Chapter 2 – Acute and Chronic Inflammation Flashcards
1
Q
____________ is a complex reaction in tissues that consists mainly of responses of blood vessels and leukocytes. The body’s principal defenders against foreign invaders are plasma proteins and circulating leukocytes (white blood cells), as well as tissue phagocytes that are derived from circulating cells.
A
Inflammation
2
Q
is rapid in onset (typically minutes) and is of short duration, lasting for hours or a few days; its main characteristics are the exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, predominantly neutrophils (also called polymorphonuclear leukocytes).
A
Acute inflammation
3
Q
may follow acute inflammation or be insidious in onset. It is of longer duration and is associated with the presence of lymphocytes and macrophages, the proliferation of blood vessels, fibrosis, and tissue destruction
A
Chronic inflammation
4
Q
Repair begins during _______________ but reaches completion usually after the injurious influence has been neutralized
A
inflammation
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 (
5
Q
In recognition of the wide-ranging harmful consequences of inflammation, the lay press has rather melodramatically referred to it as?
A
“the silent killer.”
6
Q
the four cardinal signs of inflammation:
A
rubor (redness)
tumor (swelling)
calor (heat)
dolor (pain)
loss of function (functio laesa),
was added by Rudolf Virchow in the 19th century
7
Q
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
A
Russian biologist Elie Metchnikoff
8
Q
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.
A
John Hunter
9
Q
“The Doctor’s Dilemma,” in which one physician’s cure-all is to “stimulate the phagocytes
A
George Bernard Shaw
10
Q
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.
A
Sir Thomas Lewis
11
Q
is a rapid host response that serves to deliver leukocytes and plasma proteins, such as antibodies, to sites of infection or tissue injury.
A
Acute Inflammation
12
Q
Acute inflammation has three major components:
A
(1) alterations in vascular caliber that lead to an increase in blood flow
Vascular dilation and increased blood flow (causing (RUBOR) erythema and (CALOR) warmth);
(2) structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation
extravasation and extravascular deposition of plasma fluid and proteins (edema);
(3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent
leukocyte emigration and accumulation in the site of injury.
13
Q
STIMULI FOR ACUTE INFLAMMATION
(bacterial, viral, fungal, parasitic) and microbial toxins are among the most common and medically important causes of inflammation
A
Infections
most important receptors for microbial products are the family of Toll-like receptors (TLRs)
which can detect bacteria, viruses, and fungi Engagement of these receptors triggers signaling pathways that stimulate the production of various mediators.
14
Q
STIMULI FOR ACUTE INFLAMMATION
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
A
Tissue necrosis from any cause
Several molecules released from necrotic cells are known to elicit 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
15
Q
STIMULI FOR ACUTE INFLAMMATION
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
A
Hypoxia,
16
Q
STIMULI FOR ACUTE INFLAMMATION
(splinters, dirt, sutures) typically elicit inflammation because they cause traumatic tissue injury or carry microbes
A
Foreign bodies
17
Q
STIMULI FOR ACUTE INFLAMMATION
also called hypersensitivity reactions) are reactions in which the normally protective immune system damages the individual’s own tissues
A
Immune reactions
The injurious immune responses may be directed against self antigens, causing autoimmune diseases, or may be excessive reactions against environmental substances or microbes. Inflammation is a major cause of tissue injury in these diseases
The term immune-mediated inflammatory disease is often used to refer to this group of disorders
18
Q
The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities is known as
A
exudation
19
Q
is an extravascular fluid that has a high protein concentration, contains cellular debris, and has a high specific gravity. Its presence implies an increase in the normal permeability of small blood vessels in an area of injury and, therefore, an inflammatory reaction
A
exudate
An exudate is formed in inflammation, because vascular permeability increases as a result of increased interendothelial spaces.
20
Q
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
A
transudate
A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic pressure
21
Q
denotes an excess of fluid in the interstitial tissue or serous cavities; it can be either an exudate or a transudate
A
edema
22
Q
a purulent exudate, is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells and, in many cases, microbes
A
Pus
23
Q
Proliferation of blood vessels
is prominent during repair and in chronic inflammation
A
angiogenesis
24
Q
is one of the earliest manifestations of acute inflammation; sometimes it follows a transient constriction of arterioles, lasting a few seconds
A
Vasodilation
first involves the arterioles and then leads to opening of new capillary beds in the area. The result is increased blood flow , which is the cause of heat and redness (erythema) at the site of inflammation. Vasodilation is induced by the action of several mediators, notably histamine and nitric oxide (NO), on vascular smooth muscle.
25
Vasodilation is quickly followed by ____________ with the outpouring of protein-rich fluid into the extravascular tissues
increased permeability of the microvasculature
26
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
27
hallmark of acute inflammation is increase ___________ leading to the escape of a protein-rich exudate into the extravascular tissue, causing edema
Increased Vascular Permeability (Vascular Leakage)
28
is the most common mechanism of vascular leakage and is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other chemical mediators
Contraction of endothelial cells resulting in increased interendothelial spaces
Ω immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15–30 minutes
Ω exposure to certain bacterial toxins), vascular leakage begins after a delay of 2 to 12 hours, and lasts for several hours or even days; 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.
