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MOD 1: DR > Chapter 3 > Flashcards

Chapter 3 Flashcards

1
Q

What is inflammation

A

Inflammation: a protective response of vascularized tissues to infections and damaged tissues that brings cells and molecs of host defense from the BV -> tissues where they are needed, in order to eliminate the offending agents

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2
Q

What are causes of inflammation?

A
  1. Infections (bacterial, fungal, viral or parasitic) and microbial are the most common
  2. Tissue necrosis
  3. Accumulation of endogenous substances: urate cystals (gout), cholesterol crystals (artherscleros)
  4. Foreign bodies (spliters, direct) can cause infllamation themself or can carry microbes with them
  5. Immune reactions (hypersensitivities) are reactions that attempt to protext us but can daamge our tissue
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3
Q

What are the vascular reactions that we see in actute inflammation?

A
  1. Alterations in BF (vasodilation and stasis)
  • Histamine will induce dilation of the BV, which is usually the first thing that occurs. BF increases => increase in heat and redness
  • Then, we will see alterations in the vascular permeability induced by [histamine, bradykinin and leukotrienes] => cause protein rich fluid to leak out and cause edema
  • Increase in vascular permeability and loss of protein rich fluid => decrease flow of blood and increase viscoity => stasis (engorgement of small BV with slowly moving BCs.
  1. Alterations in permeability
  • [Histamine, bradykinin and leukotrienes can increase vascular permeability] => increase interendothelial spaces
    • Immediate transient responsse
    • Delayed prolonged leakage, if damage is severe
  • Direct or leukocyte mediated injury.
  • Transcytosis: VEGF allows fluid to go through endothelium
  1. LN/LV
  • LN and LV increase when inflammation to accommadate for extra shit.
  • Lymphegenetis: inflammation of lymph vesses.
    • Often seen by read streaks following course
  • Lymphendernitis (lymphenopathy): inflammation of lymph nodes that also occurs d/t hyperplasia of lymphoid follicles and increase immune cells
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4
Q

Changes in blood flow and vascular permeability are quickly followed by an …

A

influx of leukocytes into the tissue.

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5
Q

The increased vascular permeability seen with acute inflammation happens where specifically?

A

POST-CAPILLARY VENULES!

HALLMARK!!!

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6
Q

Describe the process of leukocyte recruitment that occurs IN THE LUMEN of the BV

margination

rolling

adhesion

A
  1. Margination: In normally flowing blood in venules, red cells are confined to a central column of BV, displacing the leukocytes toward the wall of the vessel. As blood flow slows early in inflammation (stasis), hemodynamic conditions change (vasoactive substances => dilation => decreases wall shear stress), and more white cells assume a peripheral position along the wall
  2. Rolling: acommplished by low-affinity selectins
  • L-selectin (CD62L): on leukocytes (neutrophils, monocytes and T-cells)
  • E-selectin (CD62E): on endothelium
  • P-selectin (CD62P): on platelets and endothelium
  • A. Mast cells, MO and endothelial cells that sense injury will secrete TNF and IL-1, which acts on post-capillar venules.
    • Within 1-2 hours: TNF and IL-1 will promote the expression of E-selection and ligand for L-selectin.
  • Thrombin and histamine (+TNF and IL1) will then cause the relase of P-selecting from WP bodies onto the cell surface.
  • Selectins bind to Siayl-Lewis X on leukocytes with low adhesion. Increase in blood flow will cause them to roll along the endothelium.
  1. Adhesion: accomplished by integrins.
  • Without inflammation, leukocytes have low-affinity integrins (beta-1 integrin VLA-4 and beta-2 integrin LFA-1 and Mac-1). Activated rolling leukocytes convert integrins from a low => high affinity state.
  • TNF and IL-1 will induce integrin-ligands on the endothelium (VCAM-1 (CD106) and ICAM-1 (CD54)).
  • => firm adherence => cytoskelton reorganizes and they spread out on surface of endotheliun.
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7
Q

name the selectins and where they are located

A
  1. P-selectin (CD62-P): located on platelet and endothelium
  2. L-selectin (CD62-L): located on leukocyte
  3. E-selectin (CD62-E) located on endothelium
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8
Q

what do selectins bind to?

