Acute inflammation Flashcards
(133 cards)
1
Q
What is inflammation?
A
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.
2
Q
Inflammation is a complex reaction in tissues that consists mainly of responses of _____________
A
blood vessels
and leukocytes.
3
Q
The body’s principal defenders against foreign invaders are ________________
A
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
4
Q
What triggers the vascular and cellular reactions of inflammation?
A
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.
5
Q
Inflammation may be acute or chronic , depending on the:
A
nature of the stimulus and the
effectiveness of the initial reaction in eliminating the stimulus or the damaged tissues.
6
Q
Describe acute inflammation.
A
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.
7
Q
What are the main characterisitcs of acute inflammation?
A
its main characteristics are the:
- exudation of fluid and plasma proteins (edema)
- and the emigration of leukocytes,
- predominantly neutrophils (also called polymorphonuclear leukocytes).
8
Q
Describe chronic inflammation.
A
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.
9
Q
When does inflammation terminated?
A
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.
10
Q
The inflammatory response is closely intertwined with the process of repair .
T or F
A
True
11
Q
When does repair begins?
A
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
12
Q
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.
A
13
Q
T or F
Inflammation may contribute to a variety of diseases that are not thought to be primarily due to
abnormal host responses.
A
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.”
14
Q
four cardinal signs of
inflammation:
A
- rubor (redness)
- , tumor (swelling)
- , calor (heat),
- and dolor (pain).
15
Q
What is Rubor?
A
R for R
Redness
16
Q
What is Tumor?
A
Obviously its SWELLING
17
Q
What is calor ?
A
(heat)
C-heat
18
Q
What is dolor?
A
pain
Dolores is PAIN. So never name someone DOLORes
19
Q
The four cardinal signs
are typically more prominent in___________
A
acute inflammation than in chronic inflammation.
20
Q
A fifth clinical
sign, _____________- was added by Rudolf Virchow in the 19th century.
A
loss of function (functio laesa),
21
Q
inflammation is not a disease but a nonspecific response that has a salutary effect on its
host.
T or F
A
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.
22
Q
Who discovered phagocytosis?
A
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
23
Q
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:
A
- (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.
24
Q
STIMULI FOR ACUTE INFLAMMATION
Acute inflammatory reactions may be triggered by a variety of stimuli:
A
- Infections (bacterial, viral, fungal, parasitic)
- Tissue necrosis
- Foreign bodies
- Immune reactions
25
How do infections cause inflammation?
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.
26
What is a TLR?
Among the **most important receptors
for microbial products**are 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.
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).
Several **molecules released
from necrotic cells**are**known to elicit inflammation**
28
What are the mediators released from necrosis that promote inflammation?
* 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
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.
30
Why do blood vessels undergo series of changes during inflammation?
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.
31
what is an exudation?
The escape of fluid, proteins, and blood cells from the vascular system into
the interstitial tissue or body cavities is known as exudation.
32
What is a transudate?
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 ).
33
What is an edema?
Edema denotes an excess of fluid in the interstitial tissue or serous cavities; **it can be either an**
**exudate or a transudate.**
34
What is a purulent exudate?
Pus, a purulent exudate, is an **inflammatory exudate rich in leukocytes**
(mostly neutrophils), the debris of dead cells and, in many cases, microbes
35
How is a transudate formed?
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
36
What is the normal hydrostatic pressure at arterial end?
A, Normal hydrostatic pressure (blue
arrows) is about **32 mm Hg** at the **arterial end of a capillary bed**
37
What is the normal hydrostatic pressure at the venous end?
**12 mm Hg** at the venous
end;
38
What is the mean colloid osmotic pressure of tissues?
the mean colloid osmotic pressure of tissues is **approximately 25 mm Hg** (green arrows),
which is e**qual to the mean capillary pressure.**
Therefore, the net flow of fluid across the
vascular bed is almost **nil.**
39
The vascular reactions of acute inflammation consist of \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
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 .
40
Changes in Vascular Flow and Caliber
Changes in vascular flow and caliber begin **early after injury** and consist of the following.
* **Vasodilation**
* **increased permeability of the microvasculature**
* **vascular congestion**
* **stasis develops**, **blood leukocytes, principally neutrophils,** accumulate along the
vascular endothelium.
41
What is the earliest manifestations of acute inflammation?
Vasodilation is one of the earliest manifestations of acute inflammation.
42
Is it true that in inflammtion after vasodilation sometimes it
follows a t**ransient constriction of arterioles, lasting a few seconds**.
T or F
T
43
Vasodilation first
involves the : \_\_\_\_\_\_\_\_\_\_
**arterioles and then leads to opening of new capillary beds in the area**.
44
Vasodilation results in:
The
result is **increased blood flow**.
45
which is the cause of heat and redness (erythema) at the
site of inflammation.
Vasodilation
46
Vasodilation is induced by the action of several mediators, notably
\_\_\_\_\_\_\_\_ on vascular smooth muscle
histamine and nitric oxide (NO),
47
What quickly follows vasodilation?
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.
48
What quickly foillows after vasodilatation?
