Mediators of Inflammation

Slide 1 · Mediators of Inflammation

Vascular response • leukocyte recruitment • regulatory circuits

From initiating stimuli to amplified—and ultimately resolved—inflammation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Classify inflammatory mediators by origin and activation mechanism.

Link individual mediators to vascular changes, leukocyte recruitment, pain, and fever.

Explain mediator amplification, redundancy, and termination.

Connect mediator biology with representative therapeutic and disease implications.

Slide 3 · Inflammatory mediators: The central concept

Tissue infection or injury

Mediator generation

Vascular and cellular responses

Pathogen clearance or tissue injury

Slide 4 · Four major families organize acute inflammation

Mediator class

Representative examples

Dominant functions

Vasoactive amines

Histamine

Early vascular change

Eicosanoids

Prostaglandins, leukotrienes

Vessels, pain, fever, recruitment

Cytokines / chemokines

TNF, IL-1, CXCL8

Endothelial and leukocyte activation

Complement fragments

C3a, C5a, C3b

Inflammation, opsonization

Slide 5 · Cell-derived versus plasma-derived mediators

Cell-derived

Stored granules: Rapid release of histamine

Newly synthesized: Eicosanoids and cytokines

Produced at an inflammatory focus

Plasma-derived

Synthesized largely in liver

Circulate as inactive precursors

Activated through proteolytic cascades

Slide 6 · Preformed granules provide immediate signals

Trigger at tissue site

Mast-cell degranulation

Histamine release

Rapid vasodilation and permeability

Slide 7 · De novo mediator synthesis provides flexible responses

Microbial or injury signal

Intracellular signaling

Enzyme activation / gene expression

New lipid mediators or cytokines

Slide 8 · Sentinel cells initiate local mediator production

Source cell

Illustrative mediator output

Role

Mast cell

Histamine, lipid mediators

Rapid vascular response

Macrophage / dendritic cell

TNF, IL-1, chemokines

Recruitment and amplification

Endothelial cell

Eicosanoids, chemokines

Local vascular regulation

Neutrophil / platelet

Lipid mediators, PAF

Recruitment and cross-talk

Slide 9 · Mediator generation is stimulus dependent

Microbes or necrotic cells

Recognition by sentinel cells

Mediator release or synthesis

Spatially focused response

Slide 10 · Short half-lives limit collateral injury

Most inflammatory mediators act briefly and undergo rapid degradation or inactivation.

Release generally ceases when the initiating stimulus disappears.

Local generation and short-lived activity help restrict inflammation to the site of injury.

Active anti-inflammatory signals further promote termination.

Slide 11 · Amplification: Mediators activate other mediators

Complement C3a / C5a

Mast-cell histamine release

Venular permeability

Additional plasma mediator entry

Slide 12 · Redundancy makes inflammatory defense robust

Convergent effects

Histamine and leukotrienes: Permeability

TNF and IL-1: Endothelial activation

C5a and LTB₄: Leukocyte recruitment

Why it matters

Blocking one mediator may leave parallel pathways active

Overlapping pathways preserve host defense

Effects depend on cell type, location, and timing

Slide 13 · Map mediators to the response they produce

Tissue-level response

Illustrative important mediators

Vasodilation

Histamine; prostaglandins

Increased venular permeability

Histamine; LTC₄/LTD₄/LTE₄; bradykinin

Leukocyte recruitment

TNF, IL-1; chemokines; LTB₄; C5a

Pain and fever

PGE₂; bradykinin; IL-1 and TNF

Slide 14 · Histamine: A stored vasoactive mediator

Mast cells near small vessels are the richest tissue source.

Basophils and platelets also contain histamine.

Histamine is stored in preformed granules and can be released rapidly.

Its vascular effects dominate the immediate transient reaction.

Slide 15 · Three major routes to mast-cell degranulation

Physical injury, heat, cold

IgE-dependent activation

C3a / C5a signaling

Mast-cell histamine release

Slide 16 · Histamine H1 signaling changes microvessels

Histamine release

Endothelial H1 receptors

Arteriolar dilation + venular gaps

Increased blood flow and edema

Slide 17 · Why the immediate permeability phase is transient

Histamine opens interendothelial gaps principally in postcapillary venules.

