Inflammation, Cell Adhesion and Resolution 2 Flashcards
Macrophage-produced cytokines control the body’s response:
IL-1β/IL-6/TNF-α in the liver
- Acute-phase proteins (C-reactive protein, mannose-binding lectin
- Activation of complement opsonization
Macrophage-produced cytokines control the body’s response:
IL-1β/IL-6/TNF-α in the bone marrow endothelium
- Neutrophil mobilization
- Phagocytosis
Macrophage-produced cytokines control the body’s response:
IL-1β/IL-6/TNF-α in the hypothalamus
- Increased body temperature
- Decreased viral and bacterial replication
- Increased antigen processing
- Increased specific immune response
Macrophage-produced cytokines control the body’s response:
IL-1β/IL-6/TNF-α in fat and muscle
- Protein and energy mobilization to allow increased body temperature
- Decreased viral and bacterial replication
- Increased antigen processing
- Increased specific immune response
Macrophage-produced cytokines control the body’s response:
IL-1β/IL-6/TNF-α in dendritic cells
- TNF-α stimulates migration to lymph nodes and maturation
- Initiation of adaptive immune response
What is the acute phase response (APR)?
Janeway states….“APR produces molecules that bind pathogens not host cells”.
- Bacteria induce macrophages to produce IL-6, which acts on hepatocytes to induce synthesis of acute-phase proteins
- C-reactive protein binds phosphocholine on bacterial surfaces, acting as an opsonin, and also activating complement
Products bind pathogens and activate complement
MBL -> lectin pathway
CRP -> classical pathway
Afferent lymphatics- secondary lymphoid tissue- efferent lymphatics
What is inflammation?
Is it beneficial?
•hat happens when it doesn’t return to its normal state?
- A protective response to injury and infection
- BENEFICIAL
- BUT only if the tissue is returned to its PRE-INFLAMED STATE
–The tissue must go back to normal once the challenge is cleared
What happens when it doesn’t return to its normal state?CHRONIC INFLAMMATION
Chronic Inflammation & Fibrosis
What are the consequences of chronic inflammation and fibrosis
Loss of function!
- Tissue cells are lost
- Replaced by extracellular matrix
Persistent cells
- Chronic Inflammation
- Fibrosis
- Scarring
- Loss of function
Describe the resolution of inflammation
- NØ migrate to site of infection
Kill bacteria
age and die by apoptosis
- Monocytes follow & mature to MØ
- MØ
clear remaining bugs
dying neutrophils
= RESOLUTION OF INFLAMMATION
Suggests a PASSIVE end to inflammation
Draw the kinetics of acute inflammation
Explain prostaglandin E2
- Pro-inflammatory lipid mediator
- Induced by cytokines IL1b/IL6/TNFa (‘endogenous pyrogens’)
- Stimulate by Cox enzyme (Cox-2)
- Substrates are fatty acids from membranes
Released by phospholipase
- Drives…
- Vascular changes to promote inflammation
- Fever & pain by acting on the hypothalamus
- Therapy
- NSAIDs (aspirin, Ibuprofen) inhibit Cox-2
Explain active resolution
- Pro-inflammatory lipid mediators (PGE2)
- Turn on enzymes to make new eicosanoids/mediators
- Lipoxins – AA-derived
- Resolvins – PUFA-derived (DHA EPA)
- Protectins – PUFA-derived
- Maresins – DHA-derived
These ACTIVELY promote homeostasis
‘The beginning programmes the end’
Serhan & Savill
Active resolution 2
Active resolution 3
Describe the clearance of apoptotic cells
Release of extracellular vesicles (EV)
Silent clearance of apoptotic cells
Clearance of apoptotic cells is ‘silent’ = Non-phlogistic
What are the molecular mediators of apoptotic cell clearance?
- Acute Phase Response Proteins
- Pentraxins (CRP)
- Collectins (SPA, SPD, MBL)
- PRR e.g. CD14
- Integrins