29
is the most common mechanism of vascular leakage and is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other chemical mediators
Contraction of endothelial cells resulting in increased interendothelial spaces
Ω immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15–30 minutes
Ω exposure to certain bacterial toxins), vascular leakage begins after a delay of 2 to 12 hours, and lasts for several hours or even days; 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.
30
Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or by the actions of microbes that target endothelial cells. [9] Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction.
Endothelial injury, resulting in endothelial cell necrosis and detachment
31
Increased transport of fluids and proteins, through the endothelial cell is called
transcytosis
32
involve channels consisting of interconnected, uncoated vesicles and vacuoles called the______________ many of which are located close to intercellular junctions
vesiculovacuolar organelle
33
normally drain the small amount of extravascular fluid that has seeped out of capillaries
lymphatics
34
Inflamed lymph nodes are often enlarged because of hyperplasia of the ________
lymphoid follicles
is termed reactive, or inflammatory, lymphadenitis
35
lymphatics may become secondarily inflamed
For clinicians the presence of red streaks near a skin wound is a telltale sign of an infection in the wound. This streaking follows the course of the lymphatic channels and is diagnostic of
lymphangitis
36
painful enlargement of the draining lymph nodes, indicating
lymphadenitis.
37
The most important leukocytes. the ones capable of phagocytosis
neutrophils and macrophages
These leukocytes ingest and kill bacteria and other microbes, and eliminate necrotic tissue and foreign substances. Leukocytes also produce growth factors that aid in repair
38
ecruitment of Leukocytes to Sites of Infection and Injury
| The journey of leukocytes from the vessel lumen to the interstitial tissue, called
extravasation
39
extravasation,
| can be divided into the following steps
1. In the lumen: margination, rolling, and adhesion to endothelium
2. Migration across the endothelium and vessel wall
3. Migration in the tissues toward a chemotactic stimulus
40
white cells assume a peripheral position along the endothelial surface. This process of leukocyte redistribution is called
margination
41
then rows of leukocytes adhere transiently to the endothelium, detach and bind again, thus
rolling on the vessel wall
42
cells finally come to rest at some point where they adhere firmly (resembling pebbles over which a stream runs without disturbing them).
adhesion
43
three types of selectins
1. one expressed on leukocytes (L-selectin),
2. on endothelium (E-selectin),
3. one in platelets and on endothelium (P-selectin).
expression of selectins and their ligands is regulated by cytokines produced in response to infection and injury
44
counter Part for adhesion molecule?
P-selectin
Sialyl-Lewis X–modified proteins
Major Role
Rolling (neutrophils, monocytes, T lymphocytes)
45
counter Part for adhesion molecule?
E-selectin
Sialyl-Lewis X–modified proteins
Major Role
Rolling and adhesion (neutrophils, monocytes, T lymphocytes)
46
counter Part for adhesion molecule?
GlyCam-1, CD34
L-selectin [*]
Major Role
Rolling (neutrophils, monocytes)
47
counter Part for adhesion molecule?
ICAM-1 (immunoglobulin family)
CD11/CD18 (β2) integrins (LFA-1, Mac-1)
Major Role
adhesion, arrest, transmigration (neutrophils, monocytes, lymphocytes)
48
counter Part for adhesion molecule?
VCAM-1 (immunoglobulin family
VLA-4 (β1) integrin
Major Role
Adhesion (eosinophils, monocytes, lymphocytes)
49
Firm adhesion is mediated by a family of heterodimeric leukocyte surface proteins called
integrins
TNF and IL-1 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).
50
the process of leukocyte recruitment is migration of the leukocytes through the endothelium
called transmigration or diapedesis
Transmigration of leukocytes occurs mainly in post-capillary venules
51
After traversing the endothelium, leukocytes pierce the basement membrane, probably by secreting
collagenases, and enter the extravascular tissue
52
the leukocytes are able to adhere to the extracellular matrix by virtue of
of integrins and CD44 binding to matrix proteins
Thus, leukocytes are retained at the site where they are needed .
53
After exiting the circulation, leukocytes emigrate in tissues toward the site of injury by a process called ____________
which is defined as locomotion oriented along a chemical gradient. Both exogenous and endogenous substances can act as chemoattractants
chemotaxis
most common exogenous agents are bacterial products, including peptides that possess an N- formylmethionine terminal amino acid, and some lipids
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 B4 (LTB4).
54
The leukocyte moves by extending ___________ 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
filopodia
55
In most forms of acute inflammation neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hours
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 attach more firmly to the adhesion molecules that are rapidly induced on endothelial cells, such as P- and E-selectins
56
Receptors for microbial products
Toll-like receptors (TLRs) recognize components of different types of microbes.