Plasma proteins and fluid leave the intravascular compartment.

Histamine is rapidly inactivated; This early permeability response is short lived.

Other mediator families can sustain or add to subsequent vascular changes.

Slide 18 · Histamine receptors have distinct physiological roles

Receptor

Principal association

H1

Allergic response and microvascular effects

H2

Gastric acid regulation

H3

Modulation of neurotransmitter release

H4

Immune-cell functions

Slide 19 · Serotonin is not interchangeable with histamine

Histamine

Prominent mast-cell granule mediator

Arteriolar dilation and venular permeability

Well-established early inflammatory action

Serotonin

Found in platelets and neuroendocrine cells

Acts as a vasoconstrictor

Importance of this effect in inflammation is uncertain

Slide 20 · Clinical correlation: Rapid edema after allergen exposure

A patient develops raised, itchy wheals shortly after allergen exposure.

Which preformed mediator can explain the immediate vascular change?

What receptor on the microvascular endothelium mediates its dominant effect?

Discuss the mechanism before revealing the explanation in speaker notes.

Slide 21 · Arachidonic acid is a membrane-derived substrate

Membrane phospholipids

Phospholipase A2 activation

Arachidonic acid

Eicosanoid synthesis

Slide 22 · Two enzyme branches generate different eicosanoids

Arachidonic acid

Cyclooxygenase (COX-1 / COX-2) → prostaglandins

Lipoxygenase → leukotrienes / lipoxins

Slide 23 · Prostaglandins regulate vascular and systemic responses

Produced by mast cells, macrophages, endothelium, and other cells.

COX-1 and COX-2 participate in prostaglandin synthesis.

Important effects include vasodilation, edema amplification, pain, and fever.

Different prostaglandins have different vascular and platelet effects.

Slide 24 · Major prostaglandins are functionally distinct

Mediator

Emphasized inflammatory effect

PGD₂ / PGE₂

Vasodilation; increase permeability effects

PGE₂

Pain sensitization and fever

PGI₂ (prostacyclin)

Vasodilation; inhibits platelet aggregation

TXA₂ (thromboxane)

Vasoconstriction; promotes platelet aggregation

Slide 25 · Prostacyclin and thromboxane form an opposing pair

PGI₂: Endothelium

Vasodilation

Inhibits platelet aggregation

Antithrombotic vascular tendency

TXA₂: Platelets

Vasoconstriction

Promotes platelet aggregation

Prothrombotic vascular tendency

Slide 26 · PGE₂ connects inflammation to pain and fever

Inflammatory cytokine signals

Prostaglandin synthesis

PGE₂ activity

Fever and heightened pain sensitivity

Slide 27 · Leukotriene B4 is a potent neutrophil signal

Leukocyte 5-lipoxygenase

LTB₄ generation

Neutrophil chemotaxis + adhesion

Activation; ROS and lysosomal release

Slide 28 · Cysteinyl leukotrienes affect airways and vessels

Mast cells / leukocytes

LTC₄, LTD₄, LTE₄

Bronchospasm

Venular permeability increases

Slide 29 · Lipoxins counter leukocyte recruitment

LTB₄

Promotes neutrophil chemotaxis

Enhances adhesion and activation

Propagates an acute response

Lipoxins

Inhibit neutrophil chemotaxis

Reduce adhesion to endothelium

Contribute to active restraint of inflammation

Slide 30 · Lipoxin production illustrates cell cooperation

Neutrophil produces precursor

Precursor transferred to platelet

Platelet converts precursor

Biologically active lipoxin

Slide 31 · Resolution is not just loss of stimulus

Inflammatory mediator profiles can switch during the response.

Lipoxins antagonize leukotriene-driven neutrophil recruitment.

IL-10 and TGF-β also participate in anti-inflammatory signaling.

The source also describes proposed pro-resolving lipid families whose roles remain under study.