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.**
49
The loss of fluid and increased vessel diameter lead to :
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
50
What is stasis ?
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
51
What happens after stasis develops?
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 endotheliu**m, and soon afterward they migrate through the vascular wall into the interstitial tissue, in a sequence that is
described later
52
A hallmark of acute inflammation is \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
**increased vascular permeability** leading to the escape of a protein-rich exudate into the extravascular tissue, causing edema
53
Several mechanisms are
responsible for the increased vascular permeability
* Contraction of endothelial cells
* Endothelial injury
* Increased transport of fluids and proteins
54
What is the most common mechanism of vascular leakage?
* *Contraction of endothelial cells resulting in increased interendothelial spaces** is the
* *most common mechanism of vascular leakage.**
55
What is happens when there is contraction of endothelial cells?
Contraction of endothelial cells **resulting in increased interendothelial spaces is the
most common mechanism of vascular leakage**.
56
The contraction of endothelial cells resulting in increased interendothelial space is elicited by:
* histamine
* bradykinin,
* leukotrienes,
* the neuropeptide substance P,
* and many other chemical mediators. [6,] [7]
57
What is the immediate transient response?
Contraction of endothelial cells resulting in increased interendothelial spaces is the
most common mechanism of vascular leakage.
58
Why is contraction of the endothelial cells resulting in increased interendothelial space is called the immediate transient response?
## Footnote
because it **occurs rapidly after exposure to
the mediator and is usually short-lived (15–30 minutes).**
59
Give an example when vascular leakage begins after a delay of 2 to 12 hours.
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;
60
What is the reason for some cases that there is a delay in vascular leakage?
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
61
What is the result when there is endothelial injury?
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.
62
[9] Neutrophils that adhere to the
endothelium during inflammation **may also injure the endothelial cells and thus amplify
the reaction.**
**T or F**
T
In most instances leakage starts immediately after injury and is sustained
for several hours until the damaged vessels are thrombosed or repaired.
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
T
64
What is transcystosis?
**Increased transport of fluids and proteins,** called transcytosis, through the endothelial
cell.
65
Increased Vascular Permeability (Vascular Leakage)
66
What is involved in the process of transcytosis?
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.
67
Acute Inflammation events
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. I**ncreased transcytosis**: induced by **VEGF: in venules**
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
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?
In inflammation, l**ymph 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
70
What is lymphangitis?
The **lymphatics may become secondarily inflamed
(lymphangitis).**
71
What is lymphadenitis?
secondarily inflamed as may the draining lymph nodes (lymphadenitis).
72
What is reactive or inflammatory lymhphadenitis?
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 .
73
a critical function of inflammation is:
to deliver leukocytes to the site of
injury and to activate the leukocytes to eliminate the offending agents.
74
The most important
leukocytes in typical inflammatory reactions are the ones capable of \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_-
phagocytosis, namely
neutrophils and macrophages.
75
Leukocytes also produce growth factors
that aid in repair.
T or F
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
76
The processes involving leukocytes in inflammation consist of:
* their recruitment from the blood into extravascular tissues,
* recognition of microbes and necrotic tissues,
* and removal of the offending agent
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:
* 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
78
What is extravasation?
The journey of leukocytes from the vessel lumen to the interstitial tissue, called extravasation
79
What happens to the leukocytes in the lumen?
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.
80
Discuss the multistep process of leukocyte migration to blood vessels.
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.
81
What are the different molecules that play a role in the multistep process of leukocyte migration through blood vessels?
Different molecules play predominant roles in different steps of this process—
* **selectins in rolling**;
* chemokines (usually displayed bound to proteoglycans) in **activating the neutrophil**s 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.
82
Discuss margination of leukocytes. How does this happen?
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 shea**r **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
83
The adhesion of leukocytes to endothelial cells is mediated by **complementary adhesion**
molecules on the **two cell types whose expressio**n 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
\_\_\_\_\_\_\_\_\_\_
selectins
84
There are three types of selectins:
* one expressed on leukocytes (L-selectin),
* one on endothelium (E-selectin),
* and one in platelets and on endothelium (P-selectin).
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.
sialylated oligosaccharides
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).
tumor necrosis factor (TNF), [17] interleukin-1 (IL-1),
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, s**timulate the redistribution of P-selectin f**rom 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 microvill**i 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**
88
What is Weibel- Palade bodies?
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.
