Acute inflammation

Question 1

What is inflammation?

Answer 1

This is fundamentally a protective response , designed to rid the organism of both the initial cause of cell injury (e.g., microbes, toxins) and the consequences of such
injury (e.g., necrotic cells and tissues).

Without inflammation infections would go unchecked,
wounds would never heal, and injured tissues might remain permanent festering sores.

In the
practice of medicine the importance of inflammation is that it can sometimes be inappropriately
triggered or poorly controlled, and is thus the cause of tissue injury in many disorders.

Question 2

Inflammation is a complex reaction in tissues that consists mainly of responses of _____________

Answer 2

blood vessels
and leukocytes.

Question 3

The body’s principal defenders against foreign invaders are ________________

Answer 3

plasma proteins and circulating leukocytes (white blood cells), as well as tissue phagocytes that are derived
from circulating cells.

The presence of proteins and leukocytes in the blood gives them the ability to home to any site where they may be needed.

Because invaders such as microbes and
necrotic cells are typically present in tissues, outside the circulation, it follows that the circulating cells and proteins have to be rapidly recruited to these extravascular sites.

The
inflammatory response coordinates the reactions of vessels, leukocytes, and plasma proteins to
achieve this goal

Question 4

What triggers the vascular and cellular reactions of inflammation?

Answer 4

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.

Microbes, necrotic cells (whatever the cause of cell
death) and even hypoxia can trigger the elaboration of inflammatory mediators, and thus elicit
inflammation.

Such mediators initiate and amplify the inflammatory response and determine its pattern, severity, and clinical and pathologic manifestations.

Question 5

Inflammation may be acute or chronic , depending on the:

Answer 5

nature of the stimulus and the
effectiveness of the initial reaction in eliminating the stimulus or the damaged tissues.

Question 6

Describe acute inflammation.

Answer 6

Acute
inflammation is rapid in onset (typically minu its main characteristics are the exudation of fluid and plasma proteins (edema) and

the emigration of leukocytes, predominantly neutrophils (also called polymorphonuclear

leukocytes). tes) and is of short duration, lasting for hours or a
few days;

When acute inflammation is successful in eliminating the offenders the reaction
subsides, but if the response fails to clear the invaders it can progress to a chronic phase.

Question 7

What are the main characterisitcs of acute inflammation?

Answer 7

its main characteristics are the:

• exudation of fluid and plasma proteins (edema)
• and the emigration of leukocytes,
• predominantly neutrophils (also called polymorphonuclear leukocytes).

Question 8

Describe chronic inflammation.

Answer 8

Chronic inflammation may follow acute inflammation or be insidious in onset.

It is of longer
durationandis associated with the presence of lymphocytes and macrophages, theproliferation of blood vessels, fibrosis, and tissue destruction.

Question 9

When does inflammation terminated?

Answer 9

Inflammation is terminated when the offending agent is eliminated . The reaction resolves
rapidly, because the mediators are broken down and dissipated and the leukocytes have short
life spans in tissues.

In addition, anti-inflammatory mechanisms are activated that serve to
control the response and prevent it from causing excessive damage to the host.

Question 10

The inflammatory response is closely intertwined with the process of repair .

T or F

Answer 10

True

Question 11

When does repair begins?

Answer 11

At the same time
as inflammation destroys, dilutes, and walls off the injurious agent, it sets into motion a series of
events that try to heal the damaged tissue.

Repair begins during inflammation but reaches
completion usually after the injurious influence has been neutralized. In the process of repair
the injured tissue is replaced through regeneration of native parenchymal cells, by filling of the
defect with fibrous tissue (scarring) or, most commonly, by a combination of these two
processes

Question 12

Inflammation may be harmful in some situations .

Mechanisms designed to destroy foreign
invaders and necrotic tissues have an intrinsic ability to injure normal tissues.

When inflammation is inappropriately directed against self tissues or is not adequately controlled, it becomes the cause of injury and disease.

In fact, in clinical medicine, great attention is given to
the damaging consequences of inflammation. Inflammatory reactions underlie common chronic
diseases, such as rheumatoid arthritis, atherosclerosis, and lung fibrosis, as well as lifethreatening
hypersensitivity reactions to insect bites, drugs, and toxins.

For this reason our
pharmacies abound with anti-inflammatory drugs, which ideally would control the harmful
sequelae of inflammation yet not interfere with its beneficial effects.

Question 13

T or F

Inflammation may contribute to a variety of diseases that are not thought to be primarily due to
abnormal host responses.

Answer 13

TRUE

For instance, chronic inflammation may play a role in
atherosclerosis, type 2 diabetes, degenerative disorders like Alzheimer disease, and cancer. In
recognition of the wide-ranging harmful consequences of inflammation, the lay press has rather
melodramatically referred to it as “the silent killer.”