Slide 32 · NSAIDs act on the prostaglandin pathway

Arachidonic acid

COX-1 / COX-2

Prostaglandin generation

Pain and fever

Slide 33 · COX inhibition requires a benefit–risk perspective

Expected benefit

Reduced prostaglandin synthesis

Anti-inflammatory activity

Pain and fever relief

Biological trade-off

COX-1 also contributes to gastric protection

COX-2 is not exclusively pathological

Selective COX-2 blockade may shift platelet–vascular balance

Slide 34 · Selective COX-2 inhibition can alter thrombosis balance

Reduced endothelial PGI₂

Platelet TXA₂ relatively preserved

Reduced antiaggregatory restraint

Potential vascular thrombosis risk

Slide 35 · Glucocorticoids act at several inflammatory nodes

Affected biological target

Consequence

Phospholipase A2 / COX-2 pathways

Reduced eicosanoid synthesis

Pro-inflammatory cytokine gene expression

Reduced TNF and IL-1 signaling

Inducible nitric oxide synthase

Less inflammatory NO production

Multiple inflammatory proteins

Broad rather than single-pathway suppression

Slide 36 · Leukotriene-pathway therapies illustrate specificity

5-lipoxygenase inhibition

Reduces leukotriene biosynthesis

Acts outside the COX pathway

Useful strategy in asthma

Leukotriene receptor blockade

Reduces responses to leukotrienes

Acts at the target receptor

Useful strategy in asthma

Slide 37 · Clinical correlation: Asthma and leukotrienes

A patient with asthma develops reversible bronchospasm during an inflammatory episode.

Which arachidonic acid metabolites directly promote bronchospasm?

Why would a COX inhibitor not directly block their synthesis?

Discuss the mechanism before revealing the explanation in speaker notes.

Slide 38 · Cytokines provide a cell-to-cell signaling network

Proteins produced by immune cells and many stromal or epithelial cells.

Often function locally, but some also cause systemic responses.

Biological actions overlap; The outcome depends on the target cell.

Major acute-inflammatory mediators include TNF, IL-1, IL-6, and chemokines.

Slide 39 · TNF and IL-1 are triggered by danger signals

Microbes, necrosis, immune complexes

Macrophage / dendritic-cell sensing

TNF and IL-1 production

Endothelial and leukocyte activation

Slide 40 · Mature IL-1 depends on inflammasome processing

Inflammatory signals

IL-1 precursor synthesis

Inflammasome-dependent maturation

Biologically active IL-1

Slide 41 · TNF and IL-1 convert endothelium into an active interface

TNF / IL-1

Endothelial adhesion molecules

Chemokine and mediator secretion

Leukocyte adhesion and emigration

Slide 42 · Cytokines connect endothelial adhesion with chemotaxis

TNF / IL-1: Endothelial activation

Leukocyte rolling / adhesion capacity

Chemokines: Integrin activation

Firm adhesion and directed migration

Slide 43 · TNF and IL-1 amplify local cellular responses

Target

Response

Neutrophils

Enhanced responsiveness to inflammatory stimuli

Macrophages

Increased microbicidal activity; NO signaling

Fibroblasts / stromal cells

IL-1 promotes collagen synthesis and proliferation

Endothelium

Adhesion molecules and procoagulant activity

Slide 44 · Systemic cytokine effects are context dependent

Protective acute-phase response

Fever

Leukocytosis

Acute-phase protein synthesis

Excessive or sustained signaling

Metabolic disturbance

Hypotension / shock

Catabolic effects including cachexia

Slide 45 · IL-6 drives the systemic acute-phase response

Inflammatory signals

IL-6 release

Hepatic acute-phase response

CRP, fibrinogen, serum amyloid A

Slide 46 · Sustained TNF contributes to cachexia

Persistent TNF signaling

Appetite suppression

Mobilization of lipid and protein

Weight loss and wasting

Slide 47 · IL-17 recruits phagocytes indirectly

Activated T lymphocytes

IL-17 production

Local cytokines / chemokines

Recruitment of neutrophils and monocytes

Slide 48 · Chemokines are guidance cues for leukocytes

Small chemoattractant proteins with specialized receptor interactions.

Act on seven-transmembrane G protein–coupled receptors.

Displayed on endothelium and extracellular matrix proteoglycans.

Regulate leukocyte recruitment and normal tissue positioning.

