1
Q
innate immune system
A
the unchanging immune system we’re born with. It has the same response every time it’s activated (non-specific)
2
Q
adaptive immune system
A
the immune system we continually develop as we are exposed to different pathogens over our lifetime. It has memory and is unique to each person
3
Q
3 lines of defense against pathogens
A
- Innate immune system - natural barriers
- Inflammation
- Immune system - adaptive immunity
4
Q
natural barriers
A
our first line of defense that includes skin and mucous membranes. They can be mechanical or chemical barriers
5
Q
mechanical barriers
A
cilia, sloughing, mucous, etc.
6
Q
chemical barriers
A
acidic pH of stomach or vagina, saliva
7
Q
humoral immunity
A
an immune response derived from body fluids such as the plasma. Inflammation uses the complement system and the immune system uses antibodies through B cells to tag the pathogen
8
Q
cellular immunity
A
an immune response that occurs between cells. Inflammation recruits neutrophils and macrophages and lymphocytes (T and B cells) are recruited in the immune response involving an intracellular or processed antigen. Does not involve antibodies
9
Q
inflammation
A
the protective response of vascularized tissue that involves eliminating the initial cause of injury, removing damaged tissue, and building new tissue
10
Q
goals of inflammation
A
- movement of blood and cellular components to site of injury
- delivery of nutrients and blood cells to get rid of the offender
- injurious agents are diluted, confined, and eliminated
- stimulate and assist the immune system
- promote healing and generate new tissue
11
Q
how goals of inflammation are accomplished
A
- Increased metabolic rate to increase production of cellular items needed for battle
- Vasodilation to speed up delivery of cellular components to site of injury
- Increased vascular permeability to allow leukocytes (namely neutrophils), proteins, and nutrients into affected tissue
12
Q
causes of inflammation
A
- Microbes
- Immune reactions between antigen and antibody
- Trauma
- Burns
- Physical/chemical agents
- Tissue necrosis
- Temperature extremes
- Oxygen deprivation
- Nutrient deprivation
- Genetic/immune defects
- Ionizing radiation
13
Q
Characteristics of acute inflammation:
A
- Response to injury/insult that occurs early and quick (mins to hours)
- Triggered by variety of stimuli
- Doesn’t last very long, self limiting
- Non-specific (ex. response for cutting finger/stubbing toe is exactly the same)
- 2 phases (vascular and cellular)
- Results in either healing or chronic inflammation
14
Q
What cells are involved in inflammation? 7
A
- Endothelial cells
- Platelets
- Neutrophils
- Monocytes/macrophages
- Eosinophils
- Basophils
- Mast cells
15
Q
Function of endothelial cells?
A
- Line blood vessel walls, tight space under normal conditions, limits movement
- Produce antiplatelet/antithrombotic agents to prevent clots
- Regulate leukocyte extravasation through use of adhesion molecules
- Regulate immune cell proliferation
- Participate in repair process
16
Q
What are platelets also known as?
A
Thrombocytes
17
Q
Function of platelets?
A
- Primary role = hemostasis
- Activated then produce inflammatory mediators leads to increased vascular permeability, chemotaxis, adhesive and proteolytic properties of the endothelium
18
Q
Function of neutrophils?
A
- Chief phagocytic leukocytes
- Have lysosomal enzymes, called upon to destory invaders and remove debris
19
Q
What are bands?
A
Immature neutrophils
20
Q
What does it mean when the band count is elevated on a CBC?
A
Bone marrow is overworked
21
Q
Function of monocytes/macrophages?
A
- Leukocytes derived from bone marrow
- Larger and fewer lysosomes than neutrophils
- Stimulate growth of granulocytes and monocytes in the bone marrow and substances that promote wound healing
- Replace neutrophils as they die off
22
Q
When do macrophages appear?
A
Later than neutrophils (24-48 hours post injury)
23
Q
What are macrophages associated with?
A
chronic inflammation
24
Q
What do macrophages produce?
A
Potent vasoactive mediators
- Prostaglandins
- Leukotrienes
- Platelet activating fcator
- Inflammatory cytokines
- Growth factor
25
How long are macrophages lifespan?
3-4x longer than neutrophils
26
What happens to neutrophils when they die?