Question 14

four cardinal signs of
inflammation:

Answer 14

• rubor (redness)
• , tumor (swelling)
• , calor (heat),
• and dolor (pain).

Question 15

What is Rubor?

Answer 15

R for R

Redness

Question 16

What is Tumor?

Answer 16

Obviously its SWELLING

Question 17

What is calor ?

Answer 17

(heat)

C-heat

Question 18

What is dolor?

Answer 18

pain

Dolores is PAIN. So never name someone DOLORes

Question 19

The four cardinal signs
are typically more prominent in___________

Answer 19

acute inflammation than in chronic inflammation.

Question 20

A fifth clinical
sign, _____________- was added by Rudolf Virchow in the 19th century.

Answer 20

loss of function (functio laesa),

Question 21

inflammation is not a disease but a nonspecific response that has a salutary effect on its
host.

T or F

Answer 21

True

In 1793 the Scottish surgeon John Hunter noted what is now considered an obvious fact: that inflammation is not a disease but a nonspecific response that has a salutary effect on its
host.

Question 22

Who discovered phagocytosis?

Answer 22

In the 1880s the Russian biologist Elie Metchnikoff discovered the process of phagocytosis by observing the ingestion of rose thorns by amebocytes of starfish larvae and of
bacteria by mammalian leukocytes.

[3] He concluded that the purpose of inflammation was to
bring phagocytic cells to the injured area to engulf invading bacteria.

This concept was
elegantly satirized by George Bernard Shaw in his play “The Doctor’s Dilemma,” in which one
physician’s cure-all is to “stimulate the phagocytes”! Sir Thomas Lewis, studying the
inflammatory response in skin, established the concept that chemical substances, such as
histamine (produced locally in response to injury), mediate the vascular changes of
inflammation. This fundamental concept underlies the important discoveries of chemical
mediators of inflammation and the use of anti-inflammatory drugs in clinical medicine.
Historical Highlights
97

Question 23

Acute inflammation is a rapid host response that serves to deliver leukocytes and plasma proteins, such as antibodies, to sites of infection or tissue injury. Acute inflammation has three
major components:

Answer 23

• (1) alterations in vascular caliber that lead to an increase in blood flow ,
• (2) structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation,
• and (3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent

FIGURE 2-1 The major local manifestations of acute inflammation, compared to normal.

(1) Vascular dilation and increased blood flow (causing erythema and warmth);
(2) extravasation and extravascular deposition of plasma fluid and proteins (edema);
(3) leukocyte emigration and accumulation in the site of injury.

Question 24

STIMULI FOR ACUTE INFLAMMATION
Acute inflammatory reactions may be triggered by a variety of stimuli:

Answer 24

• Infections (bacterial, viral, fungal, parasitic)
• Tissue necrosis
• Foreign bodies
• Immune reactions

Question 25

How do infections cause inflammation?

Answer 25

Infections (bacterial, viral, fungal, parasitic) and microbial toxins are among the most common and medically important causes of inflammation.

Mammals possess many
mechanisms for sensing the presence of microbes.

Question 26

What is a TLR?

Answer 26

Among the most important receptors
for microbial productsare the family of Toll-like receptors (TLRs), named after the Drosophila protein Toll, and several cytoplasmic receptors,which can detect bacteria,
viruses, and fungi ( Chapter 6 ).

Engagement of these receptors triggers signaling
pathways that stimulate the production of various mediators.

Question 27

How does tissue necrosis promote inflammation?

Tissue necrosis from any cause, including ischemia (as in a myocardial infarct), trauma,
and physical and chemical injury (e.g., thermal injury, as in burns or frostbite;
irradiation; exposure to some environmental chemicals).

Answer 27

Several molecules released
from necrotic cellsareknown to elicit inflammation

Question 28

What are the mediators released from necrosis that promote inflammation?

Answer 28

• these include uric acid,
• a purine metabolite;
• adenosine triphosphate,
• the normal energy store;
• a DNA-binding protein of unknown function called HMGB-1; and even DNA when it is released into the cytoplasm
• and not sequestered in nuclei, as it should be normally.
• [4] Hypoxia, which often underlies cell injury, is also itself an inducer of the inflammatory response. This response is mediated largely by a protein called HIF-1α (hypoxia-induced factor-1α), which is produced by cells deprived of oxygen and activates the transcription of many genes involved in inflammation, including vascular endothelial growth factor (VEGF), which increases vascular permeability

Question 29

All inflammatory reactions share the same basic features, although different stimuli may induce
reactions with some distinctive characteristics. We first describe the typical sequence of events
in acute inflammation, and then the chemical mediators responsible for inflammation and the
morphologic appearance of these reactions.

Question 30

Why do blood vessels undergo series of changes during inflammation?

Answer 30

In inflammation, blood vessels undergo a series of changes that are designed to maximize the
movement of plasma proteins and circulating cells out of the circulation and into the site of
infection or injury.