Slide 49 · CXCL8 exemplifies neutrophil-directed chemotaxis

Microbes / TNF / IL-1

Macrophage or endothelial CXCL8

Neutrophil activation

Directional migration toward the injury

Slide 50 · CC chemokines target different leukocyte subsets

Illustrative chemokine

Emphasized attraction

CCL2 (MCP-1)

Monocytes

CCL11 (eotaxin)

Eosinophils

CCL3 (MIP-1α)

Monocytes and other leukocytes

CXCL8 (for contrast)

Mainly neutrophils

Slide 51 · Cysteine patterns define four chemokine families

Family

Representative

Characteristic

CXC

CXCL8

Cysteines separated by one residue

CC

CCL2 / CCL11

First two conserved cysteines adjacent

C

XCL1

Lacks two of four conserved cysteines

CX3C

CX3CL1

Three residues separate first cysteines

Slide 52 · Immobilized chemokines create a directional signal

Chemokines tethered to endothelium / ECM

Leukocyte GPCR engagement

Integrin affinity increases

Attachment and migration to inflammatory site

Slide 53 · Homeostatic chemokines also organize normal tissues

Inflammatory chemokines

Induced by microbial / tissue injury signals

Recruitment to an injured site

Often temporary

Homeostatic chemokines

Constitutively produced

Position cells in lymphoid tissues

Support tissue architecture

Slide 54 · Targeting cytokines also changes host defense

A patient receiving a TNF antagonist develops a mycobacterial infection.

How does TNF inhibition help chronic inflammatory disease?

Why can the same intervention impair defense against intracellular microbes?

Discuss the mechanism before revealing the explanation in speaker notes.

Slide 55 · TNF, IL-1, and IL-6 have overlapping but distinct emphasis

Cytokine

High-yield role

TNF

Endothelial activation; chronic catabolic effects

IL-1

Endothelial activation; important fever contribution

IL-6

Systemic acute-phase response

Chemokines

Chemotaxis and leukocyte integrin activation

Slide 56 · Complement is an amplified plasma-protein cascade

Many complement proteins circulate in inactive forms.

Proteolytic activation creates enzymatic amplification.

C3 cleavage is the central convergence step.

Cleavage fragments mediate inflammation, opsonization, and cell lysis.

Slide 57 · Three initiation pathways converge on C3

Classical: Antibody–antigen complex

Alternative: Microbial surfaces

Lectin: Microbial carbohydrate recognition

C3 convertase

Slide 58 · C3 cleavage separates soluble and surface-bound effects

C3 convertase cleaves C3

C3a → inflammatory signaling

C3b → deposition on activating surface

Slide 59 · C5 cleavage diversifies complement effector outputs

C5 convertase cleaves C5

C5a → inflammatory activation

C5b → C6–C9 membrane attack complex

Slide 60 · Anaphylatoxins promote vascular inflammation

C3a / C5a generation

Mast-cell activation

Histamine release

Vasodilation and permeability

Slide 61 · C5a recruits and activates leukocytes

C5a production

Chemotaxis of phagocytes

Leukocyte activation

Additional lipid mediator release

Slide 62 · C3b functions as a surface-bound opsonin

Microbial surface binds C3b

Phagocyte complement receptors

Recognition and engulfment

Enhanced microbial clearance

Slide 63 · The membrane attack complex directly damages membranes

C5b recruitment of C6–C9

Membrane attack complex

Ion and water permeability

Osmotic cell lysis

Slide 64 · Complement regulators protect healthy host cells

Regulator

Mechanism / disease association

C1 inhibitor

Restrains C1 activation; deficiency → hereditary angioedema

CD55 (DAF)

Restrains C3 convertase formation

CD59

Inhibits membrane attack complex assembly

Factor H

Regulates alternative pathway C3b activity

Slide 65 · Dysregulated complement illustrates disease mechanisms

Defect / context

Associated consequence

C1 inhibitor deficiency

Hereditary angioedema

Loss of GPI-anchored CD55 / CD59

Paroxysmal nocturnal hemoglobinuria

Factor H pathway dysregulation

Atypical hemolytic uremic syndrome

Terminal complement deficiency

Susceptibility to Neisseria infection

Slide 66 · Clinical correlation: Complement-mediated hemolysis

Blood cells undergo complement-mediated lysis after loss of GPI-anchored membrane proteins.