- Become exudate (pus)
| - Release chemotactic factor to attract macrophages to injury
27
When do neutrophils appear?
- Early in inflammatory process (90 mins to 6-12 hrs post injury) cells attracted to site because of chemotactic factors
28
What causes an increased demand for neutrophils?
- Severe inflammation, bone marrow cannot keep up and releases bands
29
Function of eosinophils?
- Prominent in allergic response and hypersensitivity disorders
- Good at tackling parasitic infections
- Circulate in blood until needed,
- migrate to tissue where they modulate release of inflammatory mediators
- degrade vasoactive molecules,
- controlling vascular effects of histamine and serotonin
30
What are eosinophils?
Granulocytes with many lysosomes
31
What do eosinophils do?
- Circulate in blood until needed,
- migrate to tissue where they modulate release of inflammatory mediators
- degrade vasoactive molecules,
- controlling vascular effects of histamine and serotonin
32
Function of basophils?
- Produce lipid mediators and cytokines to induce inflammatory response
- Important in allergic and hypersensitivity reactions
- Trigger histamine and vasoactive agent release
33
Function of mast cells?
- Mast cell degranulation
- Activate the 3 plasma protein systems
- Release of cell derived mediators
- Important in response to hypersensitivity and allergic reactions
34
Where are mast cells located?
Connective tissue, close to blood vessel, prevalent along mucosa of lung, GI tract and dermis of skin
35
What do mast cells produce?
Lipid mediators and cytokines which induce inflammation
36
What is within neutrophils cytoplasm??
Pre-formed granules
37
What are the contents of these granules?
- Histamine
- Serotonin
- Chemotactic factors
- Enzymes
- Proteoglycans
- Proteases
- Cytokines
38
What are the three plasma protein systems
- Complement system
- Clotting system/coagulation cascade
- Kinin system
39
What do complement fragments cause?
Vasodilation, increase vascular permeability and enhance activity of phagocytes
40
What do C3 and C5 do?
Formation of opsonins, chemotactic factors and anaphylatoxins
41
C3b?
used in the opsonization and tagging
42
C5a?
Chemotactic and anaphylatoxic factors
43
C2b?
Increase vasodilation/permeability (smooth muscle relaxation)
44
C4a?
Anaphylatoxin inducing cell degranulation with histamine release
45
What is the endpoint of the complement cascade?
Formation of membrane attack complex (MAC) composed of C5-C9, creates holes in membranes of pathogens, allows water in and causes cells to explode
46
What are the three ways to activate the complement cascade?
1. Classical pathway - activated by antibodies, immune system can take advantage of this for the destruction of bacteria
2. Lectin pathway - activated by bacterial carbohydrates, no antibody required
3. Alternative pathway - activated by gram negative bacteria, fungal cell wall polysacchardies (endotoxins) no antibody required
47
Which of the pathways requires an antibody to be activated?
The classical pathway
48
Which of the pathways does not require an antibody to be activated?
- Lectin pathway
| - Alternative pathway
49
What are the major effects of complement?
- Opsonization
- Mast cell degranulation
- Leukocyte chemotaxis
- Cell lysis
50
How is the clotting system activated?
Substances released during tissue destruction and infection, two pathways (intrinsic and extrinsic)
51
What is the goal of the clotting system?
Produce a fibrous clot, fibrous mesh network that traps offending agent and prevents the spread of infection, keeps it at the site of inflammatory activity, prevents bleeding and promotes healing
52
What is inflammation enhanced by?
By products of fragments that are produced during the clotting cascade
53
What are the byproducts and how do they enhance inflammation?
- Fibrin production, fibrinogen releases fibrinopeptides, this acts as a chemotactic for neutrophils, increases vascular permeability, enhances effect of bradykinin
- Plasmin works with complement to activate C3a and C5a causing the release of histamine
54
What does the kinin system do?
Works closely with the clotting system
55
What is the kinin system activated by?
Factor XII (XIIA) like the clotting cascade
56
What is the end result of the kinin cascade?
Production of bradykinin causes vasodilation, increased vascular permeability, smooth muscle contraction, enhances leukocyte chemotaxis, stimulates pain receptors
57
What are bradykinin effects similar to?
Histamine, the effects are shorter, appears to be of greater importance during latter phases of inflammation
58
What components of the plasma protein systems does Hageman factor activate?
