2.1 Acute Inflammation Flashcards
Main difference between acute and chronic inflammation
Acute: Neutrophils enter tissue
chronic: lymphocytes enter tissue
Acute inflammation: main hallmarks
- edema
2. neutrophils
Acute inflammation: what causes it (2 major stimuli)
- infection
2. tissue necrosis
Acute inflammation is mediated by several factors. List them (5 categories)
- TLRs
- Arachidonic acid metabolites (prostaglandins and leukotrienes)
- Mast cells (histamine, as well as AA metabolites)
- Complement
- Hageman factor (Factor XII)
CD14
A TLR on macrophages that recognizes LPS on the outer membrane of G- bacteria. Mediates acute inflammation.
How does TLR mediate acute inflammation?
TLR binds PAMP and then upregulates NF-KB, a TF that activates immune response genes.
NF-KB
Molecular switch that turns on acute inflammation. It’s a TF that activates expression of immune response genes.
Arachidonic acid mediators:
- mech of production
- products
- PLA releases AA from membrane
- Prostaglandins made from COX
- Leukotrienes made from 5-lipoxygenase
Prostaglandins:
- types
- what do they do
- made from what enzyme
- PGI2, PGD2, PGE2
- all cause vasodilation and increase vascular permeability
- PGE2 also mediates fever and pain
- made from COX enzyme
Leukotrienes:
- types
- what do they do
- made from what enzyme
- LTB4: attracts and activates neutrophils
- LTC4, LTCD4, LTE4: vasoconstriction, bronchospasm, increased vascular permeability
- made from 5-lipoxygenase
Mast cells: immediate and delayed response
- immediate: release histamine
- delayed: release AA metabolites (PGs, LTs). This occurs several hours later
Histamine, functions
- vasodilation
- increase vascular permeability
Complement pathways
- Classical
- C1 binds IgG, IgM bound to antigen - Mannose-binding Lectin (MBL) pathway
- MBL binds to mannose on microorganisms and activates complement. - Alternative pathway -directly activated by microbials
What key products do complement pathways produce?
- C3 convertase
- C5 convertase
- C5b, C6-9: MAC
C3a, C5a: combined effect
Anaphylatoxins.
- trigger mast cell histamine release
- C5a also is chemotactic for neturophils
MAC
- formed from C5b, C6-9
- lyses microbes
Hageman factor (Factor XII):
- what is it
- how activated
- what it activates
- is especially important in what disease
- Inactive proinflammatory protein produced in liver
- activated when exposed to subendothelial or tissue collagen
- Activates: Coagulaiton and fibrinolytic systems, complement, and Kinin system (produces bradykinin–vasodilation, vascular permeability, pain)
- important thing to know: plays important role in DIC by G- Sepsis
What vessels does vasodilation and increase in vascular permeability occur during inflammation?
- vasodilation occurs at arteriole
- vascular permeability occurs at post-capillary venule
What mediators attract and activate neutrophils? (4)
- LTB4
- C5a
- IL8
- Bacterial products
- (LTB4 and C5a also upregulate integrins.)
Causes of mast cell activation (3)
- Tissue trauma
- C3a, C5a
- cross-linking of cell-surface IgE by antigen
C3b
-opsonin for phagocytosis
C5a
- trigger mast cell histamine release with C3a
- also chemotactic for neutrophils
Bradykinin, functions
- vasodilation
- increase vascular permeability
- pain
What mediates pain?
- PGE2 (fever and pain)
- Bradykinin
Key mediators of each: Rubor-redness calor-warmth tumor-swelling dolor-pain fever
1, 2. Redness, warmth -caused by vasodilation: Histamine, Bradykinin, PGs 3. swelling: -Vascular permeability: Histamine, Tissue damage 4. Pain PGE2, Bradykinin 5. Fever -PGE2 released by COX in hypothalamus, activated by IL1 and TNF from macrophages
Mediators of fever
- PGE2 released by COX in hypothalamus, activated by IL1 and TNF from macrophages
- Pyrogens stimulate macrophages (eg LPS rom bacteria)
Neutrophil arrival (Diapedesis): 4 steps, briefly describe each
- Margination–vasodilation causes cells to marginate from center of flow to periphery
- Rolling–selectin speed bumps
- Adhesion–Integrins bind CAMs on endothelium
- Transmigration and Chemotaxis–neutrophils cross epithelium, attracted to 4 chemotactic mediators.