A

Siayl-Lewis X on leukocytes

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9
Q

Name the integrin ligands

where are they located

A

on endothelium

1. VCAM-1 (CD106)

2. ICAM-1 (CD54)

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10
Q

Name the integrins and where they are located

A

on leukocyte

  1. beta 1 integrin VLA-4
  2. beta 2 integrin LFA-1 and Mac-1
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11
Q

Describe

leukocyte transmigration (diapedisis): migration through the endothelium

A
  1. Firm adherence of leukocyte allows the cytoskeleton to change so it can prepare to go through endothelium of POST-CAPILLARY VENULES.
  2. Leukocytes bind to adhesion molcules located in the intracellular junctions between endothelial cells, like CD31-PECAM-1.
  3. Leukocytes then secrete collaginases to break down the BM => follow chemical gradient to injury.
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12
Q

After leukocyte transmigration is…

draw the steps out.

A

3. Leukocyte chemotaxis

  • 1. Endogenous and exogenous chemokines bind to G-proteins located on the leukocyte => activivate rac/rho/cdc 42 pathway => guide them to the site of injury
    *
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13
Q

Most common exogenous chemokines

A

bacteria that contain an N-formylmethionine terminal amino acid and some lipids

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14
Q

Most common endogenous cytokine

A
    1. IL8 is the most potent chemoattractant for neutrophil
    1. C5a
    1. Leukotriene B4
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15
Q

Which leukocyte infiltrate predominates early in the response (6-24 hours) and later in the response (24-48 hours)

A
  • Neutrophils are first and short-lived, attaching to endothelial cells and disappear.
  • Monocytes dominant in prolonged inflammatory rxns, bc they live longer and go inside tissue
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16
Q

What is the predominant leukocyte in Pseudomonas bacterial infections?

A
  • Neutrophils dominate
  • Will be continously recruited (exception to rule where neutrophils and then monocytes)
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17
Q

Hypersensitivity reactions are dominated by which immune cells?

A
  • 1. Lymphocytes
  • 2. Macrophages
  • 3. Plasma cells
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18
Q

What is the first leukocyte to respond to viral infections?

A

lymphocytes

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19
Q

Agents that block _____ are among the most sucessful therapeutics ever developed for chronic inflammatory diseases?

A

TNF; a major cytokine in leukocyte recruitment

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20
Q
  • Main cell type in an allergic reaction is the _____
    • immediate reaction == ______
    • late phase reaction == dominated by _____ (Chapter 6)
A
  • Main cell type in an allergic reaction is the eosinophil
    • immediate reaction == mast cell degranulation
    • late phase reaction == dominated by eosinophils (Chapter 6)
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21
Q

Once leukocytes have been recruited to the site of infection, they must be activated to perform their functions:

A
  1. Recognition and attachment
  2. Engulfment
  3. Killing and degrading
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22
Q

How do we activate leukocytes so that they can perform their function, which is?

A
  • Receptor signaling pathways leading to increased cytosolic Ca and activation of PKC and phospholipase A2.
  • Once activated, they can then initate phagocytosis and KILL!
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23
Q

Once activated, leukocytes than then cause phagocytosis. What are they 3 steps?

A
  1. Leukocyte phagocytic receptors recognize and attach particle to eat

2. Leukocyte inguls

3. Kill ingested material.

24
Q

Describe steps of phagocytosis.

A
    1. Leukocyte phagocytic receptors (4 types) recognition and attachment of the particle to be ingested
      * Mannose receptors
      • Mannose receptor is a lectin that binds to terminal mannose and fructose residues of glycoproteins and glycolipids which are only found on microbe (not mammal) cell walls.
        * Scavenger receptors
      • Bind to modified LDL (that can no longer interact w a conventional LDL receptor) particles and various microbes.
        * Integrins
      • Mostly Mac-1 (CD11b/CD18) bind microbes
        * Opsonin’s are proteins that enhance the efficiency of phagocytosis
      • Major ones: IgG, C3b, and mannose binding lectin.
  • 2 Leukocyte engulfment
    • After a particle is bound to the receptor on the phagocyte, extensions of the cytoplasm called pseudopods extend from leukocyte -> encircles what it wants to eat -> forms a phagosome
    • Phagosome merges with a lysosome à creating a phagolyosome => granules contents go inside phagolyosome
      • Phagocyte may also release contents into extracell space
    • The process of phagocytosis is complex and involves membrane remodeling and cytoskeletal changes. Phago­cytosis is dependent on polymerization of actin filaments; it is, therefore, not surprising that the signals that trigger phagocytosis are many of the same that are involved in chemotaxis.
  • 3 Killing/degradation of ingested material (see below in purple)
25
Q

How do we kill ingested microbes?

