Prostacyclin Vasodilator Hyperalgesic Stops platelet aggregation

Thromboxane A₂ Vasoconstrictor

Prostaglandin F₂ Bronchoconstrictor Myometrial contraction Vascular permeability Leukocyte chemotaxis

Prostaglandin D₄ Prevent platelet aggregation Vasodilator Vascular permeability Leukocyte chemotaxis

Prostaglandin E₂ Pyrogen - fever induced Vasodilator Hyperalgesic Vascular permeability Leukocyte chemotaxis

Lecture 4 - Acute inflammation: Mediators Flashcards by Damari Martin

Neutrophils: what do they do?

Phagocytosis
Generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS)

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Monocytes: what do they do?

Phagocytosis
Generation of cytokines, chemokines, ROS and RNS, prostaglandins, complementary proteins, and annexin-1

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Mast cells: what do they do?

Histamine, heparin, enzymes (tryptase, chymase), and TNF-α
Prostaglandins, leukotrienes, and cytokines

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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

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Platelets: what do they do?

Coagulation
Synthesis of serotonin, TXA₂, PAF, free radicals, and proinflammatory proteins
PDGF - repair

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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

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How do mast cells produce histamine?

Degranulate and form histamine

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Where is the majority of serotonin produced?

Platelets

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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

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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

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PGI₂

Prostacyclin

Vasodilator
Hyperalgesic
Stops platelet aggregation

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TXA₂

Thromboxane A₂

Vasoconstrictor

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PGF₂

Prostaglandin F₂

Bronchoconstrictor
Myometrial contraction
Vascular permeability
Leukocyte chemotaxis

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PGD₂

Prostaglandin D₄

Prevent platelet aggregation
Vasodilator
Vascular permeability
Leukocyte chemotaxis

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PGE₂

Prostaglandin E₂

Pyrogen - fever induced
Vasodilator
Hyperalgesic
Vascular permeability
Leukocyte chemotaxis

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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

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)