Question 31

what is an exudation?

Answer 31

The escape of fluid, proteins, and blood cells from the vascular system into
the interstitial tissue or body cavities is known as exudation.

Question 32

What is a transudate?

Answer 32

In contrast, a transudate is a fluid
with low protein content (most of which is albumin), little or no cellular material, and low specific
gravity.

It is essentially an ultrafiltrate of blood plasma that results from osmotic or hydrostatic
imbalance across the vessel wall without an increase in vascular permeability ( Chapter 4 ).

Question 33

What is an edema?

Answer 33

Edema denotes an excess of fluid in the interstitial tissue or serous cavities; it can be either an
exudate or a transudate.

Question 34

What is a purulent exudate?

Answer 34

Pus, a purulent exudate, is an inflammatory exudate rich in leukocytes
(mostly neutrophils), the debris of dead cells and, in many cases, microbes

Question 35

How is a transudate formed?

Answer 35

Formation of transudates and exudates.

B, A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic pressure.

C, An exudate is formed in
inflammation, because vascular permeability increases as a result of increased
interendothelial spaces

Question 36

What is the normal hydrostatic pressure at arterial end?

Answer 36

A, Normal hydrostatic pressure (blue
arrows) is about 32 mm Hg at the arterial end of a capillary bed

Question 37

What is the normal hydrostatic pressure at the venous end?

Answer 37

12 mm Hg at the venous
end;

Question 38

What is the mean colloid osmotic pressure of tissues?

Answer 38

the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrows),
which is equal to the mean capillary pressure.

Therefore, the net flow of fluid across the
vascular bed is almost nil.

Question 39

The vascular reactions of acute inflammation consist of ________________

Answer 39

changes in the flow of blood and the
permeability of vessels.

Proliferation of blood vessels (angiogenesis) is prominent during repair
and in chronic inflammation; this process is discussed in Chapter 3 .

Question 40

Changes in Vascular Flow and Caliber
Changes in vascular flow and caliber begin early after injury and consist of the following.

Answer 40

• Vasodilation
• increased permeability of the microvasculature
• vascular congestion
• stasis develops, blood leukocytes, principally neutrophils, accumulate along the
  vascular endothelium.

Question 41

What is the earliest manifestations of acute inflammation?

Answer 41

Vasodilation is one of the earliest manifestations of acute inflammation.

Question 42

Is it true that in inflammtion after vasodilation sometimes it
follows a transient constriction of arterioles, lasting a few seconds.

T or F

Answer 42

T

Question 43

Vasodilation first
involves the : __________

Answer 43

arterioles and then leads to opening of new capillary beds in the area.

Question 44

Vasodilation results in:

Answer 44

The
result is increased blood flow.

Question 45

which is the cause of heat and redness (erythema) at the
site of inflammation.

Answer 45

Vasodilation

Question 46

Vasodilation is induced by the action of several mediators, notably
________ on vascular smooth muscle

Answer 46

histamine and nitric oxide (NO),

Question 47

What quickly follows vasodilation?

Answer 47

Vasodilation is quickly followed by increased permeability of the microvasculature , with
the outpouring of protein-rich fluid into the extravascular tissues; this process is
described in detail below.

Question 48

What quickly foillows after vasodilatation?

Answer 48

Vasodilation is quickly followed by increased permeability of the microvasculature , with
the outpouring of protein-rich fluid into the extravascular tissues; this process is
described in detail below.

Question 49

The loss of fluid and increased vessel diameter lead to :

Answer 49

The loss of fluid and increased vessel diameter lead to slower blood flow, concentration
of red cells in small vessels, and increased viscosity of the blood.

These changes result
in dilation of small vessels that are packed with slowly moving red cells, a condition
termed stasis, which is seen as vascular congestion (producing localized redness) upon
examination of the involved tissue

Question 50

What is stasis ?

Answer 50

These changes result
in dilation of small vessels that are packed with slowly moving red cells, a condition
termed stasis, which is seen as vascular congestion (producing localized redness) upon
examination of the involved tissue

Question 51

What happens after stasis develops?

Answer 51

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, in a sequence that is
described later

Question 52

A hallmark of acute inflammation is ________________

Answer 52

increased vascular permeability leading to the escape of a protein-rich exudate into the extravascular tissue, causing edema

Question 53

Several mechanisms are
responsible for the increased vascular permeability

Answer 53

• Contraction of endothelial cells
• Endothelial injury
• Increased transport of fluids and proteins

Question 54

What is the most common mechanism of vascular leakage?

Answer 54

• *Contraction of endothelial cells resulting in increased interendothelial spaces** is the
• *most common mechanism of vascular leakage.**

Question 55

What is happens when there is contraction of endothelial cells?

