MCB Lecture 59 Inflammation II Flashcards
What are the different receptors for leukocyte activation?
- 7 pass alpha-helical receptors
- TLR
- Cytokine receptors
- Phagocic receptor
Which cells are important for removal of the cause of inflammation?
Neutrophils
Describe 7 pass alpha helical receptor activation
Chemokines, or other inflammatory mediators act as ligand.
Signal transduction:
Cytoskeletal changes
Increased integrin avidity
Outcome:
Chemotaxis and adhesion to endothelium
Describe TLR signalling in leukocyte recruitment
- PAMPs (such as LPS) bind to the TLR
2a. Production of inflammatory mediators (arachidonic acid, cytokines)
2b. Production of hydrolytic enzymes and ROS
3a. Amplification of inflammation
3b. Killing of microbes
Describe cytokine signalling in leukocyte activation
- Cytokines bind to the membrane bound receptor
2a. Production of inflammatory mediators (arachidonic acid and cytokines)
2b. Production of lysosomal enzymes and ROS
3a. Killing of microbe
3b. Amplification of the immune response
Describe phagocytic receptors role in leukocyte activation
- Opsonised microbe binds to FcR and CR
2a. Production of ROS
2b. Extension of pseudopods, phagocytosis - Killing of microbe
Which are the phagocytic receptors on leukocytes, and what do they bind to?
CR1 and CR2: bind to complement on opsonised bacteria
Fc-gamma-R: bind to IgG on opsonised bacteria
CIq: binds to collectin on microbe
What is opsonisation?
Preparing the microbe for phagocytosis by binding complement and antibody
Describe phagocyte binding to opsonised pathogen
Phagocyte binds via its receptors (CR1 and 2, Fc-gamma-R, CIq) to antibody, C3b and collectin that are bound to the microbe
What are the two modes of phagocytic pathogen killing?
O2 dependent
O2 independent
Describe O2 dependent killing
ROS preoduced in the phagocyte which disrupt the function of the microbe
Which enzymes are involved in O2 dependent killing?
NADPH: O2 -> H2O2
Myeloperoxidase: H2O2 -> HOCl (hydrochlorus radical)
Describe the reactive oxygen species that are formed, and which are the most efficient at killing pathogens that have been phagocytosed
H2O2, not very efficient at killing microbes
HOCl-: very powerful oxidant, good at killing
Peroxynitrate: very powerful oxidant
Describe briefly what O2 independent pathogen killing is
Killing of the bacteria with enzymes released from the granules of leukocytes
What compounds are found in phagocytic granules, and what does each do?
Phospholipase: degrades the microbes’ membrane
Lysozyme: degrades the cell wall
Major basic protein: cytotoxic to parasites
Defensins: puts holes in the cell membrane
Describe how leukocytes can also injury healthy tissue
a. Released toxic products have no distinction between pathogen and host
b. toxic products released when:
- Frustrated phagocytosis
- Regurgitation
- Damage to phagolysosome by ingested irate crystals
Describe broadly how inflammation is regulated
Chemical mediators
What are the two derivations of mediators of inflammation?
Plasma and cell derived
What are the plasma derived enzymatic cascades that regulate inflammation? (3)
- Complement cascade
- Kinins
- Coagulation, fibrinolysis
What is the function of the regulatory enzymatic cascades?
These amplify and coordinate the immune response
Describe the presence of the plasma derived chemical mediators under normal and inflammatory conditions
Normal: present, but inactive
Inflammation: become activated at the site of injury
Describe the complement system
There pathways of activation
Cleavage of C3
Opsonisation, lysis, inflammation
What are the two types of cell derived chemical mediators of inflammation?
Preformed
Newly synthesised
What are the preformed cell derived chemical mediators?
Histamine in leukocyte granules
Describe histamine’s role in regulation of inflammation
Histamine controls vascular change:
Increases vasodilation and vascular permeability
What are the newly synthesised chemical mediators of inflammation?
Arachidonic acid metabolites; Prostoglandin and leukotrienes
What are eicosanoids?
These are the arachidonic acid metabolites
What is are some important derivatives of arachidonic acid?
Prostoglandin and leukotrienes
What is the function of leukotrienes and Prostoglandins?
