Inflammation Flashcards
1
Q
Define inflammation
A
Inflammation is a response of vascularized tissues to infections and damaged tissues that bring cells and molecules of host defense from the circulation to the sites where they are needed, in order to eliminate the offending agents.
2
Q
What does the process of inflammation do to the damaged tissue
A
•The process of inflammation delivers phagocytic leukocytes and proteins (antibodies and complement proteins) to damaged or necrotic tissues and foreign invaders, such as microbes,
•Then activates recruited cells and molecules, which then function to get rid of the harmful or unwanted substances.
3
Q
What happens in the absence of inflammation
A
infections would go unchecked, wounds would never heal, and injured tissues might remain permanent festering sores.
4
Q
What else provides first response to infection apart from leukocytes
A
• The components of innate immunity which include natural killer cells, dendritic cells, and epithelial cells, as well as soluble factors such as the proteins of the complement system
5
Q
What are the steps of the typical inflammatory reaction
A
• The offending agent, which is located in extravascular tissues, is recognized by host cells and molecules.
• Leukocytes and plasma proteins are recruited from the
circulation to the site where the offending agent is located.
• The leukocytes and proteins are activated; together they destroy and eliminate the offending substance.
• The reaction is controlled and terminated. • The damaged tissue is repaired.
6
Q
What’s the sequence of events for inflammation of an epithelium cut buy a pin with pathogen on it
A
•Chemical signals released by the activated macrophage and mast cells at the injury site cause nearby capillaries to expand and become more permeable
•Fluid, clotting elements and anti microbial agents move from the blood to the site and clotting begins
•chemokines released by various kinds of cells attract more phagocytes from blood to injury site
•Neutrophils and macrophages phagocytose pathogens and cell debris at the site, and the tissue heals
7
Q
What types of cells are most abundant in acute and chronic nflammatory site
A
Neutrophils - acute inflammation
Lymphocytes and macrophages- chronic inflammation
8
Q
What type of cell causes Acute respiratory distress syndrome -
A
Neutrophils
9
Q
What Acute Diseases are Caused by Inflammatory Reactions
A
•Acute respiratory distress syndrome -
•Asthma
•Glomerulonephritis
•Septic shock
10
Q
What chronic Diseases are Caused by Inflammatory Reactions
A
•Arthritis
•Asthma
•Atherosclerosis
•Pulmonary fibrosis
11
Q
What cell or molecule is involved in acute respiratory distress syndrome
A
Neutrophils
12
Q
What kind of cell causes asthma
A
Eosinophils;
IgE antibodies
13
Q
What kind of cell causes glomerulonephritis
A
Antibodies and complement; neutrophils, monocytes
14
Q
What kind of cells cause septic shock
A
Cytokines
15
Q
What kind of cells cause arthritis
A
Lymphocytes,
macrophages;
antibodies
16
Q
What kind of cells cause atherosclerotis
A
Macrophages;
lymphocytes
17
Q
What kind of cells cause pulmonary fibrosis
A
Macrophages;
fibroblasts
18
Q
What is acute inflammation
A
The initial, rapid response to infections and tissue damage
•develops within minutes or hours and is of short duration, lasting for several hours or a few days
19
Q
What’s the main characteristic of acute inflammation
A
It’s main characteristics are the exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, predominantly neutrophils (also called polymorphonuclear leukocytes)
20
Q
What happens if the acute inflammation fails to clear the stimulus
A
the reaction can progress to a protracted phase (chronic inflammation)
21
Q
What is chronic inflammation
A
It is an inflammation of longer duration, slower in onset than acute inflammation
22
Q
What are the things associated with chronic inflammation
A
• more tissue destruction,
• the presence of lymphocytes and macrophages,
• proliferation of blood vessels, and the deposition of connective tissue.
23
Q
What are the cardinal signs of inflammation
A
• rubor (redness),
• tumor (swelling),
• calor (heat),
• dolor (pain).
• functio laesa (loss of function)
24
Q
What are the causes of inflammation
A
• Infections - (bacterial, viral, fungal, parasitic) and microbial toxins are among the most common and medically important causes of inflammation.