Answer 55

Contraction of endothelial cells resulting in increased interendothelial spaces is the
most common mechanism of vascular leakage.

Question 56

The contraction of endothelial cells resulting in increased interendothelial space is elicited by:

Answer 56

• histamine
• bradykinin,
• leukotrienes,
• the neuropeptide substance P,
• and many other chemical mediators. [6,] [7]

Question 57

What is the immediate transient response?

Answer 57

Contraction of endothelial cells resulting in increased interendothelial spaces is the
most common mechanism of vascular leakage.

Question 58

Why is contraction of the endothelial cells resulting in increased interendothelial space is called the immediate transient response?

Answer 58

because it occurs rapidly after exposure to
the mediator and is usually short-lived (15–30 minutes).

Question 59

Give an example when vascular leakage begins after a delay of 2 to 12 hours.

Answer 59

In some forms of mild injury
(e.g. after burns, x-irradiation or ultraviolet radiation, and exposure to certain bacterial
toxins), vascular leakage begins after a delay of 2 to 12 hours, and lasts for several
hours or even days;

Question 60

What is the reason for some cases that there is a delay in vascular leakage?

Answer 60

this delayed prolonged leakage may be caused by contraction of
endothelial cells or mild endothelial damage.

Late-appearing sunburn is a good example
of this type of leakage

Question 61

What is the result when there is endothelial injury?

Answer 61

Endothelial injury, resulting in endothelial cell necrosis and detachment .

[8] Direct
damage to the endothelium is encountered in severe injuries, for example, in burns, or
by the actions of microbes that target endothelial cells.

Question 62

[9] Neutrophils that adhere to the
endothelium during inflammation may also injure the endothelial cells and thus amplify
the reaction.

T or F

Answer 62

T

In most instances leakage starts immediately after injury and is sustained
for several hours until the damaged vessels are thrombosed or repaired.

Question 63

In most instances leakage starts immediately after injury and is sustained
for several hours until the damaged vessels are thrombosed or repaired.

T or F

Answer 63

T

Question 64

What is transcystosis?

Answer 64

Increased transport of fluids and proteins, called transcytosis, through the endothelial
cell.

Question 65

Increased Vascular Permeability (Vascular Leakage)

Question 66

What is involved in the process of transcytosis?

Answer 66

This process may involve channels consisting of interconnected, uncoated vesicles
and vacuoles called the vesiculovacuolar organelle, many of which are located close to
intercellular junctions. [10]

Certain factors, such as VEGF ( Chapter 3 ), seem to
promote vascular leakage in part by increasing the number and perhaps the size of
these channels.

Question 67

Acute Inflammation events

Answer 67

1. Retraction of endothelial cells which occurs mainly in venules and induced by histamines
2. endothelial injury which aoccurs in arterioles, capillaries and venules: rapid maybe long lived
3. leukocyte mediated vascular injury : occurs in venules, pulmonary capillaries; assoc with late stages of inflamm; long lived
4. Increased transcytosis: induced by VEGF: in venules

Question 68

Although these mechanisms of increased vascular permeability are described separately, all
probably contribute in varying degrees in responses to most stimuli

For example, at different
stages of a thermal burn, leakage results from chemically mediated endothelial contraction and
direct and leukocyte-dependent endothelial injury.

The vascular leakage induced by all these
mechanisms can cause life-threatening loss of fluid in severely burned patients

Question 69

Although much of the emphasis in our discussion of inflammation is on the reactions of blood
vessels, lymphatic vessels also participate in the response.

How does it participate?

Answer 69

In inflammation, lymph flow is increased and helps drain edema fluid that accumulates due to 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.

The lymphatics may become secondarily inflamed
(lymphangitis), as may the draining lymph nodes (lymphadenitis)

Inflamed lymph nodes are
often enlarged because of hyperplasia of the lymphoid follicles and increased numbers of
lymphocytes and macrophages.

This streaking follows the course of the
lymphatic channels and is diagnostic of lymphangitis; it may be accompanied by painful
enlargement of the draining lymph nodes, indicating lymphadenitis

Question 70

What is lymphangitis?

Answer 70

The lymphatics may become secondarily inflamed
(lymphangitis).

Question 71

What is lymphadenitis?

Answer 71

secondarily inflamed as may the draining lymph nodes (lymphadenitis).

Question 72

What is reactive or inflammatory lymhphadenitis?

Answer 72

Inflamed lymph nodes are
often enlarged because of hyperplasia of the lymphoid follicles and increased numbers of
lymphocytes and macrophages. This constellation of pathologic changes is termed reactive, or
inflammatory, lymphadenitis .

Question 73

a critical function of inflammation is:

Answer 73

to deliver leukocytes to the site of
injury and to activate the leukocytes to eliminate the offending agents.

Question 74

The most important
leukocytes in typical inflammatory reactions are the ones capable of _______________-

Answer 74

phagocytosis, namely
neutrophils and macrophages.