- Clotting cascade through factor XI (Hageman factor)
- Fibrinolytic system through conversion of plasminogen
- Kinin system by prekallekrein activator
- C1 and complement cascade
59
Where are plasma derived mediators formed?
In the liver
60
What are the major sources of cell derived mediators? 9
- Platelets
- Neutrophils
- Macrophages
- Monocytes
- Mast cells
- Endothelial cells
- Smooth muscle
- Fibroblasts
- Most epithelial cells
61
Why are mediators of inflammation important?
Without some method of control over the plasma protein systems we would be in a constant state of inflammation which would be very uncomfortable
62
Where is histamine found?
Well perfused connective tissue, circulating platelets, basophils and within mast cells granules
63
What does histamine cause?
Vasodilation, increased vascular permeability, increased adherence of leukocytes to endothelium
64
What are the negative consequences of histamine?
Smooth muscle constriction of bronchioles (makes breathing difficult during acute inflammatory reaction), antihistamines will antagonize effects of acute inflammatory response
65
What is serotonin released by?
Mast cells, basophils and platelets
66
What does serotonin do?
Causes smooth muscle contraction, small vessel dilation, increased vascular permeability
67
What are lyosomal enzymes?
Membrane enclosed sacs containing powerful enzymes
68
What is the function of lysosomal enzymes?
Fuse with phagocytes to destroy foreign invaders
69
What are arachidonic metabolites?
Fatty acids in phospholipids in the cell membrane
70
Where are arachidonic metabolites released from? What do they do when released?
- Released from mast cells
| - Initiate complex reactions which cause production of other inflammatory mediators (prostaglandins and leukotrienes)
71
What is the function of prostaglandins?
- Induce inflammation and enhance effects of histamine and other mediators
- Promote vasodilation/bronchoconstriction/increase neutrophil chemotaxis, cause pain through action on nerves and fever
72
How can you counteract the effects of prostaglandin synthesis?
Use of ASA and NSAID's
73
What is thromboxane A2 produced by?
Platelets at the site of the injury
74
What is the effects of thromboxane A2?
- Promote platelet aggregation
- Promote bronchoconstriction
- Promote vasoconstriction
75
When are leukotrienes synthesized?
While histamine is working
76
What are the effects of leukotrienes?
Increase vascular permeability, smoothing muscle contraction, constrict pulmonary airways (mediation of asthma and anaphylaxis), affect adhesion properties of endothelial cells, extravasation and chemotaxis of neutrophils, eosinophils and monocytes
77
What do leukotrienes help to do?
Prolong the inflammatory response
78
Where is platelet aggregating factor generated from?
Lipids stored in cell membrane
79
What effect does platelet aggregating factor have?
Induces platelet aggregation, activates neutrophils and acts as a chemoattractant for eosinophils
80
What are cytokines/chemokines activated by?
Macrophages and lymphocytes, endothelium, epithelium, connective tissue
81
What effect do cytokines and chemokines have?
Modulate inflammatory response by travelling and binding to and affecting the functions of those target cells
82
What effect does nitric oxide have?
- Causes smooth muscle relaxation,
- antagonizes platelet adhesion, aggregation
- degranulation
- Regulates recruitment of leukocytes
83
What occurs where there is blocked nitric oxide production?
Promotes leukocyte rolling and adhesion to capillary venules
84
What occurs with delivery of nitric oxide?
Reduces leukocyte recruitment, reduces cellular phase of inflammation
85
What occurs with impaired nitric oxide production?
Inflammatory changes associated with atherosclerosis, some microbial properties
86
When are oxygen free radicals released?
Released by leukocytes after exposure to microbes, cytokines and immune complexes or during phagocytic process
87
What do low levels of oxygen free radicals cause?
Increased expression of cytokines and adhesion molecules
88
What do high levels of oxygen free radicals cause?
Damage to endothelium and increased vascular permeability
89
Describe vascular phase of inflammation
- Brief arteriolar vasoconstriction
- Profound vasodilaton
- Increased vessel size encourages blood to go to the area
- Blood velocity slows, increases hydrostatic pressure
90
Describe cellular phase of inflammation
- Biochemical mediators retract endothelial cells, causes increased vascular permeability
- Large proteins leave vessel, move into extra-vascular space taking fluid with them
- Blood = more viscous, slows down velocity
- Leukocytes stick to endothelium then migrate out to the site of injury
91
What are the three major changes that happen to microcirculation during vascular response of inflammation?