• Tissue necrosis - ischemia (reduced blood flow, the cause of myocardial infarction), trauma, and physical and chemical injury (e.g., thermal injury, as in burns or frostbite; irradiation; exposure to some environmental chemicals).
• Foreign bodies - splinters, dirt, sutures.
• Deposition of endogenous substances – harmful when large amounts are deposited in tissues; such substances include urate crystals (in the disease gout), cholesterol crystals (in atherosclerosis), and lipids (in obesity-associated metabolic syndrome).
•Immune reactions (also called hypersensitivity) - The injurious immune responses may be directed against self antigens, causing autoimmune diseases, or may be inappropriate reactions against environmental substances, as in allergies, or against microbes.
25
What are the 3 major components of acute inflammation
•dilation of small vessels leading to an increase in blood flow,
•increased permeability of the microvasculature enabling plasma proteins and leukocytes to leave the circulation, and
•emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent
26
What are the 2 vascular changes seen in acute inflammation
•changes in the flow of blood and
•the permeability of vessels,
27
What is exudation
The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities
28
What is an exudate
extravascular fluid that has a high protein concentration and contains cellular debris.
29
What is a transudate
a fluid with low protein content (most of which is albumin), little or no cellular material, and low specific gravity.
30
When is a transudate produced
Transudate is essentially an ultrafiltrate of blood plasma that is produced as a result of osmotic or hydrostatic imbalance across the vessel wall ***without an increase in vascular permeability.***
31
What’s the difference between an exudate and a transudate
Exudate occurs due to increased vessel permeability in acute inflammation while transudate occurs due to osmotic imbalance and no increased permeability
32
What is edema
denotes an excess of fluid in the interstitial tissue or serous cavities; it can be either an ***exudate or a transudate.***
33
What is pus
a **purulent exudate**, is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells and, in many cases, microbes.
34
When does change in vascular flow and caliber occur
early after injury
35
What does change in vascular flow and caliber consist of
I. Vasodilation induced by the action of several mediators, notably histamine, on vascular smooth muscle.
II. Vasodilation is quickly followed by increased permeability of the microvasculature
36
What is one of the earliest manifestations of acute inflammation
Vasodilation
37
What vessels are dilated in acute inflammation
Vasodilation first involves the arterioles and then leads to
opening of new capillary beds in the area.
38
What causes heat and redness at the site of inflammation
increased blood flow due to vasodilation
39
What happens when there’s increased permeability of the micro vasculature
There is outpouring of protein-rich fluid into the extravascular tissues
40
What Does The loss of fluid and increased vessel diameter lead to in acute inflammation
slower blood flow, concentration of red cells in small vessels, and increased viscosity of the blood.
41
What is stasis
engorgement of small vessels with slowly moving red cells ( due to loss of protein filled fluid leaving the vessels in inflammation)
42
How is stasis seen
vascular congestion and localized redness of the involved tissue.
43
What happens as stasis develops
blood leukocytes, principally neutrophils, accumulate along the vascular endothelium.
(Endothelial cells are activated)
Leukocytes then adhere to the endothelium, and soon afterward they migrate through the vascular wall into the interstitial tissue.
44
How are endothelial cells activated
• endothelial cells are activated by mediators produced at sites of infection and tissue damage
• The endothelial cells express increased levels of adhesion molecules.
45
What are the mechanisms responsible for the increased permeability of postcapillary venules
a. Contraction of endothelial cells resulting in increased inter- endothelial spaces is the most common mechanism of vascular leakage.
b..Endothelial injury, resulting in endothelial cell necrosis and detachment
c. Increased transport of fluids and proteins, called transcytosis, through the endothelial cell.
46
What elicits contraction of endothelial cells
histamine,
bradykinin,
leukotrienes, and other chemical mediators
47
Why is contraction of endothelial cells called the immediate transient response
because it occurs rapidly after exposure to the mediator and is usually short- lived (15 to 30 minutes)
48
What is vascular leakage
Increased vascular permeability
49
How does vascular leakage occur in mild injury
In some forms of mild injury (***e.g., after burns, 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;
50
What causes delayed prolonged leakage in mild injury
caused by contraction of endothelial cells or mild endothelial damage.
