Lecture 8: Acute Inflammation: Blood Flow Flashcards
What are the 4 cardinal signs of inflammation?
Heat
Swelling
Pain
Redness
What is inflammation a response of?
Injury and infection
List the roles of inflammation
- delivers nutrients and oxygen to injured sites
- generates an exudate where toxins may be transported out of an affected area
- generates exudate which carries antibodies and other substances into affected area to neutralise harmful agents
- mobilises work force to remove debris after an injury
- mobilises defence force to eradicate harmful agents
- limits spread of harmful agents
- provides hydrolytic enzymes to digest inflammatory exudates when crisis is over
- initiates repair
What are the three types of ‘go’ signals that tissue damage unleashes?
- Neurons which release bioactive peptides in response to pain
- Broken cells which release intracellular molecules signalling the presence of damage
- Microbial products which are recognised as pathogen associated molecular patterns by pattern recognition receptors.
What are some examples of microbrial products?
Endotoxins, LIPS
What signals/intracellular molecules are released by broken cells?
damage/danger associated molecular patterns (DAMPS)
what are DAMPS and PAMPS sensed by?
pattern recognition receptors
What type of receptors are pattern recognition receptors?
they may be soluble proteins (complement) or cell bound (toll like receptors, TLRs)
Which tissue resident cells rapidly respond to the 3 types of ‘go’ signals?
Mast cells (or basophils) and macrophages
how do mast cells and macrophages initiate inflammtory responses?
- release inflammatory mediators, lipid derived signals and cytokines
what are some examples of inflammatory mediators that mast cells and macrophages release to initate an inflammatory response?
histamine, proteases, tryptases
what is an example of a cytokine that mast cells and macrophages release
tumour necrosis factor
describe mast cells
they are full of granules (storage organelles)
what do the signals released by mast cells and macrophages cause?
a rapid change in microvascular system
an elect i the redness-heat-swelling-pain response
What does vasodilation occur with
the relaxation of smooth muscles surrounding arterioles.
this increases diamter of vessles,
allowing increased blood flow into capillary network.
this casues redness and heat
what is hyperanemia
increased blood
most blood vessels are lined with what?
endothelial epithelium
what are the endothelial cells closely connected by
tight junctions and adherens junctions
When does vascular permeability occur?
when endothelial cells retract to create gaps in the endothelial lining
what happens following mild injury such as an insect bite (in relation to endothelial cells)
Inflammatory signals cause endothelial cells of small venules to rapidly and reversibly retract
what happens when these ECs retract?
gaps of 0.1-0.4 micrometer size are created between cells
what is significant about the creation of these gaps between ECs?
Gaps allow fluid and solutes (including proteins) to pass through
what is the protein rich fluid called?
inflammatory exudate
What does more severe injury lead to (in relation to endothelial cells)
EC damage and detachment from basement membrane. This results in persistent increases in vascular permeability
what happens in delayed vascular permability in relation to ECs following severe injury
leakage occurs from capillaries and venules
What are some examples of delayed EC damage following severe injury
sunburn, xrays, bacterial toxins
what happens in immediate vascular permeability in relation to ECs following severe injury
Leakge from all types of vessles occurs until vessl is blocked with clot or repaired
Give an example of what would cause immediate vascular permeability following severe injury
burns, trauma
What are the three types of ‘go’ signals that tissue damage unleashes?
- Neurons which release bioactive peptides in response to pain
- Broken cells which release intracellular molecules signalling the presence of damage
- Microbial products which are recognised as pathogen associated molecular patterns by pattern recognition receptors.
What are some examples of microbrial products?
Endotoxins, LIPS
What signals/intracellular molecules are released by broken cells?
damage/danger associated molecular patterns (DAMPS)
what are DAMPS and PAMPS sensed by?
pattern recognition receptors
What type of receptors are pattern recognition receptors?
they may be soluble proteins (complement) or cell bound (toll like receptors, TLRs)
Which tissue resident cells rapidly respond to the 3 types of ‘go’ signals?
Mast cells (or basophils) and macrophages
how do mast cells and macrophages initiate inflammtory responses?