1. Brief vasoconstriction and then vasodilation
- Increased capillary permeability
- Movement of leukocytes into tissues
92
What do the changes to microcirculation cause? (think changes in the body)
- Heat
- Redness
- Edema
- Pain
- Loss of function
93
How do leukocytes emigrate?
- During inflammation certain molecules become sticky and adhere to endothelial wall
- Leukocytes recruited to site of injury and linger there because of slowed blood flow
- Line up along endothelial wall and adhere to it
- Chemotaxis, then leukocytes encouraged to move into tissue where the injury occurred
94
What is migration?
Leukocytes move along the endothelial wall
95
What is adhesion?
Leukocytes stick to the endothelium with the help of adhesion molecules
96
What is transmigration?
Leukocytes move to the site of injury (chemotactic factors)
97
What is chemotaxis?
Response involving cell orientation or cell movement that is either toward (positive chemotaxis) or away from (negative chemotaxis) a chemical stimulus
98
How does chemotaxis work?
- Directed cell migration, leukocytes leave capillary, move in response to chemical gradient caused by chemokines, bacterial and cellular debris, and protein fragments from the complement system
99
Phagocytosis process review
1. Margination (leukocytes move, adhere to endothelium, move along periphery of blood vessels)
2. Pseudopod formation (plasma membrane of phagocyte extends finger like projections)
3. Diapedesis (leukocytes move through wide gaps in endothelium into the tissue)
4. Migration (phagocytes move toward target)
5. Opsonization
6. Engulfment (phagocytes surround and encircle target, from intracellular phagocytic vacuole or phagosome)
7. Fusion with lysosome (forms phagolysosome, works on destruction and digestion of target)
8. Destruction (target dies, phagocyte dies becomes exudate and products exit via the lymphatics)
100
How do we avoid toxicity?
Alpha-1 antitrypsin (plasma protein from liver) released and inhibits destructive effects
101
How is heat caused?
- Vasodilation -
| - Increased blood flow to the site of the injury
102
How is redness caused?
- Vasodilation
| - Increased blood flow to the site of the injury
103
How is edema caused?
- Vasodilation
- Increased blood flow to the site of the injury
- Increased capillary permeability
- Leakage of proteins and cells out of the endothelial wall (taking water with it)
- Increased fluid in tissues
104
How is pain caused?
- Increased fluid in tissues
| - Prostaglandins act on nerve endings to cause pain
105
How is pus formed?
- Neutrophils die off
| - Contents become exudate
106
How is a clot formed?
- Initiation of clot cascade
| - Thrombus sequesters invaders to site of injury
107
How does loss of function occur?
Due to edema and pain
108
When can inflammation be considered chronic?
When it lasts 2 weeks or longer
109
How is granulamatous inflammation characterized?
Inflitration of lymphocytes and macrophages, body isolates site and walls it off
110
What is a granuloma encapsulated by?
Fibrous deposits
111
How does inflammation interact with atherosclerosis?
- Elevated cholesterol causes monocytes to become sticky and attach to endothelium
- Macrophages consume foam LDLs and turn them into foam cells
- Phagocytes release cytokines which interact with local tissue cells in pro or anti-inflammatory way
- Subendothelium ecposed to blood components, platelets adhere and aggregate at the site of injury, smooth muscle poliferates and then endothelium pouches out and makes lumen smaller
- Lipids accumulate beneath endothelial layer, hard lipid core formed
- Enzymes eat at the fibrous cap
- Plaque unstable, can rupture
- Thrombus formed b/c rupture encourages thrmbus to form, platelets adhere
- Occlusion of vessel
- Myocardial infarction
112
Function of Opsonins
Coat bacteria and tag them for destruction
113
Chemotactic factors do what?
Draw other inflammatory mediators to site of injury
114
Anaphylatoxins function
Rapid degranulation of mast cells
115
What is the most potent anaphylatoxins?
C3a
116
Bradykinin Function
- causes vasodilation
- smooth muscle contraction
- enhances chemotaxis
- pain receptors
- increase vascular permeability
PATHOPHYSIOLOGY
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