51
Example of delayed prolonged leakage
Late appearing sunburn
52
What causes direct damage to the endothelium that leads to vascular leakage
Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or is induced by the actions of microbes and microbial toxins that target endothelial cells.
Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction.
53
When does vascular leakage occur
n most instances leakage starts immediately after injury and is sustained for several hours until the damaged vessels are thrombosed or repaired.
54
What is transcytosis
Increased transport of fluids and proteins, through the endothelial cells
55
What does transcytosis involve
This process may involve intracellular channels that may be stimulated by certain factors, such as ***vascular endothelial growth factor (VEGF).***
56
Im what vessel does contraction of endothelial cells cause leakage and induced by what
Mostly venules
Induced by histamine, NO, leukotrienes, bradykinin
57
In what vessels do endothelial injury causes leakage and what causes it
Arterioles, capillaries, venules
Causes- burns, microbial toxins etc
58
In what vessels do leukocytes mediated vessel injury cause leakage and when does it occur
Venules, pulmonary capillaries
Late stages of inflammation
59
In what vessels does increases transcytosis occur and what induces it
Venules
Induces by VEGF
60
What’s the duration of contraction derived vascular leakage
Rapid and short lived (minutes)
61
What’s the duration of endothelial damage derived vascular leakage
Rapid and May be long lived (hours to days)
62
What’s the duration of leukocyte mediated endothelial damage
Long lived
63
What’s the response of lymphatic vessels and lymph nodes to inflammation
• Lymph flow is increased and helps drain edema fluid
• Also 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 due to hyperplasia of the lymphoid follicles.
• This constellation of pathologic changes is termed reactive, or inflammatory lymphadenitis
64
What is the constellation of pathologic changes in lymphatic vessels and lymph nodes in response to inflammation
reactive, or inflammatory lymphadenitis
65
Why do Lymphatic vessels, like blood vessels, proliferate during inflammatory reactions
to handle the increased load.
66
What is lymphangitis
When the lymphatics become secondarily inflamed as a result of inflammation
67
What is lymphadenitis
When the draining lymph nodes become secondary inflamed as a result of inflammation
68
How does inflamed lymph nodes (lymphadenitis) occur
enlarged due to hyperplasia of the lymphoid follicles.
69
What leukocytes are most important for inflammation
Cells capable of phagocytes
Neutrophil and macrophages
70
What is The changes in blood flow and vascular permeability quickly followed by
Influx of leukocytes into the tissue
71
What’s the function of leukocytes in inflammation
•perform the key function of eliminating the offending agents
• These leukocytes ingest and destroy bacteria and other microbes, as well as necrotic tissue and foreign substances.
• Leukocytes also produce growth factors that aid in repair.
72
What mediates and controls the journey of leukocytes from the vessel lumen to the tissue
It is mediated and controlled by adhesion molecules and cytokines called chemokines.
73
What are the three sequential phases in the journey of the leukocyte from the vessel Limen to the tissue
I. In the lumen: margination, rolling, and adhesion to endothelium.
II. Migration across the endothelium and vessel wall
III. Migration in the tissues toward a chemotactic stimulus
74
Since Vascular endothelium normally does not bind circulating cells or impede their passage, how do leukocytes adhere to the endothelium
In inflammation, the endothelium is activated and can bind leukocytes as a prelude to their exit from the blood vessels. (This occurs after the change in blood flow to stasis)
75
How do leukocytes migrate out of the vessel lumen after adhesion
Insert pseudopods into endothelial cell junction and squeeze through
76
What’s is the process of adhesion and transmigration dependent on
Binding of adhesion molecules on leukocytes and endothelial cells
77
In normal flowing venule, where are the red cells and leukocytes arranged
In normally flowing blood in venules, red cells are confined to a central axial column, displacing the leukocytes toward the wall of the vessel.