Question 75

Leukocytes also produce growth factors
that aid in repair.

T or F

Answer 75

A price that is paid for the defensive potency of leukocytes is that, when
strongly activated, they may induce tissue damage and prolong inflammation, because the
leukocyte products that destroy microbes and necrotic tissues can also injure normal host
tissues

Question 76

The processes involving leukocytes in inflammation consist of:

Answer 76

• their recruitment from the blood into extravascular tissues,
• recognition of microbes and necrotic tissues,
• and removal of the offending agent

Question 77

Recruitment of Leukocytes to Sites of Infection and Injury

The journey of leukocytes from the vessel lumen to the interstitial tissue, called extravasation,
can be divided into the following steps:

Answer 77

• 1. In the lumen: margination, rolling, and adhesion to endothelium. Vascular endothelium in its normal, unactivated state does not bind circulating cells or impede their passage. In inflammation the endothelium is activated and can bind leukocytes, as a prelude to their exit from the blood vessels.
• 2. Migration across the endothelium and vessel wall
• 3. Migration in the tissues toward a chemotactic stimulus

Question 78

What is extravasation?

Answer 78

The journey of leukocytes from the vessel lumen to the interstitial tissue, called extravasation

Question 79

What happens to the leukocytes in the lumen?

Answer 79

In the lumen: margination, rolling, and adhesion to endothelium.

Vascular endothelium
in its normal, unactivated state does not bind circulating cells or impede their passage.
In inflammation the endothelium is activated and can bind leukocytes, as a prelude to
their exit from the blood vessels.

Question 80

Discuss the multistep process of leukocyte migration to blood vessels.

Answer 80

The multistep process of leukocyte migration through blood vessels.

1. The leukocytes first roll,
2. then become activated
3. and adhere to endothelium,
4. then transmigrate across the endothelium,
5. pierce the basement membrane,
6. and migrate toward chemoattractants emanating from the source of injury.

Question 81

What are the different molecules that play a role in the multistep process of leukocyte migration through blood vessels?

Answer 81

Different molecules play predominant roles in different steps of this process—

• selectins in rolling;
• chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins;
• integrins in firm adhesion;
• and CD31 (PECAM-1) in transmigration.

​Neutrophils express low levels of L-selectin; they bind to endothelial cells predom in antly via P- and E-selectins. ICAM-1, intercellular adhesion molecule 1; TNF, tumor
necrosis factor.

Question 82

Discuss margination of leukocytes. How does this happen?

Answer 82

In normally flowing blood in venules, red cells are confined to a central axial column, displacing
the leukocytes toward the wall of the vessel.

• 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, individual and then rows of 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

Question 83

The adhesion of leukocytes to endothelial cells is mediated by complementary adhesion
molecules on the two cell types whose expression is enhanced by secreted proteins called
cytokines.

Cytokines are secreted by cells in tissues in response to microbes and other injurious agents, thus ensuring that leukocytes are recruited to the tissues where these stimuli are present.

The initial rolling interactions are mediated by a family of proteins called
__________

Answer 83

selectins

Question 84

There are three types of selectins:

Answer 84

• one expressed on leukocytes (L-selectin),
• one on endothelium (E-selectin),
• and one in platelets and on endothelium (P-selectin).

Question 85

The ligands for selectins are __________bound to
mucin-like glycoprotein backbones.

The expression of selectins and their ligands is regulated
by cytokines produced in response to infection and injury.

Answer 85

sialylated oligosaccharides

Question 86

Tissue macrophages, mast cells, and
endothelial cells that encounter microbes and dead tissues respond by secreting several
cytokines, including________ [18] and chemokines (chemoattractant cytokines).

Answer 86

tumor necrosis factor (TNF), [17] interleukin-1 (IL-1),

Question 87

TNF and IL-1 act on the endothelial cells of post-capillary venules adjacent to the
infection and induce the coordinate expression of numerous adhesion molecules

Within 1 to 2 hours the endothelial cells begin to express E-selectin and the ligands for Lselectin.

Other mediators such as histamine, thrombin, and platelet-activating factor (PAF),
described later, stimulate the redistribution of P-selectin from its normal intracellular stores in
endothelial cell granules (called Weibel-Palade bodies) to the cell surface.

Leukocytes express
L-selectin at the tips of their microvilli and also express ligands for E- and P-selectins, all of
which bind to the complementary molecules on the endothelial cells.

These are low-affinity
interactions with a fast off-rate, and they are easily disrupted by the flowing blood.

As a result,
the bound leukocytes bind, detach, and bind again, and thus begin to roll along the endothelial
surface

Question 88

What is Weibel- Palade bodies?

Answer 88

Other mediators such as histamine, thrombin, and platelet-activating factor (PAF),
described later, stimulate the redistribution of P-selectin from its normal intracellular stores in
endothelial cell granules (called Weibel-Palade bodies) to the cell surface.

