Acute and Chronic Inflammation Part 2 Flashcards
Recap the 5 steps of the inflammatory response
1. Recognition 2, Recruitment 3. Removal 4. Regulation 5. Resolution
What is removed in an inflammatory response?
The agent causing the injury
What is activated during the removal step of inflammation
Leukocytes are activated, with enhanced capability to carry out their functions
What are some of the function of leukocytes during the removal phase of inflammation?
- Phagocytosis
- Secretion of microbicidal substances to remove extracellular inflammatory agent
- Release of extracellular traps
- Amplification of inflammatory response
What is the release of extracellular traps called?
Netosis
Which cells carry out Netosis
Neutrophil attack cells
What happens to cells that carry out netosis?
They die
Briefly go though the stages of phagocytosis
check slide 6 pic
- Phagocytic receptors recognise microbes or dead cells
- Microbes bind to phagocyte receptors
- Phagocyte membrane zips up around the microbe engulfing it
4 The phagosome with the ingested microbe sudeswith a lysosome forming a phagolysosome - Microbe is killed by ROS and NO
- Microbe is degraded by lysosomal enzymes in rate phagolysosome
What happens in a respiratory burst?
Superoxide is produced by the oxidation of NADPH and can also be converted into hydrogen peroxide and then hypochlorite (by MPO in neutrophils + macrophages)
What can super oxide react or do?
Superoxide can react with nitric oxide to produce peroxynitrite
Go though some damage that pathogens can carry out
- Lipid perooxidation leading to membrane damage
- Protein modifications leading to breakdown and misfiling of protein
- DNA damage leading to mutations
What extracellular activity occurs in the bosy?
- Secretion of enzymes fro neutrophil azurophilic granule
- Release of lysosomal enzymes and ROS and NO during phaogcytisus
- Secretion of chemokine and cytokines to recruit and activate macrophages
- Netosis
What does the NET in NETosis stand for?
Neutrophil extraceullar traps
What os NETosis stimulated by?
Stimulated by microbes and inflammatory signals
Which blood cells are the most predominant during acute inflammation?
Our innate white blood cells (Neutrophils, macrophages)
What process occurs alongside phagocytosis?
Respiratory burst
What is thE outcome of the respiratory burst?
Reactive oxygen species are produced
These species can kill microbes BUT also cause damage to host cells
How can reactive oxygen species damage our host cells
- Can damage our membranes as lipid peroxidation occurs
- Proteins can be damaged so incorrect folding may occur
- Can cause break in our DNA
What can prolonged spells of inflammation lead to?
Cancer possibly due to t the fact that inflammation produced reactive oxygen species which can lead to breaks in our DNA
Give examples of some microbicidal substances that are produced during an inflammatory response
- Enzymes are secreted from neneutrophil azurophilic granules
- lysosomal enzymes, Reactive oxygen species and nitric oxide are produced during phagocytosis
- Chemokines and cytokines are secreted to recruit and activate macrophages
What is NETosis?
The generation of Neutrophil Extracellular Traps (NETs)
What is NETosis stimulated by?
Microbes and inflammatory signals
What happens in NETosis?
Neutrophils are stimulated to release Neutrophil Extracellular Traps (NETs)
What are Neutrophil Extracellular Traps (NETs) made of?
Made up of nucleosomal DNA and complex with our histories
How are Neutrophil Extracellular Traps (NETs) produced?
- Neutrophils are stimulated
- Results in the formation of NADPH-oxidase and reactive oxygen species produced
- PAD4 is activated
- Nucelar chromatin decondenses and the nuclear envelope integrity is lost
- Nuclear materia fills the cell and mixes with granule content
- Nuclear and granule membrane integrity is lost and the palsma membrane ruptures
- Nuclear chromatin associated with proteinases and hastens is released into the extracellular space (these are the NETs)
How do Neutrophil Extracellular Traps (NETs) aid inflammation?
Extruded DNA produced by neutrophils form a dense net of fibres which have microbicidal molecules attached to trap and destroy microbes.
Give examples of microbicidal molecules that are attached to Neutrophil Extracellular Traps (NETs)
- Elastase
- Myloperoxidase
- Cathespsin G
- Antimicrobial peptides (LL37)
- Proteinase 3
What happens to the neutrophils after they have produced their NETS
They die :(
Where have large quantities of NETs been found in the body?
found in purulent GCF exudate in periodontitis
What does PAD stand for in PAD4?
Protein arginine deiminase
Which process does PAD4 have an important role in?
