Acute Inflammation 2 Flashcards
What are the 3 major phases of acute inflammation?
- Fluid phase
- Neutrophil phase
- Macrophage phase
When does the macrophage phase peak approximatly?
2-3 days in
What is margination?
Heavy particles predominantley sit at the centre of a blood vessel
- During vasodilation these particles can spread to the periphery of the blood vessel
What is step 1 of margination?
- Vasodilation slows blood flow in postcapillary venules
- Cells marginate from center of flow to periphery
What is step 2?
Rolling
What does rolling involve?
Large molecules hit selcetins (act like speedbumps)
What is P-selectin released from?
Weibel-Palade bodies
What is P-selectin mediated by?
Histamine
What is E-seletin induced by?
TNF and IL-1
What are the 2 key proteins within Weibel-Palade bodies?
- Von Willebrand
- P-selectin
What protein on neutrophils binds to selectin, allowing the leukocytes to roll along the vessel wall?
Sialyl Lewis X
What are cellular adhesion molecules upregulated on the endothelium by?
- TNF
- IL-1
What is the 5 steps involved for neutrophils in acute inflammation?
- Margination (migration to periphery)
- Rolling
- Adhesion
- Transmigration and chemotaxis
- Phagocytosis
What are integrins upregulated on leukocytes by?
- C5a
- LTB4
What does the interaction between integrins (from the leukocyte) and cellular adhesion molecules allow for?
Firm adhesion to vessel wall
What do the endothelial cells express to allow for adhesion?
Cellular adhesion molecules
What is the defect in leukocyte adhesion deficiency?
AR
- Defect of integrins
- CD18 subunit
What are the high yield clinical features associated with Leukocyte Adhesion Deficiency? (3)
- Delayed seperation of umbilical cord
- Increased circulating neutrophils
- Recurrent bacterial infections lacking pus
What is pus?
Dead neutrophils sitting in fluid
What are neutrophils attracted by?
- IL-8
- C5a
- LTB4
What is phagocytosis enhanced by?
Opsonins (IgG and C3b)
At what point in the blood vessel do leukocytes transmigrate across the endothelium?
Postcapillary venules
Describe how phagocytosis occurs
The leukocyte will draw out pseudopods (arm like structures) around the pathogen and consume it
- This will then create a vesicle inside the leukocyte - known as a phagosome
- This will then merge witha lysosome to create a phagolysosome
What is the mechanism behind Chediak-Higashi Syndrome?
- Protein trafficking (Microtubule) defect
- Impaired phagolysosome formation - infections
How is Chediak-Higashi Syndrome inherited?
AR
What are the clinical features of Chediak-Higashi syndrome?
- Increased risk of pyogenic infections
- Neutropenia
- Giant granules in leukocytes
- Defective primary hemostasis
- Albinism (melanin transport)
- Peripheral neuropathy
What cells create melanin and what cells express it?
Melanin is created by melanocytes but transported to keratinocytes which express it - show pigmentation
What does NADPH oxidase convert?
O2 into superoxide
What does superoxide dismutase convert?
Superoxide into Hydrogen peroxide (H2O2)
What does myeloperoxide convert?
Hydrogen peroxide (H2O2) into HOCl
What substance is generated in phagocytes in O2-dependent killing?
- Known as ‘Oxidative burst’
Bleach (HOCl)
What enzyme is there a defect in in Chronic Granulomatous Disease (CGD)?
NADPH oxidase defect
- Poor O2-dependent killing
How is CGD inherited?
- X-linked OR
- Aut Recessive
What type of organisms are those with CGD vulnerable to?
Catalase +ve organisms
What are the catalase +ve organisms?
- S. aureus
- P cepacia
- S marcescens
- Nocardia
- Aspergillus
Via what pathway can the leukocytes create bleach in individuals with CGD?
They can take hydrogen peroxide from the bacteria to create bleach
Why are those with CGD vulnerable to catalase +ve organisms?
Bacteria with catalase can break down hydrogen peroxide therefore, the bacteria cannot use the hydrogen peroxide to make bleach
What does the Nitroblue tetrazolium test screen for?
CGD
What does the Nitroblue tetrazolium test involve?
Turns blue if O2- (superoxide) is created from O2
- Blue if NADPH oxidase is working
- Colourless if NADPH oxidase is defective
What are MPO deficient patients vulnerable to (what organisms)?
Usually asymptomatic
- Candida
What will a NBT (Nitroblue tetrazolium) test show in MPO deficiency?
Normal
- Turns blue
What step of the conversion to bleach is defective in MPO deficiency?
H2O2 to HOCl-
What does O2-independent killing occur via?
Enzymes present in leukocyte secondary granules (e.g. lysozyme and major basic protein)
What is more effective O2 dependent or independent killing?
O2 dependent
What is the final step for neutrophils in inflammation?
Resolution - Apoptosis
- Disappear within 24 hrs after resolution of inflammatory stimulus
- Creates pus
What cells predominate after neutrophils in acute inflammation?
Macrophages
When do macrophages peak after inflammation?
2-3 days after inflammation occurs
How do macrophages destroy material?
- Ingest via phagocytosis
- Destroy phagocytosed material using enzymes in secondary granules
What do the macrophages produce to start resolution and healing?
IL-10 and TGF-Beta
What can macrophages produce to continue acute inflammation?
IL-8
What can macrophages create which is known as an area of walled off acute inflammation?
Abscess
What do macrophages express antigens on to produce chronic inflammation?
MHC class II