Question 89

Endothelial-Leukocyte Adhesion Molecules

Endothelial
Molecule

Answer 89

• P-selectin
• E-selectin
• GlyCam-1, CD34
• ICAM-1
  (immunoglobulin
  family)
• VCAM-1
  (immunoglobulin
  family)

Question 90

TABLE 2-1 – Endothelial-Leukocyte Adhesion Molecules

P-selectin : Leukocyte Molecule : Major Role

Answer 90

Sialyl-Lewis X–modified proteins :Rolling (neutrophils, monocytes, T lymphocytes)

Question 91

TABLE 2-1 – Endothelial-Leukocyte Adhesion Molecules

Endothelial Molecule : E-selectin

Leukocyte Molecule

Major Role

Answer 91

Endothelial Molecule : E-selectin

Leukocyte Molecule :Sialyl-Lewis X–modified
proteins

Major Role: Rolling and adhesion (neutrophils, monocytes, T lymphocytes)

Question 92

TABLE 2-1 – Endothelial-Leukocyte Adhesion Molecules

Endothelial Molecule : GlyCam-1, CD34

Leukocyte Molecule

Major Role

Answer 92

Endothelial Molecule : GlyCam-1, CD34

Leukocyte Molecule L-selectin [*]

Major Role: Rolling (neutrophils, monocytes)

Question 93

TABLE 2-1 – Endothelial-Leukocyte Adhesion Molecules

Endothelial Molecule : ICAM-1 (immunoglobulin family)

Leukocyte Molecule

Major Ro le

Answer 93

Endothelial Molecule : ICAM-1 (immunoglobulin family)

Leukocyte Molecule : CD11/CD18 (β2) integrins (LFA-1, Mac-1)

Major Ro le: Adhesion, arrest, transmigration (neutrophils,
monocytes, lymphocytes)

Question 94

TABLE 2-1 – Endothelial-Leukocyte Adhesion Molecules

Endothelial Molecule :VCAM-1 (immunoglobulin family)

Leukocyte Molecule

Major Ro le

Answer 94

Endothelial Molecule :VCAM-1 (immunoglobulin family)

Leukocyte Molecule : VLA-4 (β1) integrin

Major Ro le : Adhesion (eosinophils, monocytes,
lymphocytes)

Question 95

L-selectin is expressed weakly on neutrophils.

It is involved in the binding of circulating Tlymphocytes
to the high endothelial venules in lymph nodes and mucosal lymphoid tissues, and
subsequent “homing” of lymphocytes to these tissues.

Question 96

These weak rolling interactions slow down the leukocytes and give them the opportunity to bind
more firmly to the endothelium.

Question 97

What are integrins?

Answer 97

Firm adhesion is mediated by a family of heterodimeric
leukocyte surface proteins called integrins

Question 98

__________induce
endothelial expression of ligands for integrins, mainly vascular cell adhesion molecule 1 (VCAM-
1, the ligand for the VLA-4 integrin) and intercellular adhesion molecule-1 (ICAM-1, the ligand
for the LFA-1 and Mac-1 integrins)

Answer 98

TNF and IL-1

Question 99

Leukocytes normally express integrins in a low-affinity state.

Meanwhile, chemokines that were produced at the site of injury enter the blood vessel, bind to
endothelial cell proteoglycans, and are displayed at high concentrations on the endothelial
surface.

These chemokines bind to and activate the rolling leukocytes. One of the consequences of activation is the conversion of VLA-4 and LFA-1 integrins on the leukocytes to
a high-affinity state. [22]

The combination of cytokine-induced expression of integrin ligands on the endothelium and activation of integrins on the leukocytes results in firm integrin-mediated binding of the leukocytes to the endothelium at the site of inflammation.

The leukocytes stop
rolling, their cytoskeleton is reorganized, and they spread out on the endothelial surface.

Question 100

What is the next step in the process of leukocyte recruitment?

Answer 100

The next step in the process of leukocyte recruitment is migration of the leukocytes through the
endothelium, called transmigration or diapedesis

Question 101

What is diapedesis?

Answer 101

• *migration of the leukocytes** through the
• *endothelium**, called transmigration or diapedesis

Question 102

Transmigration of leukocytes occurs mainly in
_________-

Answer 102

post-capillary venules.

Question 103

What do chemokines do to leukocytes?

Answer 103

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

Question 104

adhesion molecules include a member of the immunoglobulin
superfamily called ____________

Answer 104

PECAM-1 (platelet endothelial cell adhesion molecule) or CD31 [24] and
several junctional adhesion molecules.

Question 105

After traversing the endothelium, leukocytes pierce
the basement membrane, probably by ___________

Answer 105

probably by secreting collagenases, and enter the extravascular
tissue.