Due to slow blood flow (stasis) and hemodynamic conditions change (wall shear stress decreases), more white cells assume a peripheral position along the endothelial surface.
78
What is margination
Due to slow blood flow (stasis) and hemodynamic conditions change (wall shear stress decreases), more white cells assume a peripheral position along the endothelial surface.
79
What occurs to leukocytes after margination
Subsequently, leukocytes adhere transiently to the endothelium,
detach and bind again, thus rolling on the vessel wall.
80
What do leukocytes resemble when they adhere firmly to the endothelial cells
resemble pebbles over which a stream runs without disturbing them
81
What mediates the adherence of leukocytes on endothelium
The attachment of leukocytes to endothelial cells is mediated by complementary adhesion molecules (selectin and integrins) on the two cell types whose expression is enhanced by cytokines.
82
How are cytokines secreted
Cytokines are secreted by ***sentinel cells*** in tissues in response to microbes and other injurious agents.
83
What are The two major families of molecules involved in leukocyte adhesion and migration and where are they expressed
selectins and integrins, and their ligands.
Expressed on leukocytes and endothelial cells
84
What’s the function of cytokines in adhesion
This ensures that leukocytes are recruited to the tissues where these stimuli are present.
85
What mediates the leukocytes rolling interaction
Selectins
86
What are he three types of selectins
• L-selectin – expressed on leukocytes,
• E-selectin – expressed on endothelium, and
• P-selectin - platelets and on endothelium
87
What are the ligands for selectins
***sialylated oligosaccharides bound to mucin***- like glycoprotein backbones
88
What regulates the expression of selectins and their ligands
Cytokins
89
How do Tissue macrophages, mast cells, and endothelial cells that encounter microbes and dead tissues respond
respond by secreting several cytokines, including tumor necrosis factor (TNF), IL-1, and chemokines (chemoattractant cytokines).
90
What does TNF and IL-1 act on
act on the endothelial cells of postcapillary venules adjacent to the infection and induce the coordinate expression of numerous adhesion molecules.
91
How long before the endothelial cells begin to secrete E selectin
Within 1 to 2 hours
92
What is the normal intracellular stores in endothelial cell granules for P selectin called
Weibel-Palade bodies)
93
What stimulates redistribution of p selectin from Weibel-Palade bodies to cell surface
Other mediators such as ***histamine and thrombin,*** stimulate the redistribution of P-selectin from its normal intracellular stores in endothelial cell granules (called Weibel-Palade bodies) to the cell surface.
94
Where do leukocytes express L selectin
At the tip of their microvilli
95
What selectins do leukocytes contain
L selectin
And ligands for E and P selectins
96
What kind of interaction is between the leukocytes that adheres it’s ***selectin*** to the endothelium
low-affinity interactions with a fast off rate
97
What happens as a result of the low-affinity interactions with a fast off rate between leukocytes and endothelium
• As a result, the bound leukocytes bind, detach, and bind again, and thus begin to roll along the endothelial surface.
98
What effect does the rolling interaction have on the leukocytes
Slows down the leukocytes
99
What mediates ***firm*** adhesion of leukocytes to endothelium
mediated by a family of heterodimeric leukocyte surface proteins called ***integrins***
100
What induces endothelial expression of ligands for integrin
***TNF and IL-1*** induce endothelial expression of ligands for integrins, mainly vascular cell adhesion molecule 1 (VCAM-1, the ligand for the β1 integrin VLA-4) and intercellular adhesion molecule-1 (ICAM-1, the ligand for the β2 integrins LFA-1 and Mac-1).