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
57
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
substances that do this are opsonins
include antibodies, complement proteins, and lectins
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
58
the major macrophage-activating cytokine.
interferon-γ (IFN-γ),
Leukocytes express receptors for cytokines that are produced in response to microbes
59
Phagocytosis involves three sequential steps
(1) recognition and attachment of the particle to be ingested by the leukocyte;
(2) its engulfment, with subsequent formation of a phagocytic vacuole;
(3) killing or degradation of the ingested material
60
recognizes microbes and not host cells
mannose receptor
The macrophage mannose receptor is a lectin that binds terminal mannose and fucose residues of glycoproteins and glycolipids. These sugars are typically part of molecules found on microbial cell walls
61
were originally defined as molecules that bind and mediate endocytosis of oxidized or acetylated low-density lipoprotein (LDL) particles that can no longer interact with the conventional LDL receptor
Scavenger receptors
Macrophage scavenger receptors bind a variety of microbes in addition to modified LDL particles. Macrophage integrins, notably Mac-1 (CD11b/CD18), may also bind microbes for phagocytosis
62
plasma membrane pinches off to form a vesicle that encloses the particle
phagosome
During this process the phagocyte may also release granule contents into the extracellular space
63
Microbial killing is accomplished largely by
reactive oxygen species
reactive nitrogen species, mainly derived from NO
generation of ROS is due to the rapid assembly and activation of a multicomponent oxidase (NADPH oxidase, also called phagocyte oxidase), which oxidizes NADPH (reduced nicotinamide-adenine dinucleotide phosphate) and, in the process, reduces
oxygen to superoxide anion
the ROS are produced within the lysosome
64
In neutrophils, this rapid oxidative reaction is triggered by activating signals and accompanies phagocytosis, and is called
respiratory burst.
65
converts H2O2 to hypochlorite
the azurophilic granules of neutrophils contain the enzyme myeloperoxidase (MPO), which, in the presence of a halide such as Cl - , converts H2O2 to hypochlorite (OCl•, the active ingredient in household bleach
66
the most efficient bactericidal system of neutrophils
The H2O2-MPO-halide system
67
cationic arginine-rich granule peptides that are toxic to microbes
defensins,
68
antimicrobial proteins found in neutrophils and other cells
cathelicidins
69
produce a number of growth factors that stimulate the proliferation of endothelial cells and fibroblasts and the synthesis of collagen, and enzymes that remodel connective tissues
macrophages,
70
are induced by microbial products and cytokines, particularly IFN-γ, and are microbicidal and involved in potentially harmful inflammation
Classically activated macrophages
71
are induced by other cytokines and in response to helminths (not shown), and are important in tissue repair and the resolution of inflammation (and may play a role in defense against helminthic parasites
Alternatively activated macrophages
72
Clinical Examples of Leukocyte-Induced Injury
ACUTE
Cells and Molecules Involved in Injury?
ACUTE RESPIRATORY DISTRESS SYNDROME
Neutrophils
73
Clinical Examples of Leukocyte-Induced Injury
ACUTE
Cells and Molecules Involved in Injury?
Acute transplant rejection
Lymphocytes; antibodies and complement
74
Clinical Examples of Leukocyte-Induced Injury
ACUTE
Cells and Molecules Involved in Injury?
Asthma
Eosinophils; IgE antibodies
75
Clinical Examples of Leukocyte-Induced Injury
ACUTE
Cells and Molecules Involved in Injury?
Glomerulonephritis
Neutrophils, monocytes; antibodies and complement
76
Clinical Examples of Leukocyte-Induced Injury
ACUTE
Cells and Molecules Involved in Injury?
Septic shock
Cytokines
77
Clinical Examples of Leukocyte-Induced Injury
ACUTE
Cells and Molecules Involved in Injury?
Lung abscess
Neutrophils (and bacteria)
78
Clinical Examples of Leukocyte-Induced Injury
CHRONIC
Cells and Molecules Involved in Injury?
Arthritis
Lymphocytes, macrophages; antibodies
79
Clinical Examples of Leukocyte-Induced Injury
CHRONIC
Cells and Molecules Involved in Injury
Asthma
Eosinophils; IgE antibodies
80
Clinical Examples of Leukocyte-Induced Injury
CHRONIC
Cells and Molecules Involved in Injury?
Atherosclerosis
Macrophages; lymphocytes?
81
Clinical Examples of Leukocyte-Induced Injury
CHRONIC
Cells and Molecules Involved in Injury?
Chronic transplant rejection
Lymphocytes; cytokines
82
Clinical Examples of Leukocyte-Induced Injury
CHRONIC
Cells and Molecules Involved in Injury?
Pulmonary fibrosis
Macrophages; fibroblasts
83
the inability of the leukocytes to surround and ingest these substances
triggers strong activation, and the release of large amounts of lysosomal enzymes into the extracellular environment
(frustrated phagocytosis)
84
genetic defects of integrins and selectin-ligands that cause leukocyte adhesion deficiencies types 1 and 2. The major clinical problem in both is recurrent bacterial infections.
