation:
a. Leukocytosis: high count 15,000-20,000
b. Neutrophilia, lymphocytosis

Lecture 7: Inflammation and wound repair

1. TNF, IL-1, and IL-6 cause fever
2. PGE2 stimulates neurotransmitters that set temp high
a. Acute phase proteins: From liver
b. CRP(c-reactive proteins), SAA protein
1. These proteins bind to microbial cell walls and help complement
do its thing
2. Bind chromatin as well to help clear necrotic cell nuclei
c. Fibrogen: binds red cells, forms stacks(rouleaux)
d. Hepcidin: iron regulating peptide, responsible for anemia associated with chronic
inflammation