The cells then migrate toward the chemotactic gradient created by chemokines and
accumulate in the extravascular site.

In the connective tissue, the leukocytes are able to adhere
to the extracellular matrix by virtue of integrins and CD44 binding to matrix proteins.

Thus,
leukocytes are retained at the site where they are needed .

Question 106

The most telling proof of the importance of leukocyte adhesion molecules is the existence of

Answer 106

genetic deficiencies in these molecules, which result in recurrent bacterial infections as a
consequence of impaired leukocyte adhesion and defective inflammation.

Question 107

What is the deficiency in individuals with leukocyte adhesion deficiency type 1?

Answer 107

Individuals with
leukocyte adhesion deficiency type 1 have a defect in the biosynthesis of the β2 chain shared
by the LFA-1 and Mac-1 integrins.

Question 108

What is the deficiency in individuals with leukocyte adhesion deficiency type 2?

Answer 108

Leukocyte adhesion deficiency type 2 is caused by the
absence of sialyl-Lewis X, the fucose-containing ligand for E- and P-selectins, as a result of a
defect in a fucosyl transferase, the enzyme that attaches fucose moieties to protein backbones.

Question 109

What is chemotaxis?

Answer 109

After exiting the circulation, leukocytes emigrate in tissues toward the site of injury by a process
called chemotaxis, which is defined as locomotion oriented along a chemical gradient

Question 110

Both
exogenous and endogenous substances can act as chemoattractants.

T or F

Answer 110

T

Question 111

The most common
exogenous agents are _______________-

Answer 111

bacterial products, including peptides that possess an Nformylmethionine
terminal amino acid, and some lipids.

Question 112

Endogenous chemoattractants include
several chemical mediators (described later):

Answer 112

• (1) cytokines, particularly those of the chemokine family (e.g., IL-8);
• (2) components of the complement system, particularly C5a ;
• and (3) arachidonic acid (AA) metabolites, mainly leukotriene B 4 (LTB4).

Question 113

All these chemotactic agents
bind to specific seven-transmembrane G protein–coupled receptors on the surface of
leukocytes. [27]

Signals initiated from these receptors result in activation of second messengers
that increase cytosolic calciumandactivate small guanosine triphosphatases of the
Rac/Rho/cdc42 family as well as numerous kinases.

These signals induce polymerization of
actin,resulting inincreased amounts of polymerized actin at the leading edge of the cell and
localization of myosin filaments at the back.

The leukocyte moves by extending filopodia that
pull the back of the cell in the direction of extension, much as an automobile with front-wheel
drive is pulled by the wheels in front ( Fig. 2-6 ).

The net result is that leukocytes migrate toward
the inflammatory stimulus in the direction of the gradient of locally produced chemoattractants.

Question 114

The nature of the leukocyte infiltrate varies with the ___________

Answer 114

• *age of the inflammatory response** and the
• *type of stimulus.**

Question 115

In most forms of acute inflammation _________predominate in the
inflammatory infiltrate during the first 6 to 24 hours

Answer 115

neutrophils

Question 116

In most forms of acute inflammation neutrophils predominate in the
inflammatory infiltrate during the first 6 to 24 hours and are replaced by __________in 24 to 48
hours

Answer 116

monocytes

Question 117

Several reasons account for the early appearance of neutrophils:

Answer 117

• they are more numerous in the blood,
• they respond more rapidly to chemokines,
• and they may attachmore firmly to the adhesion molecules that are rapidly induced on endothelial cells, such as Pand E-selectins.

Question 118

Whta happens to neutrophils after entering tissues,

Answer 118

neutrophils are short-lived; they undergo apoptosis and disappear after 24 to 48 hours.

Question 119

Monocytes not only survive longer but may proliferate in the tissues, and thus become the dominant population in chronic inflammatory reactions.

There
are, however, exceptions to this pattern of cellular infiltration.

In certain infections—for example,
those produced by____________—the cellular infiltrate is dominated by continuously recruited neutrophils for several days; in viral infections, lymphocytes may be the first cells to
arrive; in some hypersensitivity reactions, eosinophils may be the main cell type.

Answer 119

Pseudomonas bacteria

Question 120

The molecular understanding of leukocyte recruitment and migration has provided a large number of potential therapeutic targets for controlling harmful inflammation. [14]

Agents that
block TNF, one of the major cytokines in leukocyte recruitment, are among the most successful
therapeutics ever developed for chronic inflammatory diseases, and antagonists of leukocyte
integrins (e.g. VLA-4), selectins, and chemokines are approved for inflammatory diseases or in
clinical trials. Predictably, these antagonists not only have the desired effect of controlling the
inflammation but can compromise the ability of treated patients to defend themselves against
microbes, which, of course, is the physiologic function of the inflammatory response.