Inherited defects in leukocyte adhesion
85
disorder is CHÉDIAK-HIGASHI SYNDROME, an autosomal recessive condition characterized by defective fusion of phagosomes and lysosomes in phagocytes (causing susceptibility to infections), and abnormalities in melanocytes (leading to albinism), cells of the nervous system (associated with nerve defects), and platelets (causing bleeding disorders).
Inherited defects in phagolysosome function
86
defects in bacterial killing and render patients susceptible to recurrent bacterial infection
results from inherited defects in the genes encoding
components of phagocyte oxidase, which generates O2-
Inherited defects in microbicidal activity
chronic granulomatous disease
87
the most frequent cause of leukocyte defects
Acquired deficiencies
bone marrow suppression, leading to decreased production of leukocytes. This is seen following therapies for cancer (radiation and chemotherapy) and when the marrow space is compromised by tumors, which may arise in the marrow (e.g., leukemias) or be metastatic from other sites.
88
Defects in Leukocyte Functions
GENETIC or ACQUIRED
Defective leukocyte adhesion because of mutations in β chain of CD11/CD18 integrins
GENETIC
Leukocyte adhesion deficiency 1
89
Defects in Leukocyte Functions
GENETIC or ACQUIRED
Defective leukocyte adhesion because of mutations in fucosyl transferase required for synthesis of sialylated oligosaccharide (ligand for selectins)
GENETIC
Leukocyte adhesion
deficiency 2
90
Defects in Leukocyte Functions
GENETIC or ACQUIRED
Decreased oxidative burst
GENETIC
Chronic granulomatous disease
91
Defects in Leukocyte Functions
GENETIC or ACQUIRED
Phagocyte oxidase (membrane component)
GENETIC
X-linked
92
Defects in Leukocyte Functions
GENETIC or ACQUIRED
Phagocyte oxidase (cytoplasmic components)
GENETIC
Autosomal recessive
93
Defects in Leukocyte Functions
GENETIC or ACQUIRED
Decreased microbial killing because of defective MPO—H2O2 system
GENETIC
| MPO deficiency
94
Defects in Leukocyte Functions
GENETIC or ACQUIRED
Decreased leukocyte functions because of mutations affecting protein involved in lysosomal membrane traffic
GENETIC
Chédiak-Higashi syndrome
95
Defects in Leukocyte Functions
GENETIC or ACQUIRED
Bone marrow suppression: tumors, radiation, and chemotherapy
ACQUIRED
PROBLEM in Production of leukocytes
96
Defects in Leukocyte Functions
GENETIC or ACQUIRED
Diabetes, malignancy, sepsis, chronic dialysis
ACQUIRED
| Problem in Adhesion and chemotaxis
97
Defects in Leukocyte Functions
GENETIC or ACQUIRED
Leukemia, anemia, sepsis, diabetes, malnutrition
ACQUIRED
Problem in Phagocytosis and microbicidal activity
98
cells resident in tissues also serve important functions in initiating acute inflammation. The two most important of these cell types are?
Ω mast cells
These cells release histamine, leukotrienes, enzymes, and many cytokines (including TNF, IL-1, and chemokines), all of which contribute to inflammation
Ω tissue macrophages.
These “sentinel” cells are stationed in tissues to rapidly recognize potentially injurious stimuli and initiate the host defense reaction
99
mediators are normally sequestered in
intracellular granules and can be rapidly secreted by granule exocytosis (e.g., histamine in mast cell granules) or are synthesized de novo (e.g., prostaglandins, cytokines) in response to a stimulus
100
The major cell types that produce mediators of acute inflammation are
platelets, neutrophils, monocytes/macrophages, and mast cells, but mesenchymal cells (endothelium, smooth muscle, fibroblasts) and most epithelia can also be induced to elaborate some of the mediators. Plasma-derived mediators (e.g., complement proteins, kinins) are produced mainly in the liver and present in the circulation as inactive precursors that must be activated, usually by a series of proteolytic cleavages, to acquire their biologic properties.
101
the cytokine TNF acts on endothelial cells to stimulate the production of another
cytokine, IL-1, and many chemokines. The secondary mediators may have the same actions as the initial mediators but may also have different and even opposing activities. Such cascades provide mechanisms for amplifying—or, in certain instances, counteracting—the initial action of a mediator.
102
These are the PRINCIPAL SOURCES what CELL-DERIVED?
Mast cells, basophils, platelets
Histamine
Vasodilation, increased vascular permeability, endothelial activation
103
These are the PRINCIPAL SOURCES what CELL-DERIVED?
Platelets
Serotonin
Vasodilation, increased vascular permeability
104
These are the PRINCIPAL SOURCES what CELL-DERIVED?
Mast cells,
leukocytes
Prostaglandins
Vasodilation, pain, fever
105
These are the PRINCIPAL SOURCES what CELL-DERIVED?