101
What’s the ligand for β1 integrin VLA-4
vascular cell adhesion molecule 1 (VCAM-1)
102
What’s the ligand for β2 integrins LFA-1 and Mac-1).
intercellular adhesion molecule-1 (ICAM-1)
103
At what state do leukocytes normally express integrins
In a low affinity state
104
What do chemokines bind to on the endothelial cells
Endothelial cell proteoglycan
105
What binds to and activate rolling leukocytes
Chemokines
106
At what con are cytokines present on the endothelial surface
At a high concentration
107
Consequences of activation of rolling leukocytes by cytokines
One of the consequences of activation is the conversion of VLA-4 (β1 integrin) and LFA-1 (β2 integrins) integrins on the leukocytes to a ***high-affinity state.***
108
When the cytokines activate the rolling leukocytes, it converts the integrin on the leukocytes to high affinity
What does this lead to
The combination of cytokine-induced expression of integrin ligands on the endothelium and increased integrin affinity 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.***
109
What does the firm integrin-mediated binding of the leukocytes to the endothelium at the site of inflammation (caused by activation of rolling leukocytes) cause
The leukocytes stop rolling, their cytoskeleton is reorganized, and they spread out on the endothelial surface
110
What’s another name for transmigration of the leukocyte through the endothelium
diapedesis
111
What kind of vessels does transmigration of leukocytes occur mainly
postcapillary venules.
112
What acts on the adherent leukocytes and stimulate the cells to migrate
Chemokines
113
Where do the leukocytes migrate through and to
through inter endothelial spaces toward the chemical concentration gradient.
114
Other than chemokines, what’s involved in the migration of leukocytes.
Several adhesion molecules present in the intercellular junctions between endothelial cells
115
Examples of adhesion molecules present in the intercellular junctions between endothelial cells
include a member of the immunoglobulin superfamily called CD31 or PECAM-1 (platelet endothelial cell adhesion molecule).
116
What happens after leukocytes traverse the endothelium
After traversing the endothelium, leukocytes pierce the basement membrane, probably by secreting collagenases, and enter the extravascular tissue
117
What creates the chemotactic gradient
chemokines and other chemoattractants
118
What does the leukocytes do after crossing the basement membrane to the extra vascular tissue
The cells then migrate toward the chemotactic gradient created by chemokines and other chemoattractants and accumulate in the extravascular site
119
What’s the The most telling proof of the importance of leukocyte adhesion molecules
is the existence of genetic deficiencies in these molecules that result in recurrent bacterial
120
What does chemotoxis mean
Chemotaxis is defined as locomotion of leukocytes along a chemical gradient towards the site of injury.
121
What kind of substances act as chemoattractants
Both exogenous and endogenous substances
122
What are the most common exogenous agents as chemoattractants
bacterial products and some
lipids.
123
Examples of Endogenous chemoattractants
include several chemical mediators:
cytokines, particularly those of the chemokine family (e.g., IL-8);
components of the complement system, particularly C5a; and
arachidonic acid (AA) metabolites, mainly leukotriene B4 (LTB4).
124
Where do chemotactic agents bind on the surface of the leukocyte
All these chemotactic agents bind to specific seven transmembrane G protein-coupled receptors on the surface of leukocytes.
125
What kind of signal is elicited from the receptor chemotactic agents bind to on the leukocyte
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.***
This induce polymerization of actin at the leading edge of the cell and localization of myosin filaments at the back.
126
What does polymerization of actin at the leading edge of the cell and localization of myosin filaments at the back. (A result of binding of chemotactic agents to GCPR receptors on leukocytes)
• The leukocyte moves by extending filopodia that pull the back of the cell in the direction of extension.
• The net result is that leukocytes migrate toward the inflammatory stimulus in the direction of the locally produced chemoattractants.
127
What does the nature of the leukocyte infiltrate vary upon with example
varies with the age of the inflammatory response and the type of stimulus.
Eg In 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.
128
Why are neutrophils replaced from the inflamed tissues after 24 hours
After entering tissues, neutrophils are short-lived; they undergo apoptosis and disappear within 24 to 48 hours.