- release inflammatory mediators, lipid derived signals and cytokines
what are some examples of inflammatory mediators that mast cells and macrophages release to initate an inflammatory response?
histamine, proteases, tryptases
what is an example of a cytokine that mast cells and macrophages release
tumour necrosis factor
describe mast cells
they are full of granules (storage organelles)
what do the signals released by mast cells and macrophages cause?
a rapid change in microvascular system
an elect i the redness-heat-swelling-pain response
What does vasodilation occur with
the relaxation of smooth muscles surrounding arterioles.
this increases diamter of vessles,
allowing increased blood flow into capillary network.
this casues redness and heat
what is hyperanemia
increased blood
most blood vessels are lined with what?
endothelial epithelium
what are the endothelial cells closely connected by
tight junctions and adherens junctions
When does vascular permeability occur?
when endothelial cells retract to create gaps in the endothelial lining
what happens following mild injury such as an insect bite (in relation to endothelial cells)
Inflammatory signals cause endothelial cells of small venules to rapidly and reversibly retract
what happens when these ECs retract?
gaps of 0.1-0.4 micrometer size are created between cells
what is significant about the creation of these gaps between ECs?
Gaps allow fluid and solutes (including proteins) to pass through
what is the protein rich fluid called?
inflammatory exudate
What does more severe injury lead to (in relation to endothelial cells)
EC damage and detachment from basement membrane. This results in persistent increases in vascular permeability
what happens in delayed vascular permability in relation to ECs following severe injury
leakage occurs from capillaries and venules
What are some examples of delayed EC damage following severe injury
sunburn, xrays, bacterial toxins
what happens in immediate vascular permeability in relation to ECs following severe injury
Leakge from all types of vessles occurs until vessl is blocked with clot or repaired
Give an example of what would cause immediate vascular permeability following severe injury
burns, trauma
What pushes fluid from capillaries at arteriolar end normally?
Hydrostatic pressure normally forces fluid out this way
What happens during inflammation in terms of hydrostatic pressure
Increased hydrostatic pressure in capillaries + increased water binding capacity of proteins in exudate => retained fluid in the extravasulcar space between cells
What is the extra vascular space between cells called?
The interstitium
What does accumulated fluid generate?
Swelling, aka oedema
What is the result of oedema ?
Stretches tissue and along with chemical mediators, causes pain
Give some examples of chemical mediators
PGE2 and bradykinin
During inflammation, Where are chemical signals which control blood vessel function secreted?
Locally, by cells
During inflammation, What are chemical signals that control blood vessel function also derived from?
Circulating plasma proteins
Where is histamine stored?
In performed granules of mast cells/basophils and platelets
What does histamine release cause?
Vasopermeability
Endothelial adhesion
Synthesis of lipid mediators
Bronchi constriction
Give a situation in which vasopermeability occurs as a result of histamine release
The watery fluid experienced by a runny nose when having cold or hayfever is called exudate
What is endothelial adhesion for?
To make it easier for neutrophils
What are examples of lipid mediators which are synthesised as a result of histamine release
Prostacyclin I2
And platelet-activating factor (PAF)
These lead to vasodilation
What is histamine?
A vasoactive amine
Where are serine proteases released from?
Mast cells
What do serine proteases cleave?
Protease-activated receptors (PARs) on other mast cells, endothelium and neutrophils
What happens as a result of PAR cleavage?
The same results as histamine release,
Vasopermeability
Endothelial adhesion for leu yes
Platelet activating factor release with vasodilation
Probably also involved in bronchonconstriction
What is an example of a tryptase?
Serine protease
What do inflammatory signals acting through intracellular Ca2+ activate?
Cytosolic phospholipase A2 (PLA2)
What does cytosolic phospholipase A2 (PLA2) do?
Cleaves membrane phospholipids like phosphatidylcholine into lysophosphatidylcholine and arachidonic acid
What is PLA2
Phspholipase A2
What is an arachidonic acid?
A 20Carbon unsaturated fatty acid
What is platelet activating factor derived from?
Lysophosphatidylcholine
Where is PAF found?