Netosis
How does PAD4 aid NETosis?
The arginine in PAD4 makes a key change to the histone proteins that hold our DNA together
arginine amino acids are altered to citrulline in the DNA sequence
This changes the electrostatic charge of the molecule causes the DNA to condense
Why does the alteration of arginine into citrulline have a significant effect on our cells?
As arginine is positively charged and citrulline is neutral
This change in electrostatic charge means that DNA condenses
Name some chemical mediators of inflammation
- Vasoactive amines
- Arachidonic metabolites
- Cytokines and chemokines;
- Lysosomal enzymes;
- Nitric oxide
- Reactive oxygen species
- Compliment proteins
- Coagulation proteins
- Kinins
Give examples of Vasoactive amines
histamine / seratonin
How do Vasoactive amines like histamine regulate the inflammatory response?
They cause:
Vasodilation and vascular permeability
Give examples of Arachidonic metabolites
prostagladins / leukotrienes
How do Arachidonic metabolites like prostagladins regulate the inflammatory response?
They cause:
Vascular reactions
Chemotaxis
Give examples of Cytokines and chemokines;
TNF
IL-1
IL-6
CXCL8
How do Cytokines and chemokines like TNF regulate the inflammatory response?
They lead to:
Leukocyte recruitment
endothelial activation
Give examples of lysosomal enzymes
NE
PR3
Collagenase
CG
How do lysosomal enzymes regulate the inflammatory response
They are Microbicidal and cause tissue injury
How does nitric oxide regulate the inflammatory response
It causes vasodilation and is microbicidal
How do reactive oxygen species regulate the inflammatory response
They are microbicidal and lead to tissue injury
How are chemical mediators of inflammation categorised?
By where they are produces:
- Local to the site of inflammation
- In the liver and then transported to the inflammation site where they are activated
Which Chemical mediators of inflammation are produced local to the site of inflammation?
- Vasoactive amines
- Arachidonic metabolites
- Cytokines and chemokines;
- Lysosomal enzymes;
- Nitric oxide
- reactive oxygen species
Which Chemical mediators of inflammation are produced in the liver?
- Compliment proteins
- Coagulation proteins
- Kinins
How do Compliment proteins regulate the inflammatory response
They cause Leukocyte chemotaxis, opsonisation, MAC
How do Coagulation proteins regulate the inflammatory response
They lead to:
Endothelial activation
leukocyte recruitmen
How do Kinins regulate the inflammatory response
They lead to:
Vascular reactions and pain
Which molecules induce the acute phase response?
IL-1 β
IL-6
TNF-α
Which cells and parts of the body are affected by IL-1 β, IL-6, TNF-α ?
- Liver
- Bone marrow endothelium
- Hypothalamus
- Fat and muscle
- Dendritic cells
How is the liver affected by IL-1 β, IL-6, TNF-α ?
Acute phase proteins are produced which activate compliment and lead to opsonisation
How is the Bone marrow endothelium affected by IL-1 β, IL-6, TNF-α ?
Neutrophils are mobilised leading to increased phagocytosis
How is the Hypothalamus affected by IL-1 β, IL-6, TNF-α ?
Body temperature is increased this leads to:
- Decreased viral and bacterial replication
- Increased antigen processing
- Increased specific immune response
How is the Fat and muscle affected by IL-1 β, IL-6, TNF-α ?
Protein and energy is mobbed to allow the body temperature to increase. this leads to
1. Decreased viral and bacterial replication
2. Increased antigen processing
3. Increased specific immune response
:
How is are Dendritic cells affected by IL-1 β, IL-6, TNF-α ?
TNF alpha is stimulated to migrate to lymph nodes and mature
This leads to the initiation of the adaptive immune response
Which organ releases acute phase proteins?
The liver
Name some acute phase proteins
- Serum amyloid protein
- C reactive protein
- Fibrinogen
- Mannose binding lectin
What do C reactive proteins do?
They bind to phosphocholine on bacterial surfaces acting as an opsonin and also activates complement
What do mannose binding lectin do?
They bind to mannose residues on bacterial surfaces acting as an opsonin and also activate complement
The the 2 enzymes that aid arachidonic acid metabolism?
- Cyclooxygenase
2. 5-Lipoxygenase
What does Cyclooxygenase metabolise arachidonic acid into into?
- Prostacyclin (PGI2)
- Thromboxane A2 (TXA2)
- Prostaglandins
What does 5-Lipoxygenase metabolise arachidonic acid into into?