129
What leukocytes are dominant in prolonged inflammatory reactions and why
• Monocytes survive longer and also proliferate in the tissues, and thus they become the dominant population in prolonged inflammatory reaction
130
What are the exceptions to the normal stereotypical pattern of cellular infiltration. (Neutrophils - 6-24 hrs, monocytes - 24-48 hrs)
• Pseudomonas bacteria - the cellular infiltrate is dominated by continuously recruited neutrophils for several days;
• viral infections - lymphocytes may be the first cells to arrive;
• some hypersensitivity reactions are dominated by activated lymphocytes, macrophages, and plasma cells (reflecting the immune response);
• Allergic reactions - eosinophils may be the main cell type.
131
One example of the most successful therapeutics ever developed for chronic inflammatory diseases
Agents that block TNF, one of the major cytokines in leukocyte recruitment,
132
What is leukocyte activation
Recognition of microbes or dead cells induces several responses in leukocytes that are collectively called leukocyte activation.
133
How does leukocyte’s activation come about
results from signaling pathways that are triggered in leukocytes, resulting in increases in cytosolic Ca2+ and activation of enzymes such as protein kinase C and phospholipase A2.
134
What functional responses
are most important for destruction of microbes and other offender
phagocytosis and intracellular killing.
135
What are the 3 sequential steps in phagocytosis
• recognition and attachment of the particle to be ingested by the leukocyte;
• engulfment, with subsequent formation of a phagocytic vacuole; and
• killing or degradation of the ingested material.
136
Examples of phagocytic receptors
Mannose receptors,
scavenger receptors,
and receptors for various opsonins bind and ingest microbes.
137
What is the macrophage mannose receptor
The macrophage mannose receptor is a lectin that binds terminal mannose and fucose residues of glycoproteins and glycolipids.
138
What do the macrophage mannose receptor recognize
The mannose receptor recognizes microbes and not host cells
139
What else can bind microbes for phagocytosis
Macrophage integrins notably Mac-1 (CD11b/CD18),
140
What enhances the efficiency of phagocytes
The efficiency of phagocytosis is greatly enhanced when microbes are opsonized by specific proteins (opsonins) for which the phagocytes express high affinity receptors.
141
What are the major opsonized
• IgG antibodies,
• the C3b breakdown product of complement, and
• Certain plasma lectins, notably mannose-binding lectin.
142
What is engulfment
After a particle is bound to phagocyte receptors, extensions of the cytoplasm (pseudopods) flow around it, and the plasma membrane pinches off to form a vesicle (phagosome) that encloses the particle.
143
What is a phagolysosome
• The phagosome fuses with a lysosomal granule, resulting in phagolysosome
144
What kind of process is phagocytosis
The process of phagocytosis is complex and involves the integration of many receptor-initiated signals that lead to membrane remodeling and cytoskeletal changes.
145
What is phagocytosis dependent on
• Phagocytosis is dependent on polymerization of actin filaments;
146
The killing of microbes is accomplished by what
reactive oxygen species (ROS, also called reactive oxygen
intermediates),
reactive nitrogen species, mainly derived from nitric oxide
(NO),
lysosomal enzymes that destroy phagocytosed debris.
147
What is the final step in the elimination of infectious agents and necrotic cells.
Intracellular destruction of microbes and debris
148
When does the killing and degradation of microbes and dead cell debris within neutrophils and macrophages occur most efficiently
after activation of the phagocytes.
149
Where are all the killing mechanisms normally sequestered
• All these killing mechanisms are normally sequestered in lysosomes, to which phagocytosed materials are brought.
150
How are ROS produced
ROS are produced by 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.***
151
In neutrophils, what triggers the formation of ROS
In neutrophils, this oxidative reaction is triggered by activating signals and accompanies phagocytosis, and is called the respiratory burst.
152
What is respiratory burst
The formation of ROS in neutrophils during phagocytosis
153
Where are ROS produced in the cell
ROS are produced within the lysosome and phagolysosome, where they can act on ingested particles without damaging the host cell.
154
What happens after the respiratory burst (production of ROS for phagocytosis)
• O2 is then converted into hydrogen peroxide H2O2
• Enzyme myeloperoxidase (MPO) in the presence of a halide such as Cl−, converts H2O2 to ***hypochlorite (OCl2)***
• The H2O2-MPO-halide system is the most efficient bactericidal system of neutrophils.