A

1. ROS

2. RNS (derived from NO)

3. Lyosomal enzymes

26
Q

One way to kill ingested microbes in with ROS. How do we make ROS in phagocytes to allow them to kill?

A

Respiratory burst

  1. Goal: [NADPH => superoxide anion] via NADPH (phagocyte) oxidase
    1. In neutrophils, NADPH oxidase has 7 parts, with some of them located in the cytosol and some in the membarne
    2. When activated, all parts move to the membrane, creating a whole functioning oxidase => creates ROS ONLY in phagolysosome/ lysosome, preventing damage of host cell.
    3. Superoxide anion => H202 via spontanous mismutation, a not very dangerous substance
    4. MPO from neutrophil combines with Cl-, to convert [H202 => hypocholrite (OCl2-)/bleach or OH-]
      1. Hypochlorite kills via halogenation or oxidation of lipids/ proteins (lipid peroxidation))
      2. OH- is just turned into water with glutathionine.

Note that if ROS goes into the ECF => causes more tissue damage with inflammation .

27
Q

What are the 5 anti-oxidant mechanisms to combat ROS produced during the killing of microbes and protect the host?

A

1) SOD (superoxide dismutase)
2) Catalase: detoxifies H2O2
3) Glutathione peroxidase: detoxifies H2O2
4) Ceruloplasmin
5) Iron-free fraction of serum transferrin

28
Q

Nitric oxide (NO) is produced by NOS, of which there are 3 different types, what are they?

How/when is each expressed?

A
  • eNOS (endothelial-vascular tone) and nNOS (neuronal-NT) are constitutively expressed at low levels
  • iNOS (inducible) kills microbes and induced by IFN-y or microbial products
29
Q

NO reacts with what to produce what ROS that attacks lipids, proteins, and nuclei acids of microbes and host cells?

A

NO reacts with superoxide anion to makes ONOO- (peroxynitrate)

30
Q

Lysosomal enzymes, if not controlled, can damage the host. Which antiproteases in the serum and tissue fluids serve as protection?

Major inhibitor of?

A
  1. - α​1-antitrypsin is major inhibitor of n_eutrophil elastase_
  2. - α2-macroglobulin
31
Q

Neutrophils have 2 types of granules:

A
  • Secondary (smaller, specific) granules
    • Lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase.
  • Primary (larger, azurophilic) Granules
    • Myeloperoxidase (H202- MPO-halide system)*, bactericidal factors (lysozyme, defensins), acid hydrolases, and a variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases, proteinase 3).
32
Q
  • _________ is how the body protects itself from itself
A
  • α1-antitrypsin is how the body protects itself from itself
33
Q
  • _________ defieincy–> sustained activation of leukocyte proteases –> chronic inflammation and tissue destruction
    • _______ == emphysema
A
  • Antiprotease deficiency
34
Q

What is the function of major basic protein?

A

Cationic protein of eosinophils, that is cytotoxic to many parasites

35
Q

What are

Neutrophil Extracellular Trap (NET)

A

Meshwork of chromatin made by neutrophils in response to [bacteria, fungi and inflammattory mediators] that binds and hold onto granule proteins such as antimicrobial peptides and enzymes, to prevent the spread of microbes. When neutrophils make these, they lose their nucleus and die.

36
Q

The nuclear chromatin in the NETs, which includes histones and associated DNA, has been postulated to be a source of nuclear antigens in which diseases?

A

Systemic autoimmune diseases, particularly lupus

37
Q

In what siutations can leukocytes injur normal cells?

A
  1. Collateral damage of adjacent tissue is the infection persists
  2. Autoimmune disease causes them kill host cell
  3. Allergies; reaction against harmless shit
38
Q

What is fustrated phagocutosis?