Mast cells, leukocytes
Leukotrienes
ncreased vascular permeability, chemotaxis, leukocyte adhesion and activation
106
These are the PRINCIPAL SOURCES what CELL-DERIVED?
Leukocytes
Reactive oxygen species
Killing of microbes, tissue damage
107
These are the PRINCIPAL SOURCES what CELL-DERIVED?
Endothelium, macrophages
Nitric oxide
Vascular smooth muscle relaxation, killing of microbes
108
These are the PRINCIPAL SOURCES what CELL-DERIVED?
Macrophages, endothelial cells, mast cells

Cytokines (TNF, IL-1)
Local endothelial activation (expression of adhesion molecules), fever/pain/anorexia/hypotension, decreased vascular resistance (shock)
109
These are the PRINCIPAL SOURCES what CELL-DERIVED?
Leukocytes, mast cells
Platelet- activating
Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst
110
These are the PRINCIPAL SOURCES what CELL-DERIVED?
Leukocytes, activated macrophages
Chemokines
Chemotaxis, leukocyte activation
111
PLASM A PROTEIN–DERIVED
Plasma (produced in liver)
Complement products (C5a, C3a, C4a)
Leukocyte chemotaxis and activation, vasodilation (mast cell stimulation)
112
PLASM A PROTEIN–DERIVED
Plasma (produced in liver)
Increased vascular permeability, smooth muscle contraction, vasodilation, pain
113
PLASM A PROTEIN–DERIVED
Plasma (produced in liver)
Proteases activated during coagulation
Endothelial activation, leukocyte recruitment
114
TNF
tumor necrosis factor
115
MAC
membrane attack complex;
116
IL-1
interleukin-1
117
The two major Vasoactive Amines
named because they have important actions on blood vessels,
Histamine and Serotonin
118
mast cell release degranulation in response to a variety of stimuli,
(1) physical injury such as trauma, cold, or heat;
(2) binding of antibodies to mast cells, which underlies allergic reactions
(3) fragments of complement called anaphylatoxins (C3a and C5a);
(4) histamine-releasing proteins derived from leukocytes;
(5) neuropeptides (e.g., substance P); and (6) cytokines (IL-1, IL-8).
119
causes dilation of arterioles and increases the permeability of venules. It is considered to be the principal mediator of the immediate transient phase of increased vascular permeability, producing interendothelial gaps in venules, as we have seen. Its vasoactive effects are mediated mainly via binding to H1 receptors on microvascular endothelial cells.
stored as preformed molecules in cells and are therefore among the first mediators to be released during inflammation
histamine
120
is a preformed vasoactive mediator with actions similar to those of histamine. It is present in platelets and certain neuroendocrine cells, e.g. in the gastrointestinal tract, and in mast cells in rodents but not humans
Serotonin (5-hydroxytryptamine)
121
Arachidonic Acid (AA) Metabolites
Prostaglandins, Leukotrienes, and Lipoxins
122
is a 20-carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid) that is derived from dietary sources or by conversion from the essential fatty acid linoleic acid. It does not occur free in the cell but is normally esterified in membrane phospholipids
Arachidonic Acid (AA)
123
Mechanical, chemical, and physical stimuli or other mediators (e.g., C5a) release AA from membrane phospholipids through the action of
phospholipase A2
activation of phospholipase A2 include an increase in cytoplasmic Ca 2+ and activation of various kinases in response to external stimuli
124
are synthesized by two major classes of enzymes: cyclooxygenases (which generate prostaglandins) and lipoxygenases (which produce leukotrienes and lipoxins)
eicosanoids
125
are produced by mast cells, macrophages, endothelial cells, and many other cell types, and are involved in the vascular and systemic reactions of inflammation. They are produced by the actions of two cyclooxgenases, the constitutively expressed COX-1 and the inducible enzyme COX-2.
Prostaglandins (PGs)
126
Prostaglandins (PGs) that are most important ones in inflammation are?
