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Pathology - Quiz 1 > Mediators of Inflammation > Flashcards

Mediators of Inflammation Flashcards

0
Q

What is the purpose of inflammation?

A

Recruit and equip other cells
Liquefy surrounding tissue to prevent microbial metastasis
Induce healing of damaged tissues

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1
Q

What is inflammation?

A

A tissue-based startle reaction to trauma

Based in integration of molecular clues indicating tissue penetration by microbes

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2
Q

What are the consequences of unresolved inflammation?

A

Mediator-induced tissue damage
Granuloma (aggregates of lymphocytes/macrophages)
Fibrosis (distortion of repair mechanism)
Neoplastic transformation from persistent inflammation

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3
Q

What cells link the innate and adaptive immune systems?

A

Dendritic cells

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4
Q

What are the three sources of inflammatory mediators?

A
  1. Pre-stored in cells, active when released
  2. Present in plasma, circulates as zymogen, needs activation
  3. Needs synthesis de novo (i.e. gene activation)
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5
Q

Describe mediators originating from plasma.

A

Proteins that circulate as zymogens
Need activation via proteolysis
Amplification to turn on and negative feedback to shut off
Circulating inhibitors ensure stoppage of aberrantly active mediators

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6
Q

Describe the two types of cell-derived mediators.

A

Rapid: (minutes) prestored in granules and ready for release

Slower: (minutes to hours) synthesized de novo in response to stimulus

Can work together, have feedback

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7
Q

Three ways mediators act

A

Bind to receptors on target cells
Direct enzymatic activity (like lysosomal proteases)
Oxidative damage

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8
Q

What organ is a major source of inflammatory mediators?

A

Liver

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9
Q

Define diapedesis.

A

The passage of blood, or any of its formed elements, through the intact walls of blood vessels
Necessary for immune cells to get to interstitium to do their jobs

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10
Q

List the three stages of migration of immune cells and what factors mediate each.

A

Rolling (transient adhesion): selectins
Sticking (firm adhesion): chemokines and integrins
Diapedesis: integrins and chemokines

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11
Q

How do integrins function?

A

Resting: bent over, low affinity
Active: pop up into extended state when activated by things like chemokines; can now move laterally, have high affinity for immune cells

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12
Q

Sources of histamine

A

Synthesized and stored in mast cells in CT, adjacent to blood vessels
Also in circulating basophils, platelets

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13
Q

Stimuli that lead to release of histamine

A

Physical stimuli (like scratching your skin)
Immune reactions (cross-linking of surface bound IgE on mast cells)
C3a, C5a (anaphylatoxins)
Cytokines IL-1, IL-8

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14
Q

Result of histamine release

A

Dilation of arterioles
Increased vascular permeability of venules (principle mediator of immediate vascular permeability/swelling)
Effect through H1 receptors

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15
Q

Sources of serotonin

A

Stored in platelets

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16
Q

What induces serotonin release?

A

Platelet aggregation: induced by….

  • Collagen contact
  • Thrombin
  • ADP
  • Ag-Ab complexes
17
Q

Actions of serotonin

A

Similar to histamine (increased vascular permeability)

18
Q

Describe the classic experiment that named complement

A

Fresh serum with antibacterial antibody will lyse bacteria, but NOT if heated first
Conclusion: there is a heat-labile activity required to COMPLEMENT antibody activity

19
Q

What is complement?

A

A system of functionally linked proteins that interact with one another in a highly regulated manner to provide many of the effector functions of humoral immunity and of inflammation

20
Q

Functions of complement (6)

A 
Cytolysis by formation of the MAC
Opsonization of foreign organisms
Inflammatory manifestations
Chemotaxis
Anaphylatoxins
Solubilization and clearance of Ab-Ag complexes
21
Q

List the important characteristics of complement

A

Multiple proteolytic enzymes -> sequential activation -> amplification
Inactive until activated by Ag-Ab complexes or surfaces of pathogens
Highly regulated

22
Q

Complement cascade

A

Central component: C3
C3 convertase: C3 -> C3a + C3b
C3b cleaves C5
C5b + C6-9 -> C5-9 (MAC)

23
Q

Activities of C3a and C5a

A

Histamine dependent: bind mast cells, release histamine
Histamine independent:
-C5a:
1. activates lipoxygenase pathway in PMN -> leukotrienes -> increased permeability
2. Chemoattractant for PMNs
3. Increases leukocyte adhesion tk endothelium

24
Q

What is PNH? What two proteins are involved?