A

Furstrated phagocytosis occurs when a activated leukocyte encounters a substane that is difficult to digest (immune complex). This results in a strong activation and release of ALOT of granules into the extracellar environment that damages tissue.

39
Q

Which T lymphocytes play an important role in acute inflammation?

What do they produce?

Deficiency produces; increased susceptibility to?

A

- TH17 cells

  • Produce IL-17, which induces secretion of chemokines that recruit leukocytes
  • Deficiency = cold abscesses with no warmth or redness= more susceptible to bacterial and fungal infections

–

40
Q

4 things occur that all terminate acute reactions. What are they?

A
  • 1. When offending agents are removed because mediators of inflammation are made in rapid bursts, have short-half lives as long as the stimulus persist.
    1. Neutrophils have a short 1/2 life and die a few hours after leaving blood.
    1. As inflammation develops, it also triggers stop signals to end inflammation:
      * A. switch the type of arachidonic acid that is made from proinflammatory leukotrienes => anti-inflammatory lipoxins
      * B. Macrophages release anit-inflammatory cytokines (TGF–B and IL-10).
    1. Neural: PNS inhibits production of TNF in macrophages
41
Q

During termination of the acute inflammatory response which anti-inflammatory cytokines are released?

A

TGF-β and IL-10

42
Q
  • The most important mediators of acute inflammation
A
  1. Vasoactive amines
  2. prostaglandins
  3. leukotrienes
  4. cytokines
  5. chemokines,
  6. products of complement activation.
43
Q
  • The most important mediators of acute inflammation come from what 2 places?
A
  1. Granules inside cells
  2. Made from plasma proteins
44
Q
  • What are the major cell type that makes mediators for acute inflammation?
A

sentinels that detect invaders and damage in tissues:

  1. macrophages,
  2. DCs,
  3. mast cells
45
Q
  • Plasma derived mediators (ex. compliment proteins) are made mainly in the _____ and must be activated by _______
A

liver

proteolytic cleavage

46
Q

What is the life span of mediators?

A

Short-lived

47
Q
  • One mediator can stimulate the release of other mediators. Give 2 examples
A
  1. Products of compliment activation => release Histamine
  2. TNF => causes release of IL-1 from endothelial cells.
48
Q
  • What are the main actions of prostaglandins?
A
  • Vasodilation
  • pain
  • fever
49
Q
  • Main actions of leukotrienes
A
  1. Increased vascular permeability (rmbr; works with histamine and bradykinin)
  2. chemotaxis
  3. leukocyte adhesion and activation.
50
Q

leukotriene antagonists are good treatment for ____

A

asthma

51
Q
  • The most important mediators of acute inflammation
    • Vasoactive amines, prostaglandins, leukotrienes, cytokines, chemokines, and products of complement activation.

Vasoactive amines include: Histamine and serotonin.

  • Q: Where are they stored?
  • Q: Where are they found in greatest concentration?
A

Inside granules of the celll, thus, they can be released 1st in iflammation.

Histamine: Mast cells -> blood basophils and platelets.

5HT: platelets and neuroendrone cells in GI tract.

52
Q

What is needed to release histamine from the mast cell granules?

A
  1. injury
  2. binding of Ab to mast cell
  3. C3a, c5a (anaphaltoxins)
  4. IL-1 and 8
  5. Substance P
53
Q
  • Mechanism of histamine
  • Where does it bind?
A
  • Main mediator of _immediate transient phas_e of increased vascular permeability.
    • causes vasodilation and some contraction of smooth muscle/endothelium –> increased interendothelial gaps in venules
  • Effects mostly come from binding to H1 receptors.

actions: [vasodilation, increase vascular permeability and activates endothelium]

54
Q

5HT action

A
55
Q

How do we make

prostaglandin and leukotrienes?

A
  • Phospholipase A2 (which increases intracell Ca and activates kinalses) releases arachidonic acid from membrane phospholipids =>
56
Q

Why are eicosanoids considered dynamic?

A
  • Bind GPCRs on many cell types and can mediate virtually every step of inflammation

MOD 1: DR (11 decks)

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