In activated inflammatory cells,
endothelial cells and
injured tissue cells
What are the functions of PAF
Increase permeability and vasodilation
Activate and aggregate platelets
Leukocyte adhesion and chemotaxis - reduce blood loss
Describe the type of response arachidonic acid generates
Rapid, short half life, short range derivatives
What are the two derivatives of arachidonic acid
Cyclooxygenases & 5-lipooxygenases
What is COX1/2
Cyclooxygenases, a derivative of arachidonic acid
What do cyclooxygenases generate?
Prostaglandins
What are some examples of prostaglandins generated by cyclooxygenases?
Thromboxanes
Prostacyclins
What are cyclooxygenases inhibited by?
Non steroidal anti-inflammatory drugs (NSAIDs)
What are some examples of NSAIDs
Aspirin, ibuprofen/neurofen, diclofenac/voltaren
What is 5-lipoxygenase?
The other derivative of arachidonic acid
What does 5-lipoxygenase generate?
Leukotrienes
What does LTB4 potentially recruit?
Neutrophils
What is LTB4
Leukotriene B4
What were cysteinyl leukotrienes called?
Slow reacting substance if anaphylaxis
What do cysteinyl LTs induce?
Vasopermeability and bronchoconstriction
List the agents which are of prostaglandin class
Thromboxane, PCI2 and PGE2
What does TXA2 induce
Vasoconstriction, platelet aggregatoon
What does PCI2 induce
Vasodilation, platelet disaggregation
What does PGE2 induce?
Vasodilation, pain
What are agents of the leukotrienes class?
LTB4 and cysLTC4, D4, E4,
What does leukotrieneB4 induce?
Neutrophil chemotaxis and activation
Which agents induce vasopermeability and bronchoconstriction
Cysteinyl leukotrienes C4, D4 and E4
Where to components of interconnected inflammatory signalling cascades circulate?
In the blood
What do proteolytic events activate
The coagulation of fibrinolytic, Kinin and complement cascades
What do proteolytic events lead to
Rapid development of inflammation with potent vasoactive effects
Name the four types of interconnected inflammatory cascades
- Coagulation
- Fibrinolytic
- Kinin
- Complement
The coagulation cascade is induced following damage to what?
Vascular endothelium
Where is tissue factor released
- From apoptotic endothelial cells on micro particles and
2. From exposed basement membrane
What does tissue factor release lead to?
Activation of thrombin
What does thrombin do?
- It cleaves soluble fibrinogen into fibrin
2, cleaves protease activated receptors
What is the importance of fibrin?
Traps platelets and other cells to form clots with the arrest of bleeding (haemostasis)
What do PARs do?
Induce vascular permeability,
platelet activating factor release with vasodilation,
Leukocyte adhesion like mast cell tryptases
What does hageman factor do?
Activates thrombin to propagate clots as thrombi which may occlude blood vessels
How is FXII activated?
In vino
By poly phosphates from activated platelets,
Heparin from mast cells or
RNA from damaged cells
What does fibrinolytic system generate?
The protease plasmin
What does plasmin do?
- Degrades fibrin (which allows blood flow to occur again)
- Cleaves extracellular matrix proteins
- Activates matrix metalloproteases - remodelling tissues during wound healing
- Cleaves cell surface receptors to induce release of inflammatory signals
What are MMPs
Matrix metalloproteases
What does FXII mediate?
Proteolytic activation of the protease kallikrein
What does the protease kallikrein do?
It releases the peptide bradykinin ( from the Kinin system)
What effects does bradykinin have?
Vascular dilation,
Vascular permeability
Pain inducing
What is the antimicrobial complement system activated by ?
Proteases, antigen-antibody complexes, and bacterial products
List some proteolytic cleavage products
C3a, C3b, C5a and components of a membrane attack complex
List the functions of the complement system
- Mast cell degranulation, vascular permeability, neutrophil chemotaxis (by C3a and C5a)
- Opsonisation - the promoting of phagocytosis of particles (by C3b)
- Part of membrane attack complex for bacterial cell lysis (by C5b)