155
What is the most efficient bactericidal system of neutrophils.
The H2O2-MPO-halide system
156
What is NO
• NO, a soluble gas produced from arginine by the action of nitric oxide synthase (NOS), also participates in microbial killing
157
What are the 3 types of Nitric Oxide Synthase
endothelial (eNOS),
neuronal (nNOS), and
Inducible (iNOS).
158
Characteristics of eNOS and nNOS
constitutively expressed at low levels and the NO they generate functions to maintain vascular tone and as a neurotransmitter, respectively.
159
Which of the NOS produces NO used in microbial killing
iNOS
160
Characterized of iNOS
the type that is involved in microbial killing, is induced when macrophages and neutrophils are activated by cytokines (e.g., IFN- γ) or microbial products.
161
What does NO react with in macrophages, and to produce what
In macrophages, NO reacts with superoxide (O2 • ) to generate the highly reactive free radical peroxynitrite (ONOO−).
162
How are Reactive Nitrogen Species produced
NO reacts with superoxide (O2 • ) to generate the highly reactive free radical ***peroxynitrite (ONOO−).***
163
What are the 2 main types of granules contained in the lysosome
• The smaller (or secondary) granules
• The larger azurophil (or primary) granules
164
What enzymes are contained in the smaller (secondary) lysosome granule
lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase.
165
What enzymes are contained in the larger azurophil (primary) lysosome granule
myeloperoxidase, bactericidal factors (lysozyme, defensins), acid hydrolases, and a variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases, proteinase 3).
166
What granule of lysosome fuses with the engulfed material
Both types of granules can fuse with phagocytic vacuoles containing engulfed material, or the granule contents can be released into the extracellular space.
167
What’s the function of acid proteases in the granule of lysosomes
degrade bacteria and debris within the phagolysosomes,
168
Function of neutral proteases in the larger granules of lysosome
capable of degrading various extracellular components, such as collagen, basement membrane, fibrin, elastin, and cartilage, resulting in the tissue destruction that accompanies inflammatory processes.
It can also cleave C3 and C5
169
What controls the harmful proteases in the lysosome
These harmful proteases, however, are normally controlled by a system of antiproteases in the serum and tissue fluids.
170
Give examples of antiproteases in the tissue and body fluid that regulates the proteases
• Foremost among these is ***α1-antitrypsin***, which is the 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
• α2-Macroglobulin is another antiprotease found in serum and various secretions.
171
What does α1-antitrypsin inhibit
major inhibitor of neutrophil elastase
172
What are Neutrophil extracellular traps (NETs).
They are extracellular fibrillar networks that provide a high concentration of antimicrobial substances at sites of infection and prevent the spread of the microbes by trapping them in the fibrils
173
When are Neutrophil Extracellular Traps produced
They are produced by neutrophils in response to infectious pathogens (mainly bacteria and fungi) and inflammatory mediators (e.g., chemokines, cytokines [mainly interferons], complement proteins, and ROS).
174
What does the extracellular traps in NETs consist of
The extracellular traps consist of a ***viscous meshwork of nuclear chromatin*** that binds and concentrates granule proteins such as antimicrobial peptides and enzymes.
175
When can the leukocyte cause injury to normal cell and tissue (leukocyte mediated injury)
• In some infections that are difficult to eradicate, such as tuberculosis and certain viral diseases, the prolonged host response contributes more to the pathology than does the microbe itself
The inflammatory response is inappropriately directed against host tissues, as in certain autoimmune diseases.
176
How does the host react to environmental substances in leukocytes mediated tissue injury
• The host reacts excessively against usually harmless environmental substances, as in allergic diseases, including asthma.
177
In leukocyte mediated tissue injury, what mechanism does the leukocyte use
• In all these situations, the mechanisms by which leukocytes damage normal tissues are the same as the mechanisms involved in antimicrobial defense,
• The contents of lysosomal granules are secreted by leukocytes into the extracellular milieu by several mechanisms.