Question 121

Once leukocytes (neutrophils and monocytes) have been recruited to a site of infection or cell
death, they must be activated to perform their functions. The responses of leukocytes consist of
two sequential sets of events:

Answer 121

(1) recognition of the offending agents, which deliver signals that
(2) activate the leukocytes to ingest and destroy the offending agents and amplify the
inflammatory reaction

Question 122

Leukocytes express several receptors that recognize external stimuli and deliver activating
signals ( Fig. 2-8 ).

Answer 122

• Receptors for microbial products: Toll-like receptors (TLRs
• G protein–coupled receptors found on neutrophils, macrophages, and most other typesof leukocytes recognize short bacterial peptides containing N-formylmethionyl residues.
• Receptors for opsonins
• Receptors for cytokines

Question 123

Receptors for microbial products:

What are TLRs?

Answer 123

Toll-like receptors (TLRs) recognize components of

• *different types of microbes**. Thus far 10 mammalian TLRs have been identified, and each seems to be required for responses to different classes of infectious
  pathogens. [28]

Different TLRs play essential roles in cellular responses to bacterial lipopolysaccharide (LPS, or endotoxin), other bacterial proteoglycans and lipids, and
unmethylated CpG nucleotides, all of which are abundant in bacteria, as well as doublestranded
RNA, which is produced by some viruses.

TLRs are present on the cell surface
and in the endosomal vesicles of leukocytes (and many other cell types), so they are able to sense products of extracellular and ingested microbes.

These receptors function
through receptor-associated kinases to stimulate the production of microbicidal substances and cytokines by the leukocytes. Various other cytoplasmic proteins in leukocytes recognize bacterial peptides and viral RNA

Question 124

How do G protein–coupled receptors found on neutrophils, macrophages, and most other types of leukocytes recognize short bacterial peptides containing N-formylmethionyl residues

Answer 124

Because all bacterial proteins and few mammalian proteins (only those synthesized
within mitochondria) are initiated by N-formylmethionine, this receptorenables
neutrophils to detect and respond to bacterial proteins.

Other G protein–coupled
receptors recognize chemokines, breakdown products of complement such as C5a, and
lipid mediators, including platelet activating factor, prostaglandins, and leukotrienes, allof which are produced in response to microbes and cell injury.

Binding of ligands, such
as microbial products and mediators, to the G protein–coupled receptors induces
migration of the cells from the blood through the endothelium and production of
microbicidal substances by activation of the respiratory burst.

Question 125

What is an opsonization?

Answer 125

Leukocytes express receptors for proteins that coat microbes.
The process of coating a particle, such as a microbe, to target it for ingestion
(phagocytosis) is called opsonization, and substances that do this are opsonins.

Question 126

What are opsonins?

Answer 126

These
substances include antibodies, complement proteins, and lectins.

Question 127

One of the most
efficient ways of enhancing the phagocytosis of particles is________

Answer 127

coating the particles with IgG
antibodies specific for the particles, which are then recognized by the high-affinity Fcγ
receptor of phagocytes, called FcγRI ( Chapter 6 ).

Question 128

What is type 1 complement receptor?

Answer 128

Components of the complement
system, especially fragments of the complement protein C3, are also potent opsonins,
because these fragments bind to microbes and phagocytes express a receptor, called
the type 1 complement receptor (CR1), that recognizes breakdown products of C3
(discussed later).

Plasma lectins, mainly mannan-binding lectin, also bind to bacteria
and deliver them to leukocytes. The binding of opsonized particles to leukocyte Fc or C3
receptors promotes phagocytosis of the particles and activates the cells.

Question 129

Receptors for cytokines:

Leukocytes express receptors for cytokines that are produced
in response to microbes

. One of the most important of these cytokines is __________, which is secreted by natural killer cells reacting to microbes and by antigenactivated
T lymphocytes during adaptive immune responses ( Chapter 6 ).

Answer 129

interferon-γ (IFN-γ)

Question 130

What is the
major macrophage-activating cytokine.

Answer 130

IFN-γ is the
major macrophage-activating cytokine.

Question 131

Recognition of microbes or dead cells by the receptors described above induces several
responses in leukocytes that are referred to under the rubric of leukocyte activation (see Fig. 2-
8 ). Activation results from :

Answer 131

signaling pathways that are triggered in leukocytes, resulting in increases in cytosolic Ca 2+ and activation of enzymes such as protein kinase C and
phospholipase A2.

The functional responses that are most important for destruction of microbes
and other offenders are phagocytosis and intracellular killing. Several other responses aid in
the defensive functions of inflammation and may contribute to its injurious consequences.

Question 132

Phagocytosis involves three sequential steps ( Fig. 2-9 ):

Answer 132

• (1) recognition and attachment of the particle to be ingested by the leukocyte;
• (2) its engulfment, with subsequent formation of a phagocytic vacuole; and
• (3) killing or degradation of the ingested material. [30]