A

Paroxysmal nocturnal hemoglobinuria

  1. DAF: inhibits binding of factor B to C3b; lack of DAF on RBC -> activation of MAC and inappropriate lysis
  2. MIRL: blocks MAC formation by blocking C7, C8 binding; lack of MIRL -> activation of MAC and inappropriate lysis
25
Q

What is HANE? What protein is involved?

A

Heriditary angioneurotic edema

C1 inhibitor (SERPIN): binds to active forms of C1; lack of C1 inhibitor -> deregulated classical pathway -> acute, intermittent attacks of skin an mucosal edema

26
Q

What are eicosanoids?

A

Local short-range hormones
Formed rapidly
Short lived
Formed in lipid bodies

27
Q

What is the COX pathway?

A

COX-1 and COX-2

Produces prostaglandins

28
Q

What prostaglandins do platelets produce? Endothelium?

A

Platelets: TxA2 - vasoconstrictor
Endothelium: PGI2 - vasodilator

29
Q

What are lipoxins?

A

Produced in platelets from leukotrienes from neutrophils
Some pro-inflammatory, some anti-inflammatory
Inhibit neutrophil chemotaxis

30
Q

What are chemokines? List the four classes.

A

A superfamily of small proteins that activate and chemoattract leukocytes
Secrete ad bind to cell surface proteoglycans to form a gradient

  1. CXC (alpha): have one aa separating first two conserved cys residues
  2. C-C (beta): first two cys are adjacent
  3. C (gamma)
  4. CxxxC
31
Q

Briefly describe chemokine receptors.

A

7-helix TM proteins

Act through G proteins

32
Q

What does nitric oxide do? Where does it come from? What is an important sink for NO?

A

Potent vasodilator
Acts as local paracrine factor
Extremely short-lived
Function: forms adducts with thiol groups on proteins

Source: endothelial cells (eNOS), also neurons (nNOS), macrophages (iNOS)
Sink: hemoglobin

33
Q

How is NO synthesized?

A

Produced from L-arginine by NOS

  • Constitutive form (e or n-NOS): low levels, Ca activated
  • Inducible form (iNOS): requires de novo synthesis, no Ca needed
34
Q

How does NO function in host defense?

A

Reactive species -> potent anti-microbial activity

Important for killing intracellular bacteria (like Listeria)

35
Q

What are cytokines?

A

Intercellular signaling molecules
Can have local and systemic effects
Lead to inflammation, repair, and systemic manifestations of inflammation

36
Q

What is NF-kB?

A

A heterodimer of two proteins (p50 and p65)

Activates transcription of many pro-inflammatory genes

37
Q

List the steps in the NF-kB activation pathway

A

Kept in cytoplasm by I-kB(alpha)

  1. Receptor (TLR or IL-1 receptor or other) activated by TNFalpha, IL-1, IL-17, H2O2, LPS, many others
  2. Phosphorylation of I-kB by I-kB kinase-> polyubiquitination -> degradation
  3. NF-kB translocation to nucleus
  4. Activates transcription of inflammatory gene
38
Q

Why is it important to know about NF-kB?

A

Many drugs that we use affect components of this pathway

39
Q

How do glucocorticoids and aspirin interact with NF-kB?

A

Glucocorticoids: receptor directly interacts with NF-kB; also receptor activates I-kB transcription

Aspirin: inhibits I-kB kinases -> retention of NF-kB in cytoplasm -> lack of production of inflammatory mediators

40
Q

What do etanercept and cA2 do?

A

Drugs that serve as a sink to soak up TNF

Help in rheumatoid arthritis, Crohn’s disease

Pathology - Quiz 1 (11 decks)

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