- Synthesised locally
2. mediate the steps in inflammation (eg. vascular change)
Describe the removal of the cell derived mediators
Decayspontaneously, or are degraded by enzymes afterwards
How does aspirin work?
What does it target?
What does this bring about?
Aspirin targets the synthesis of eicosanoids
Without these, fever and pain is reduced
Describe how cell derived chemical mediators of inflammation are only locally acting
Only cells in the area receiving the correct stimulation will degranulate
The compounds decay or are degraded rapidly
What is the aim of resolution of inflammation?
Regenerate damaged tissue
Regain function
Minimal damage
Sort lived inflammation
Describe some of the things that must happen for resolution of inflammation
- Leukocytes stop being recruited
- Vascularisation returns to normal
- Draining of oedema
- Decay and degredation of mediators
- Apoptosis of leukocytes
Describe how inhibition of inflammation works
Lipoxins are an arachidonic acid metabolite that inhibits PMN adhesion and chemotaxis
They negatively regulate the leukotrienes
What are the features of systemic acute phase inflammation? (9)
- Fever
- Acute phase proteins
- High BP
- Fast heart rate
- Reduced sweating, presence of rigors and chills
- Anorexia
- Cachexia
- Lots of leukocytes
- Sepsis
Describe what is happening in fever
The individual’s body the petite increases by 1-4 degrees in an aim to perhaps reduce the ability of the microbes to replicate
Which molecules cause fever?
What are these molecules called?
Pyrogens cause fever
Exogenous: bacterial and viral molecules
Endogenous: cytokines
What is thought to be the aim in fever?
Reduce the replication rate of the microorganisms
What are the acute phase proteins, and why are they important?
SAA (serum amyloid A)
C reactive protein
Fibrinogen
These molecules in the blood are an indicator that there is inflammation
Describe why erythrocytes sedimentation rate is important
Increased sedimentation rate indicates that there is fibrinogen bound to RBCs –> inflammation
What is leukocytosis and what does it indicate?
Outline the different ones (3)
This is increased leukocytes in the blood
Neutrophillia: bacterial infection
Eosinophilia: hypersensitivities, parasite infection
Lymphoctosis: viral infection
Why is there decreased sweating, rigors and chills during systemic acute phase reaction?
This is related to the change of the body’s temperature set point
What causes anorexia during system acute phase reaction?
Cytokine action on the brain
What is cachexia?
What is the mechanism?
This is mobilisation of the body’s fat stores due to TNF –> wasting
What is sepsis?
This is large amounts of microbes in the blood
What is the outcome of sepsis?
- Vasodilation of the entire vascularisation –> hypotensive shock
- Hypoglycaemia
- Disseminated intra vascular coagulation (small blood clots)
What causes hypotensive shock?
Widespread vasodilation, due to many cytokines circulating in the blood
What are the different morphologies of acute inflammation?
Serous
Fibrinous
Supparative
Describe the features of serous inflammation
Serous membranes (pleural, peritoneal, pericardial) surround the serous cavity, which is filled with a transudate
When is serous inflammation seen?
Burns
Viral infections
What is the mechanism of fibrinous inflammation?
- Increased vascular permeability –>
2. Large deposits of fibrinogen from the exudate
How is fibrinous inflammation resolved?
Fibrinolysis
Macrophages clean up the debris
When does fibrinous inflammation occur?
Meningitis
Pleurisy
Pericarditis
What is the appearance and structure of supparative inflammation, and why is this so?
Abscesses of pus
The green colour is from the myeloperoxidase from the PMN
When does supparative inflammation occur?
Pyogenic bacterial infection; staphylococci
What is ulceration?
This is the loss of layers of tissue from the surface
What causes ulceration?
Necrosis or inflammation
Where can ulceration occur?
Mucosa of the mouth
Gastrointestinal tract
Genitourinary tract
Lower extremities if circulation is poor
What are the clinical symptoms of systemic acute phase inflammation?
Broadly, what causes these symptoms?
Fever
Myalgia
Arthralgia
Anorexia
These are caused by the host’s response to injury, not the injury itself
What is collectin?
Collectin is a protein that binds to a sugar on the coat of a microbe