178
How does inflammation come to an end
• Neutrophils also have short half-lives in tissues and die by apoptosis within a few hours after leaving the blood.
• In addition, as inflammation develops, the process itself triggers a variety of stop signals that actively terminate the reaction.
179
What are active termination mechanism that are triggered by inflammation to stop it
• a switch in the type of arachidonic acid metabolite produced, from proinflammatory leukotrienes to antiinflammatory lipoxins
• liberation of anti-inflammatory cytokines, including transforming growth factor-β (TGF-β) and IL-10.
180
Which inflammation cardinal signs are as a result of vasodilation
Rubor and Calor
181
Which cardinal sign is as a result of vascular permeability
Tumor
182
Of the chemicals responsible for vasodilation, which is preformed and which is synthesized
Histamine is preformed
Prostaglandin E2 is synthesized
183
What are prostaglandin and leukotrienes gotten from
Lipid in membrane—- Arachidonic acid —— Leukotrienes and Prostaglandins
184
What are the types of leukotrienes
LTB4 LTC4 LTD4
185
What are the types of prostaglandins
PGF2
FGF2
PGK2
186
What converts lipid in membrane (in leukocytes) to arachidonic acid
Phospholipase A2
187
What’s the function of Bradykinine
Vasodilation
Increases vascular permeability
Pajn
188
How is Bradykinin gotten
Factor 12—- Prekalikreine—-Kalikreine—-Bradykinin
189
How is Bradykinin degraded
ACE
190
What’s a side effect of Bradykinin
Angioedema
191
What vessel undergoes vascular permeability
Post capillary venules
192
What causes endothelial contractions
Bradykinin, prostaglandins, Histermine
193
What vessel does fluid leak from
Post capillary venules
194
What causes transudate leak
Low protein and specific gravity
195
What are examples of things that cause fever in inflammation
They are pyrogenes
LPS
IL1
TNF
Prostaglandin E2
196
What are acute phase reactants
inflammation markers that exhibit significant changes in serum concentration during inflammation (produced in the liver)
197
Examples of acute phase reactants
C reactive proteins
Serum amyloid A
Ferritin
Hepsidin
Fibrinogen
198
Why is there increased ESR in inflammation
Increased acute phase reactants
199
What type of inflammation in part of innate immunity
Acute inflammation
200
What are the signaling tags on the inflammation
DAMPS( Damage associated molecular pattern) and PAMPS(pathogen associated molecular pattern)
201
Which of the signaling tags is present in human being
DAMPS
202
Example of PAMPS
LPS
203
What receptors do macrophages use to bind to DAMP and PAMP
Toll like receptors called pattern recognition receptors (cell membrane and endosome)
204
How long do neutrophils circulate for
5 days
205
How do neutrophils exit vascular system
At post capillary venules
206
Where are Evselectin and P selectin found
Endothelium
207
What does E selectin bind to
WEAKLY binds to **Sialyl Lewis x** on neutrophil
208
What mediates firm adhesion
VCAM and ICAM
209
What binds to VCAM and ICAM for strong adhesion
Integrins
210
What IL mediates integrin action
IL8
211
What’s another name for neutrophil transmigrations
Diapedesis
212
What mediates diapedesis
PECAM- CD31
(Platelets endothelial cell adhesion molecule)
213
What are chemotactic factors
Direct neutrophils to site of damage
Eg C5A IL8 Leukotrienes
214
Examples of opsonin
C5A
C3B
IGG
215
What mediates respiratory burst
NADPH oxidase
216
Describe the pathway that leads to bacteria killing
O3
|NADPH oxidase
|
O2
|superoxide dismal taste
|
H2O2
|myeloperoxidase
|
HOCl
217
What causes chronic granulomatos
A defect in the enzymes that cause bacterial kill (superoxide dismultase, myeloperoxidase)
218
What is LAD1
Leukocytes adhesion disorder
Problem with integrins
219
LAD2
Problem with Sialyl Lewis x
220
What’s CHEDIAK HEGASHI syndrome
Failure to form pahgolysosome
(Problem with mucrotubles)