Selectins:
- types
- what increases them
- what does it bind to
- “speed bumps” of Rolling step in diapedesis
- P selectin: released from Weibel-palade bodies, mediated by histamine
- E selectin, induced by TNF and IL1
- binds to Sialyl Lewis X on leukocytes
Neutrophil function after diapedesis. 3 steps
- Phagocytosis
- Destruction of phagocytosed material
- Resolution
Adhesion step of Diapedesis
- CAMs on epithelium bind to Integrins on leukocytes
- Cell adhesion molecules–ICAM and VCAM
What upregulates CAMs
TNF, IL1
What upregulates Integrins
C5a, LTB4 (which also are chemotactic for neutrophils)
Leukocyte Adhesion deficiency:
- mech
- name of specific protein
- clinical features (3)
- Integrin defect, CD18 subunit
- auto recessive
1. higher neutrophil level in blood (1/2 of neutrophils normally hang on vessels, like bats in a cave)
2. delayed separation of umbilical cord (lack of neutrophils in acute inflammation means cord cells are delayed in necrosis)
3. recurrent bacterial infections without pus
Main opsonins
- IgG
- C3b
Chediak-Higashi syndrome
-mech
- protein trafficking defect, microtubules (think Railroad track defect!)
- Impaired phagolysosome formation–cannot destroy phagocytized particles
Chediak-Higashi syndrome
-clinical features (6)
- increased risk of pyogenic infections
- neutropenia (railroad track defects make it tough to separate components in mitosis of neutrophils)
- Giant granules in leukocytes (railroad track defects–granules pile up)
- Defective primary hemostasis (platelets depend on granule function, same as 3)
- Albinism (melanocyte cannot use tracks to distribute melanin to many keratinocytes)
- Peripheral neuropathy (nerves rely on tracks for protein transportation)
Destruction of phagocytosed material in neutrophils: name the 2 methods
- O2 dependent (oxidative burst). More effective
2. O2 independent (enzymes such as lysozyme)
Oxidative burst, biochem reactions/enzymes
O2 to .O2- to H2O2 to HOCl (bleach)
- H2O2 to HOCl is by MPO (myeloperoxidase)
- Catalase can also take away H2O2
Chronic granulomatous disease
- Lack of NADPH oxidase leads to no H2O2 to make HOCl, so H2O2 must be taken from bacteria. However, catalase can react with H2O2, so Cat+ bacteria removes H2O2 that could be made into HOCl for respiratory burst
- leads to infection and granuloma formation
- Test: nitroblue tetrazolium test to screen CGD to test enzyme
MPO deficiency
- myeloperoxidase deficiency
- cannot convert H2O2 to HOCl (bleach) for oxidative burst
- similar to CGD
Resolution of neutrophil function:
- what happens
- time frame
- neutrophils undergo apoptosis, create pus
- within 24 hours
Phases of acute inflammation
- Fluid
- Neutrophils (peak 24 hours)
- Macrophage (peak 2-3 days)
How do macrophages ‘manage’ the next stages of inflammation?
Options that macrophage can do:
- Stop acute inflammation, IL10 and TGF-B
- Continue acute inflammation, IL8
- Abscess formation–Wall off the infection and continue acute inflammation
- Call in chronic inflammation–when they know that lymphocytes are needed (eg virus infection)
Which cytokines shut down inflammation? Secreted by what?
Macrophages (as ‘managers’ of inflammation) secrete IL10 and TGF-B if they think inflammation should end.
Which cytokine does macrophage secrete to recruit more neutrophils?
- IL8
- Clinical sign is pus formation. This means acute inflammation is still happening, even if many weeks have passed
Transudate vs Exudate
transudate–fluid leakage
exudate–fluid with protein and maybe cells