89
Endothelial-Leukocyte Adhesion Molecules
Endothelial
Molecule
* P-selectin
* E-selectin
* GlyCam-1, CD34
* ICAM-1
(immunoglobulin
family)
* VCAM-1
(immunoglobulin
family)
90
TABLE 2-1 -- Endothelial-Leukocyte Adhesion Molecules
P-selectin : Leukocyte Molecule : Major Role
Sialyl-Lewis X–modified proteins :Rolling (neutrophils, monocytes, T lymphocytes)
91
TABLE 2-1 -- Endothelial-Leukocyte Adhesion Molecules
Endothelial Molecule : E-selectin
Leukocyte Molecule
Major Role
Endothelial Molecule : **E-selectin**
Leukocyte Molecule :**Sialyl-Lewis X–modified**
proteins
Major Role: **Rolling and adhesion** (neutrophils, monocytes, T lymphocytes)
92
TABLE 2-1 -- Endothelial-Leukocyte Adhesion Molecules
Endothelial Molecule : GlyCam-1, CD34
Leukocyte Molecule
Major Role
Endothelial Molecule : GlyCam-1, CD34
Leukocyte Molecule L-selectin [\*]
Major Role: Rolling (neutrophils, monocytes)
93
TABLE 2-1 -- Endothelial-Leukocyte Adhesion Molecules
Endothelial Molecule : ICAM-1 (immunoglobulin family)
Leukocyte Molecule
Major Ro le
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)
94
TABLE 2-1 -- Endothelial-Leukocyte Adhesion Molecules
Endothelial Molecule :VCAM-1 (immunoglobulin family)
Leukocyte Molecule
Major Ro le
Endothelial Molecule :VCAM-1 (immunoglobulin family)
Leukocyte Molecule : VLA-4 (β1) integrin
Major Ro le : Adhesion (eosinophils, monocytes,
lymphocytes)
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.
96
These weak rolling interactions slow down the leukocytes and give them the **opportunity to bind
more firmly to the endothelium.**
97
What are integrins?
**Firm adhesio**n is mediated by a family of heterodimeric
leukocyte surface proteins called integrins
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)**
TNF and IL-1
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.
100
What is the next step in the process of leukocyte recruitment?
The next step in the process of leukocyte recruitment is **migration of the leukocytes through the
endothelium, called transmigration or diapedesis**
101
What is diapedesis?
* *migration of the leukocytes** through the
* *endothelium**, called transmigration or diapedesis
102
Transmigration of leukocytes occurs mainly in
\_\_\_\_\_\_\_\_\_-
post-capillary venules.
103
What do chemokines do to leukocytes?
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
104
adhesion molecules include a member of the immunoglobulin
superfamily called \_\_\_\_\_\_\_\_\_\_\_\_
PECAM-1 (platelet endothelial cell adhesion molecule) or CD31 [24] and
several junctional adhesion molecules.
105
After traversing the endothelium, leukocytes pierce
the basement membrane, probably by \_\_\_\_\_\_\_\_\_\_\_
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 .
106
The most telling proof of the importance of leukocyte adhesion molecules is the existence of
genetic deficiencies in these molecules, which result in recurrent bacterial infections as a
consequence of impaired leukocyte adhesion and defective inflammation.
107
What is the deficiency in individuals with leukocyte adhesion deficiency type 1?
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.**
108
What is the deficiency in individuals with leukocyte adhesion deficiency type 2?
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.
109
What is chemotaxis?
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
110
Both
exogenous and endogenous substances can act as chemoattractants.
T or F
T
111
The most common
exogenous agents are \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_-
**bacterial produc**ts, including peptides that possess an **Nformylmethionine**
terminal amino acid, and some lipids.
112
Endogenous chemoattractants include
several chemical mediators (described later):
* (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).
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 calcium**and**activate small guanosine triphosphatases of the
Rac/Rho/cdc42** family as well as numerous kinases.
These signals i**nduce polymerization of
actin,**resulting in**increased 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.
114
The nature of the leukocyte infiltrate varies with the \_\_\_\_\_\_\_\_\_\_\_
* *age of the inflammatory response** and the
* *type of stimulus.**
115
In most forms of acute inflammation \_\_\_\_\_\_\_\_\_predominate in the
inflammatory infiltrate during the first 6 to 24 hours
neutrophils
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
monocytes
117
Several reasons account for the early appearance of neutrophils:
* 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.
118
Whta happens to neutrophils after entering tissues,
neutrophils are short-lived; they undergo apoptosis and disappear after 24 to 48 hours.
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.
Pseudomonas bacteria
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**
i**ntegrins (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.
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:
```
(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
122
Leukocytes express several receptors that recognize external stimuli and deliver activating
signals ( Fig. 2-8 ).
* 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
123
Receptors for microbial products:
What are TLRs?
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 e**ndosomal vesicles of leukocyt**es (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
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**
Because **all bacterial proteins and few mammalian proteins (only those synthesized
within mitochondria) are initiated by N-formylmethionine**, this receptor**enables
neutrophils to detect and respond to bacterial protein**s.
Other G protein–coupled
receptors recognize chemokines, breakdown products of **complement such as C5a, and
lipid mediators, including platelet activating factor, prostaglandins, and leukotrienes, all**of 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.
125
What is an opsonization?
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.
126
What are opsonins?
These
substances include **antibodies, complement proteins, and lectins.**
127
One of the most
efficient ways of enhancing the phagocytosis of particles is\_\_\_\_\_\_\_\_
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 ).
128
What is type 1 complement receptor?
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.
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 ).
interferon-γ (IFN-γ)
130
What is the
major macrophage-activating cytokine.
IFN-γ is the
major macrophage-activating cytokine.
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 :
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.
132
Phagocytosis involves three sequential steps ( Fig. 2-9 ):
* (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]
133