PGE2,
the major prostaglandin made by mast cells
PGD2,
the major prostaglandin made by mast cellsPGF2α,
PGD2 is a chemoattractant for neutrophils
PGI2 (PROSTACYCLIN)
Vascular endothelium lacks thromboxane synthetase but possesses prostacyclin synthetase
TXA2 (THROMBOXANE),
platelets contain the enzyme thromboxane synthetase, and hence txa2 is the major product
127
enzymes are responsible for the production of leukotrienes, which are secreted mainly by leukocytes, are chemoattractants for leukocytes, and also have vascular effects
lipoxygenase
128
three different lipoxygenases
5-LIPOXYGENASE BEING the predominant one in neutrophils. This enzyme converts AA to 5-hydroxyeicosatetraenoic acid, which is chemotactic for neutrophils
129
LTB4 is a potent chemotactic agent and activator of neutrophils, causing aggregation and adhesion of the cells to venular endothelium, generation of ROS, and release of lysosomal enzymes
go
130
cysteinylcontaining leukotrienes
C4, D4, and E4 (LTC4, LTD4, LTE4)
cause intense vasoconstriction, bronchospasm (important in asthma), and increased vascular permeability. The vascular leakage, as with histamine, is restricted to venules
131
are much more potent than is histamine in increasing vascular permeability and causing bronchospasm
Leukotrienes
132
are inhibitors of inflammation from AA
lipoxins
The principal actions of lipoxins are to inhibit leukocyte recruitment and the cellular components of inflammation
inhibit neutrophil chemotaxis and adhesion to endothelium
133
Action
| ; PGI2 (prostacyclin), PGE1, PGE2, PGD2
Vasodilation
134
Action
| ; Thromboxane A2, leukotrienes C4, D4, E4
Vasoconstriction
135
Action Leukotrienes C4, D4, E4
Increased vascular permeability
136
Action
| ;Leukotriene B4, HETE
Chemotaxis, leukocyte adhesion
137
HETE
hydroxyeicosatetraenoic acid
138
include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin. They inhibit both COX-1 and COX-2 and thus inhibit prostaglandin synthesis
• Cyclooxygenase inhibitors
aspirin does this by irreversibly acetylating and inactivating cyclooxygenases
139
should be anti-inflammatory without having the toxicities of the nonselective inhibitors, such as gastric ulceration
COX-2 inhibitors
may increase the risk of cardiovascular and cerebrovascular events
impair endothelial cell production of prostacyclin, a vasodilator and inhibitor of platelet aggregation
140
Lipoxygenase inhibitors
5-lipoxygenase is not affected by NSAIDs, and many new inhibitors of this enzyme pathway have been developed. Pharmacologic agents that inhibit leukotriene production (e.g. Zileuton) or block leukotriene receptors (e.g. Montelukast) are useful in the treatment of asthma.
Lipoxygenase inhibitors
141
powerful anti-inflammatory agents may act by reducing the transcription of genes encoding COX-2, phospholipase A2, pro-inflammatory cytokines (such as IL-1 and TNF), and iNOS
• Broad-spectrum inhibitors include corticosteroids
142
serve as poor substrates for conversion to active metabolites by both the cyclooxygenase and lipoxygenase pathways but are excellent substrates for the production of anti-inflammatory lipid products called RESOLVINS AND PROTECTINS
consumption of fish oil
143
another phospholipid-derived mediator
causes vasoconstriction and bronchoconstriction, and at extremely low concentrations it induces vasodilation and increased venular permeability with a potency 100 to 10,000 times greater than that of histamine
also causes increased leukocyte adhesion to endothelium (by enhancing integrin-mediated leukocyte binding), chemotaxis, degranulation, and the oxidative burst
boosts the synthesis of other mediators, particularly eicosanoids, by leukocytes and other cells
Platelet-Activating Factor (PAF)
144
Inactivation of antiproteases
with increased destruction of extracellular matrix. In the lung, such inhibition of anti-proteases contributes to destruction of elastic tissues, as in emphysema
α1-antitrypsin
145
antioxidants
enzyme superoxide dismutase
catalase, which detoxifies H2O2
glutathione peroxidase, another powerful H2O2 detoxifier
copper-containing serum protein
ceruloplasmin
the iron-free fraction of serum transferrin
146
a soluble gas that is produced not only by endothelial cells but also by macrophages and some neurons in the brain. It acts in a paracrine manner on target cells through induction of CYCLIC GUANOSINE
leading to a response, such as the relaxation of vascular smooth muscle cells
Nitric Oxide (NO)
147
NO is synthesized from
L-arginine by the enzyme nitric oxide synthase (NOS
148
three different types of NOS
endothelial (eNOS),
neuronal (nNOS), and
inducible (iNOS)
induced when macrophages and other cells are activated by cytokines (e.g., TNF, IFN-γ) or microbial products.
149
reduces platelet aggregation and adhesion inhibits several features of mast cell–induced inflammation, and inhibits leukocyte recruitment.
NO
production of NO is thought to be an endogenous mechanism for controlling inflammatory responses
150
are proteins produced by many cell types (principally activated lymphocytes and macrophages, but also endothelial, epithelial, and connective tissue cells) that modulate the functions of other cell types
Cytokines
151
TNF
INACUTEINFLAMMATION
Macrophages, mast cells, T lymphocytes
Stimulates expression of endothelial adhesion molecules and secretion of other cytokines; systemic effects
152
IL-1
INACUTEINFLAMMATION
Macrophages, endothelial cells, some epithelial cells
Similar to TNF; greater role in fever
153
IL-6
INACUTEINFLAMMATION
ages, other cells
Systemic effects (acute-phase response)
154
Chemokines
INACUTEINFLAMMATION
Macrophages, endothelial cells, T lymphocytes, mast cells, other cell types
Recruitment of leukocytes to sites of inflammation; migration of cells to normal tissues
155
IL-12
CHRONIC INFLAMMATION
Dendritic cells, macrophages
Increased production of IFN-γ
156
IFN-γ
CHRONIC INFLAMMATION
T lymphocytes, NK cells
Activation of macrophages (increased ability to kill microbes and tumor cells)
157
IL-17
CHRONIC INFLAMMATION
T lymphocytes
Recruitment of neutrophils and monocytes
158
are two of the major cytokines that mediate inflammation. They are produced mainly by activated macrophages.
