Mediators of Inflammation Flashcards
What is the purpose of inflammation?
Recruit and equip other cells
Liquefy surrounding tissue to prevent microbial metastasis
Induce healing of damaged tissues
What is inflammation?
A tissue-based startle reaction to trauma
Based in integration of molecular clues indicating tissue penetration by microbes
What are the consequences of unresolved inflammation?
Mediator-induced tissue damage
Granuloma (aggregates of lymphocytes/macrophages)
Fibrosis (distortion of repair mechanism)
Neoplastic transformation from persistent inflammation
What cells link the innate and adaptive immune systems?
Dendritic cells
What are the three sources of inflammatory mediators?
- Pre-stored in cells, active when released
- Present in plasma, circulates as zymogen, needs activation
- Needs synthesis de novo (i.e. gene activation)
Describe mediators originating from plasma.
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
Describe the two types of cell-derived mediators.
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
Three ways mediators act
Bind to receptors on target cells
Direct enzymatic activity (like lysosomal proteases)
Oxidative damage
What organ is a major source of inflammatory mediators?
Liver
Define diapedesis.
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
List the three stages of migration of immune cells and what factors mediate each.
Rolling (transient adhesion): selectins
Sticking (firm adhesion): chemokines and integrins
Diapedesis: integrins and chemokines
How do integrins function?
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
Sources of histamine
Synthesized and stored in mast cells in CT, adjacent to blood vessels
Also in circulating basophils, platelets
Stimuli that lead to release of histamine
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
Result of histamine release
Dilation of arterioles
Increased vascular permeability of venules (principle mediator of immediate vascular permeability/swelling)
Effect through H1 receptors
Sources of serotonin
Stored in platelets
What induces serotonin release?
Platelet aggregation: induced by….
- Collagen contact
- Thrombin
- ADP
- Ag-Ab complexes
Actions of serotonin
Similar to histamine (increased vascular permeability)
Describe the classic experiment that named complement
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
What is complement?
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
Functions of complement (6)
Cytolysis by formation of the MAC Opsonization of foreign organisms Inflammatory manifestations Chemotaxis Anaphylatoxins Solubilization and clearance of Ab-Ag complexes
List the important characteristics of complement
Multiple proteolytic enzymes -> sequential activation -> amplification
Inactive until activated by Ag-Ab complexes or surfaces of pathogens
Highly regulated
Complement cascade
Central component: C3
C3 convertase: C3 -> C3a + C3b
C3b cleaves C5
C5b + C6-9 -> C5-9 (MAC)
Activities of C3a and C5a
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
What is PNH? What two proteins are involved?
Paroxysmal nocturnal hemoglobinuria
- DAF: inhibits binding of factor B to C3b; lack of DAF on RBC -> activation of MAC and inappropriate lysis
- MIRL: blocks MAC formation by blocking C7, C8 binding; lack of MIRL -> activation of MAC and inappropriate lysis
What is HANE? What protein is involved?
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
What are eicosanoids?
Local short-range hormones
Formed rapidly
Short lived
Formed in lipid bodies
What is the COX pathway?
COX-1 and COX-2
Produces prostaglandins
What prostaglandins do platelets produce? Endothelium?
Platelets: TxA2 - vasoconstrictor
Endothelium: PGI2 - vasodilator
What are lipoxins?
Produced in platelets from leukotrienes from neutrophils
Some pro-inflammatory, some anti-inflammatory
Inhibit neutrophil chemotaxis
What are chemokines? List the four classes.
A superfamily of small proteins that activate and chemoattract leukocytes
Secrete ad bind to cell surface proteoglycans to form a gradient
- CXC (alpha): have one aa separating first two conserved cys residues
- C-C (beta): first two cys are adjacent
- C (gamma)
- CxxxC
Briefly describe chemokine receptors.
7-helix TM proteins
Act through G proteins
What does nitric oxide do? Where does it come from? What is an important sink for NO?
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
How is NO synthesized?
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
How does NO function in host defense?
Reactive species -> potent anti-microbial activity
Important for killing intracellular bacteria (like Listeria)
What are cytokines?
Intercellular signaling molecules
Can have local and systemic effects
Lead to inflammation, repair, and systemic manifestations of inflammation
What is NF-kB?
A heterodimer of two proteins (p50 and p65)
Activates transcription of many pro-inflammatory genes
List the steps in the NF-kB activation pathway
Kept in cytoplasm by I-kB(alpha)
- Receptor (TLR or IL-1 receptor or other) activated by TNFalpha, IL-1, IL-17, H2O2, LPS, many others
- Phosphorylation of I-kB by I-kB kinase-> polyubiquitination -> degradation
- NF-kB translocation to nucleus
- Activates transcription of inflammatory gene
Why is it important to know about NF-kB?
Many drugs that we use affect components of this pathway
How do glucocorticoids and aspirin interact with NF-kB?
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
What do etanercept and cA2 do?
Drugs that serve as a sink to soak up TNF
Help in rheumatoid arthritis, Crohn’s disease
