Lecture 4 - Acute inflammation: Mediators Flashcards
Neutrophils: what do they do?
- Phagocytosis
- Generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS)
Monocytes: what do they do?
- Phagocytosis
- Generation of cytokines, chemokines, ROS and RNS, prostaglandins, complementary proteins, and annexin-1
Mast cells: what do they do?
- Histamine, heparin, enzymes (tryptase, chymase), and TNF-α
- Prostaglandins, leukotrienes, and cytokines
Endothelial cells: what do they do?
- Release of nitric oxide
- Expression of adhesion molecules (leukocyte binding)
- Synthesis of prostaglandins, clotting factors, and cytokines
- Angiogenesis in the resolution of inflammation and chronic inflammation
Platelets: what do they do?
- Coagulation
- Synthesis of serotonin, TXA₂, PAF, free radicals, and proinflammatory proteins
- PDGF - repair
Chemical mediators: vasoactivators
Autacoids - substances that have a brief, localised effect in the body:
* Histamine
* Serotonin (5-HT (5-hydroxytryptamine))
* Kinins - kallikrein cleaves kininogens (pain)
* Eicosinoids
How do mast cells produce histamine?
Degranulate and form histamine
Where is the majority of serotonin produced?
Platelets
Eicosanoids: what are they, what are the three main ones,
Lipid mediators that are produced from fatty acid precursors when required and not stored preformed in cells like with histamine
Prostaglandins, thromboxanes, and leukotrienes
How are eicosanoids formed?
Phospholipase A2 gets phosphorylated and converts arachidonic acid into any of the eicosanoids
- Cyclooxygenase will perform prostaglandins and thromboxane A2
- Lipoxygenase will form leukotrienes
PGI₂
Prostacyclin
- Vasodilator
- Hyperalgesic
- Stops platelet aggregation
TXA₂
Thromboxane A₂
- Vasoconstrictor
PGF₂
Prostaglandin F₂
- Bronchoconstrictor
- Myometrial contraction
- Vascular permeability
- Leukocyte chemotaxis
PGD₂
Prostaglandin D₄
- Prevent platelet aggregation
- Vasodilator
- Vascular permeability
- Leukocyte chemotaxis
PGE₂
Prostaglandin E₂
- Pyrogen - fever induced
- Vasodilator
- Hyperalgesic
- Vascular permeability
- Leukocyte chemotaxis
LTC₄, LTD₄, LTE₄
Leukotriene C₄, leukotriene D₄, and leukotriene E₄
- Activated neutrophils
- Generates ROS
- Release of lysosomal enzymes
- Bronchoconstrictors
- Vasoconstrictors
- Increase vascular permeability
LTB₄
Leukotriene B₄
- Chemotaxin (chemotaxis?)
- Activate neutrophils
- Generates ROS
- Release of lysosomal enzymes
Lipoxins: relation to the other eicosanoids and function
While the others are pro-inflammatory, lipoxins are anti-inflammatory and inhibit neutrophil chemotaxis and adhesion
PAF: what is it, what is it produced by, and how much more effective is it than histamine?
Platelet-activated factor - not formed from arachidonate - not an eicosanoid (but often grouped with them)
Produced by basophils, macrophages, mast cells, neutrophils, endothelial cells, and platelets
100-10,000x more potent than histamine at inducing vasodilation and increasing vascular permeability
TNFα: what are they produced by and what do they do?
- Macrophages
- Monocytes
- Mast cells
- T lymphocytes
Local effects:
* Vascular endothelium - Increased procoagulant, decreased anticoagulant, leukocyte adhesion molecule expression, and IL-1 cytokine production - Inflammation
* Leukocytes - activation, production of cytokines - Inflammation
* Fibroblasts - proliferation, collagen synthesis - Repair
Systemic effects:
* Fever - IL-6
* Leukocytosis - IL-6
* Acute phase proteins - IL-6
* Increased sleep
* Decreased appetite
IL-1β: what are they produced by and what do they do?
- Macrophages
- Monocytes
- endothelium
- Dendritic cells
- Some epithelia
Local effects:
* Vascular endothelium - Increased procoagulant, decreased anticoagulant, leukocyte adhesion molecule expression, and IL-1 cytokine production - Inflammation
* Leukocytes - activation, production of cytokines - Inflammation
* Fibroblasts - proliferation, collagen synthesis - Repair
Systemic effects:
* Fever - IL-6
* Leukocytosis - IL-6
* Acute phase proteins - IL-6
* Increased sleep
* Decreased appetite
IL-6: what are they produced by and what do they do?