can be stimulated by endotoxin and other microbial products, immune complexes, physical injury, and a variety of inflammatory stimuli
TNF and IL-1 are
most important actions in inflammation are their effects on endothelium, leukocytes, and fibroblasts, and induction of systemic acute-phase reactions ( Fig. 2-13 ). In endothelium they induce a spectrum of changes referred to as ENDOTHELIAL
ACTIVATION.
expression of endothelial adhesion molecules; synthesis of chemical mediators, including other cytokines, chemokines, growth factors, eicosanoids, and NO; production of enzymes associated with matrix remodeling
159
The production of IL-1 is controlled by a multi-protein cellular complex, sometimes called the
“inflammasome
responds to stimuli from microbes and dead cells
160
inherited autoinflammatory syndromes, the best known of which is familial Mediterranean fever
mutant proteins either constitutively activate the inflammatory caspases or interfere with the negative regulation of this enzymatic process. The net result is unregulated IL-1 production
161
IL-1 and TNF (as well as IL-6) induce the systemic acute-phase responses associated with infection or injury
TNF also regulates energy balance by promoting lipid and protein mobilization and by suppressing appetite. Therefore, sustained production of TNF contributes to CACHEXIA, a pathologic state characterized by weight loss and anorexia that accompanies some chronic infections and neoplastic diseases
162
primarily as chemoattractants for specific types of leukocytes
Chemokines
two main functions: they stimulate leukocyte recruitment in inflammation and control the normal migration of cells through various tissues
163
chemokines have are classified into four major groups, according to the arrangement of the conserved cysteine (C) residues in the mature proteins
C-X-C chemokines (also called α chemokines) chemokines act primarily on neutrophils
164
which include monocyte chemoattractant protein (MCP-1), eotaxin, macrophage inflammatory protein-1α (MIP-1α), and RANTES (regulated and normal T-cell expressed and secreted), generally attract monocytes, eosinophils, basophils, and lymphocytes but not neutrophils
C-C chemokines (also called β chemokines) have
165
The C chemokines (e.g., lymphotactin) are relatively specific for lymphocytes.
C chemokines (also called γ chemokines)
166
xists in two forms: the cell surface-bound protein can be induced on endothelial cells by inflammatory cytokines and promotes strong adhesion of monocytes and T cells, and a soluble form, derived by proteolysis of the membrane-bound protein, has potent chemoattractant activity for the same cells.
CX3C chemokines
fractalkine
167
Neutrophils have two main types of granules
The smaller specific (or secondary) granules contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase.
The larger azurophil (or primary) granules contain myeloperoxidase, bactericidal factors (lysozyme, defensins), acid hydrolases, and a variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases, proteinase
3). [40] Both types of granules can fuse with phagocytic vacuoles containing engulfed material, or the granule contents can be released into the extracellular space.
168
Acid proteases
degrade bacteria and debris within the phagolysosomes, in which an acid pH is readily reached
169
Neutral proteases
are capable of degrading various extracellular components, such as collagen, basement membrane, fibrin, elastin, and cartilage, resulting in the tissue destruction that accompanies inflammatory processes.
170
Monocytes and macrophages
contain acid hydrolases, collagenase, elastase, phospholipase, and plasminogen activator. These may be particularly active in chronic inflammatory reactions.
171
α1-antitrypsin,
major inhibitor of neutrophil elastase. A deficiency of these inhibitors may lead to sustained action of leukocyte proteases, as is the case in patients with α1-antitrypsin deficiency
172
substance P and neurokinin A
belong to a family of tachykinin neuropeptides produced in the central and peripheral nervous systems. [69] Nerve fibers containing substance P are prominent in the lung and gastrointestinal tract. Substance P has many biologic functions, including the transmission of pain signals, regulation of blood pressure, stimulation of secretion by endocrine cells, and increasing vascular permeability
173
consists of more than 20 proteins
cause increased vascular permeability, chemotaxis, and opsonization
complement system
174
critical step in complement activation is the proteolysis of the third (and most abundant) component
Cleavage of C3
175
Cleavage of C3 can occur by one of three pathways:
the classical pathway , which is triggered by fixation of C1 to antibody (IgM or IgG) that has combined with antigen
the alternative pathway, which can be triggered by microbial surface molecules (e.g., endotoxin, or LPS), complex polysaccharides, cobra venom, and other substances, in the absence of antibody
lectin pathway, in which plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1.