- Leukotriene
2. Lipoxin
What is significant about arachidonic acid metabolism?
Arachidonic acid metabolites are important mediators of inflammation
How do prostaglandins contribute to inflammation?
They increase our sensitivity to pain
Initiate fever
What is Thromboxane responsible for?
Cause vasoconstriction
Promotes platlets aggrgation
Which cells metabolise arachidonic acids using Lipoxygenase?
Neutrophils
What do Leukotriene play an important role in?
- Important for chemotaxis
2. Change the permeability of our vascular
How do anti inflammatory drugs work?
They work by inhibiting the metabolism of arachidonic acid via the Cyclooxygenase pathway
Give examples of aninflammatory drugs that work by inhibiting the Cyclooxygenase pathway of arachidonic acid metabolism
- Aspirin
- brufen
- Neproxin
Does the loss of mediators switch off the signal for inflammation?
No just the loss of mediators is not sufficient to stop the inflammatory response
What initiates the resolution of inflammation response?
A class switch in the production of mediator molecules to produce Immunoresolvents
Give examples of Immunoresolvents
- IL-10
- Resolvins
- Lipoxins
- Protectins
- Maresins
What do Lipoxins do?
They inhibit neutrophil adhesion and inhibit chemotaxis
This switches off the inflammatory response
What events occur during the resolution phase of inflammation
- Stimulus has ben removed
- Inflammation signals subside
- secrete inflammatoire IL-10
4 Lipid mediator class switch produces Lipoxins and Resolvins which inhibit of leukocyte infiltration.
What is chronic inflammation?
Chronic inflammation refers to an inflammatory response of prolonged duration
What needs to occur simultaneously for chronic inflammation to occur
these events will occur simultaneously:
- continuing inflammation
- tissue injury
- attempts at repair by fibrosis and angiogenesis
What are the causes of chronic inflammation?
- Persistent infections
- Immune mediated inflammatory disease
- Prolonged exposure to toxic agents
What does the failure to resolve acute inflammation lead to?
Changes in the cel infiltrate which leads to chronic inflammation
Give some characteristics of chronic inflammation
- infiltrate prodominently made up of Mononuclear cells
- Tissue destruction
- Granulomatous tissue
- Fibrosis
Which cells makes up the majority of the infiltrate in chronic inflammation?
Macrophages
Give an example of a disease which presents both acute and chronic inflammation
dental abscesses
Site of acute inflammation isn’t resolved which results in monocytic cells surrounding and “wall off” PMNs so theres some chronic and acute inflammation
Name the 2 types of macrophages
- Pro inflammatory
2. Anti inflammatory
How are monocytes stimulated to form macrophages?
By:
1. Microbes and INF gamma (Classically activated)
or
2. IL-13 and IL-4 (alternatively activated)
What is INF gamma?
Interferon gamma
What is INF gamma produced by?
CD4 T cells
T helper 1 cells
Macrophages activated by Microbes and INF gamma become what?
Classically activated macrophage 1 (M1)
Macrophages activated by IL-13 and IL-4 become what?
Alternatively activated macrophage 2 (M2)
Which macrophage M1 or M2 is pro inflammatory?
Classically activated macrophage 1 (M1)
What are the functions of M2?
- Microbicidal actions like increasing phagocytosis
2. Inflammation
What does M1 release?
It is pro inflammatory so it releases:
- Reactive oxygen species
- Nitric oxide
- Lysosomal enzymes
- iL-1 IL-12 IL-23 and chemokines
What effect do IL-1 IL-12 IL-23 and chemokine have on the body?
They cause inflammation
What effect do Reactive oxygen species and Nitric oxide have on the body?
They have a microbicdal action:
- Phagocytosis
- Killing of bacteria and fungi
What are the functions of M2?
- Repairs tissue
- Fibrosis
- Anti inflammatory effect s
What type of macrophage is M2
It is anti inflammatory
What does M2 release
- Growth factors TGF beta
2. IL-10
There is a B__________ d_____________ between our lymphocytes and macrophages
Bidirectional interaction
What does the Bidirectional interaction between our lymphocytes and macrophages sustain?
It fuels and sustains chronic inflammation
Give examples of inflammatory diseases
- Periodontitis
- Rheumatoid arthritis
- Athersclerosis
- Diabetes
What Is Periodontitis linked with?
Thought to have a negative impact and have and increased risk of getting:
- Cardiovascular disease
- Rheumatoid arthritis
- Inflammation induced pregnancy complications
Has a negative impact on diabetes