- Macrophages
Systemic effects (acute phase proteins)
Chemokines: what are they produced by and what do they do?
Macrophages, T lymphocytes, endothelium, and mast cells
Leukocyte recruitment
Chemokine nomenclature
- C-chemokines; one cysteine (specific for recruiting lymphocytes)
- C-C chemokines: where there are two adjacent conserved cysteine residues
- C-X-C chemokines: one amino acid separating the first two conserved cysteine residues - Act primarily on neutrophils to cause activation and chemotaxis of neutrophils, IL-8 is a prime example - Predominantly involved in acute inflammatory responses
- C-XXX-C chemokines: contain three amino acids between the two cysteines
Acute phase proteins: what causes their release, what do they cause to occur, and what do they do?
Release caused by interleukins, e.g., IL-1, IL-6, TNFα
- 2-5 fold ↑: fibrinogen, mannose-binding lectin (see PRR) and complement (C3b)
- 100-1000 fold ↑: serum amyloid, C-reactive protein (CRP)
Opsonisation: form link between microbe & phagocyte
Activation of complement cascade
Complement cascade: what is it, what three pathways activate it, what are the major proteins, and what does it cause?
The body’s reaction to infection using antibodies and phagocytes to destroy microbes
Classical (C1, Antibody, Antigen), lectin (microbes + mannose-binding lectin), and alternative (LPS/endotoxin) pathways
9 major protein components: C1 – C9
activate the proteolytic cascade and links with coagulation & fibrinolytic cascade
Complement cascade: the process
C3 interacts with C3 convertase, either forming C3a (resulting in inflammation, chemotaxis, and releases histamine/spasmogen)or C3b (phagocytosis - opsonin)
C3b can then form either C5a (Inflammation: chemotaxis, activates phagocytic cells, releases histamine) from C5 convertase or C5/C6/C7/C8/C9 which lyse bacteria
Phagocytosis: the process
- Microbe binds to phagocyte receptor
- Microbe brought into the cell in a phagosome using opsonin
- Phagosome and lysosome fuse
- Microbe is then killed: lysosomal enzymes lyse the microbe or ROS and NO kills the microbe
Reactive oxygen species
Activated by NADPH oxidase which oxidises NADPH into NADP⁺ and produces the superoxide anion (O₂*⁻) from oxygen
The superoxide can then do two different pathways to form ROS:
* Forming H₂O₂ -> myeloperoxidase causes a halide to form which reacts with H₂O₂ -> HOCl/OCl⁻ and OH*
* Nitric oxide synthase (iNOS) converts arginine into nitric oxide which forms OONO*
ROS: what are the examples, what do they do, and how are they controlled?
Peroxynitrite, hydroxyl radical, hypochlorite, superoxide, and H₂O₂
Intracellular destruction of pathogens, activating chemokines, cytokines, and adhesion molecules
- SOD: O₂*⁻ -> H₂O₂
- Catalase: H₂O₂ -> H₂O
- MPO: H₂O₂ -> HOCl
NOS: what is it produced by, which is the main one in inflammation, and what
NO synthase (NOS) - endothelial (eNOS) and neural (nNOS)
iNOS - important in inflammation
bacterial lipopolysaccharide
cytokines
Nitric oxide: how does it cause vasodilation,
It binds to the haem of guanylyl, converting GTP into cGMP which causes vasodilation
L-arginine + O₂ is catalysed by NO synthase -> L-citrulline + NO + superoxide anion (O₂*⁻) -> cytotoxic peroxynitrite anion
Inflammatory response: Vasodilation key chemical mediators
- Histamine and serotonin/5-HT
- Kinins
- Prostaglandins (PGI2, D2, E1 & E2)
- NO
Inflammatory response: Vascular permeability key chemical mediators
- Histamine and serotonin/5-HT
- NO
- Kinins
- C3a and C5a (indirect action by liberating vasoactive amines from mast cells)
- Leukotrienes C4, D4, E4
Inflammatory response: Chemotaxis, leukocyte recruitment and activation key chemical mediators
- TNF, IL-1
- Chemokines
- C3a, C5a
- Leukotriene B4
Inflammatory response: Fever key chemical mediators
- IL-1, TNF
- Prostaglandins
Inflammatory response: Pain key chemical mediators
- Prostaglandins (PGI₂, E₂)
- Bradykinin
Inflammatory response: Tissue damage key chemical mediators
- Lysosomal enzymes
- Reactive oxygen species
- LTB4 (indirectly via release of lysosomal enzymes)