THEY ALL LEAD TO THE FORMATION OF AN ACTIVE ENZYME CALLED THE C3 CONVERTASE, WHICH SPLITS C3 INTO TWO FUNCTIONALLY DISTINCT FRAGMENTS, C3A AND C3B.
C3a is released
C3b becomes covalently attached to the cell or molecule where complement is being activated
C3b then binds to the previously generated fragments to form C5 convertase
which cleaves C5 to release C5a and leave C5b attached to the cell surface
C5b binds the late components (C6–C9), culminating in the formation of the membrane attack complex (MAC, composed of multiple C9 molecules
176
complement system fall into three general categories
Inflammation
ANAPHYLATOXINS
C3a, C5a, and, to a lesser extent, C4a are cleavage products of the corresponding complement components that stimulate histamine release from mast cells and thereby increase vascular permeability and cause vasodilation
Phagocytosis
C3b and its cleavage product iC3b (inactive C3b), when fixed to a microbial cell wall, act as OPSONINS and promote phagocytosis by neutrophils and macrophages, which bear cell surface receptors for the complement fragments
Cell lysis
The deposition of the MAC on cells makes these cells permeable to water and ions and results in death (lysis) of the cells.
177
The intrinsic clotting pathway is a series of plasma proteins that can be activated by
Hageman factor (factor XII
XII), a protein synthesized by the liver that circulates in an inactive form. Factor XII is activated upon contact with negatively charged surfaces, for instance when vascular permeability increases and plasma proteins leak into the extravascular space and come into contact with collagen, or when it comes into contact with basement membranes exposed as a result of endothelial damage.
178
thrombin, a product of clotting, promotes inflammation by engaging receptors that are called protease-activated receptors (PARs) because they bind multiple trypsin-like serine proteases in addition to thrombin
coagulation and inflammation can initiate a vicious cycle of amplification
interfering with clotting is a potential therapeutic strategy for the systemic inflammatory disease seen with severe, disseminated bacterial infections. This is the rationale for treating this disorder with the anticoagulant, activated protein C, which may benefit a subset of the patients
179
are vasoactive peptides derived from plasma proteins, called kininogens, by the action of specific proteases called kallikreins
Kinins
Kallikrein itself is a potent activator of Hageman factor, allowing for autocatalytic amplification of the initial stimulus
180
increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain when injected into the skin
bradykinin
181
XIIa is inducing fibrin clot formation, it activates the fibrinolytic system.
go
182
plasminogen,
plasma protein that binds to the evolving fibrin clot to generate plasmin, a multifunctional protease
primary function of plasmin is to lyse fibrin clots, during inflammation it also cleaves the complement protein C3 to produce C3 fragments, and it degrades fibrin to form fibrin split products,
183
Activated Hageman factor (factor XIIa
initiates four systems involved in the inflammatory response:
(1) the kinin system, which produces vasoactive kinins;
(2) the clotting system, which induces formation of thrombin, which has inflammatory properties;
(3) the fibrinolytic system, which produces plasmin and degrades fibrin to produce fibrinopeptides, which induce inflammation; and
(4) the complement system, which produces anaphylatoxins and other mediators.
Some of the products of this initiation —particularly kallikrein—can, by feedback, activate Hageman factor, resulting in amplification of the reaction.
184
C3a and C5a can be generated by several types of reactions
(1) immunologic reactions, involving antibodies and complement (the classical pathway);
(2) activation of the alternative and lectin complement pathways by microbes, in the absence of antibodies; and
(3) agents not directly related to immune responses, such as plasmin, kallikrein, and some serine proteases found in normal tissue.
185
Prostaglandins
Nitric oxide
Histamine
causes
Vasodilation
186
```
Histamine and serotonin
C3a and C5a (by liberating vasoactive amines from mast cells, other cells)
Bradykinin
Leukotrienes C4, D4, E4
PAF
Substance P
```
causes
Increased vascular permeability
187
```
TNF, IL-1
Chemokines
C3a, C5a
Leukotriene B4
(Bacterial products, e.g., N-formyl methyl peptides)
```
causes
Chemotaxis, leukocyte recruitment and activation
188
IL-1, TNF
Prostaglandins
causes
Fever
189
Prostaglandins
Bradykinin
causes
Pain
190
Lysosomal enzymes of leukocytes
Reactive oxygen species
Nitric oxide
causes
Tissue damage
191
Outcomes of Acute Inflammation
may have one of three outcome
Complete resolution.
resolution and is the usual outcome when the injury is limited or short-lived or when there has been little tissue destruction and the damaged parenchymal cells can regenerate
Healing by connective tissue replacement (fibrosis
incapable of regeneration, or when there is abundant fibrin exudation in tissue or serous cavities (pleura, peritoneum) that cannot be adequately cleared
ORGANIZATION
connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous tissue—a process also called
Progression of the response to chronic inflammation
Acute to chronic transition occurs when the acute inflammatory response cannot be resolved, as a result of either the persistence of the injurious agent or some interference with the normal process of healing