Which two regulators are reduced on affected cells?

What disease results from loss of this complement protection?

Discuss the mechanism before revealing the explanation in speaker notes.

Slide 67 · Platelet-activating factor links several cell types

PAF is a phospholipid-derived mediator produced by platelets and multiple inflammatory cells.

It can induce platelet aggregation and leukocyte activation.

Concentration-dependent effects include vascular and bronchial responses.

PAF antagonists have not established therapeutic benefit in studied inflammatory diseases.

Slide 68 · Bradykinin comes from a plasma proteolytic pathway

High-molecular-weight kininogen

Kallikrein cleavage

Bradykinin

Vascular permeability + pain

Slide 69 · Histamine and bradykinin overlap, but differ in origin

Histamine

Stored mainly in mast-cell granules

Very rapid release on degranulation

Vascular H1-receptor effects

Bradykinin

Cleaved from circulating kininogen

Generated by kallikrein

Pain, permeability, vasodilation

Slide 70 · Coagulation and inflammation share signaling interfaces

Thrombin can activate protease-activated receptors on several cell types.

Coagulation and inflammation often occur in the same injured tissue.

Fibrin cleavage products may have inflammatory effects.

A direct causal role of clotting products in every inflammatory setting is not established.

Slide 71 · Neuropeptides provide neuroimmune communication

Sensory nerves / leukocytes

Substance P and related peptides

Pain signaling + vascular effects

Bidirectional neural–immune interaction

Slide 72 · Tissue damage may arise from leukocyte effector products

Leukocyte activation

ROS and lysosomal enzyme release

Microbial killing

Potential bystander tissue injury

Slide 73 · Use the response to identify likely mediators

Observed phenomenon

Prioritize these signals

Immediate arteriolar dilation

Histamine; vasodilator prostaglandins

Early edema

Histamine, bradykinin; cysteinyl leukotrienes

Neutrophil chemotaxis

CXCL8, LTB₄, C5a

Systemic fever / acute-phase reaction

IL-1, TNF, IL-6; PGE₂

Slide 74 · One mediator can affect several compartments

TNF released locally

Endothelium: Adhesion response

Leukocytes: Amplified activation

Systemic effects if sufficiently widespread

Slide 75 · Three forms of mediator interaction

Relationship

Example

Consequences

Amplification

C5a → mast-cell histamine

Accelerated vascular response

Convergence

TNF + IL-1 → endothelium

Overlapping recruitment programs

Antagonism

Lipoxins opposing leukotriene actions

Restriction of neutrophil traffic

Slide 76 · Removing the insult does not instantly reset tissue

Offending stimulus removed

Mediator generation declines

Short-lived mediators decay

Active anti-inflammatory signals support resolution

Slide 77 · Clinical synthesis: Inflammatory pain and swelling

After a minor tissue injury, warmth, swelling, and tenderness appear.

Identify a mediator explaining local vasodilation.

Identify one pathway explaining edema and one mediator implicated in pain.

Discuss the mechanism before revealing the explanation in speaker notes.

Slide 78 · Interpret mediator-directed treatment by its target

Intervention class

Direct target

Major limitation / trade-off

H1 blockade

Histamine H1 signaling

Does not block all edema pathways

NSAIDs

Cyclooxygenase activity

Physiological prostanoid functions also affected

TNF antagonism

TNF signaling

Can compromise antimycobacterial host defense

Complement inhibitors

Selected C3 / C5 activation

Host-defense implications depend on target

Slide 79 · Retrieval practice: Interpret five mediator effects

Which mediator is preformed in mast-cell granules?

Which arachidonic-acid product activates neutrophils?

Which cytokine drives a major acute-phase protein response?

Which complement fragment is a major opsonin?

Which plasma-derived peptide causes pain and increased permeability?

Slide 80 · Core distinctions to retain

Question

Answer

Rapid preformed vascular mediator?

Histamine

Lipid mediator favoring resolution?

Lipoxins

Endothelial-activation cytokines?

TNF and IL-1

Opsonin from complement?

C3b

Leukocyte-guidance protein family?

Chemokines

Slide 81 · Reference and scope

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026).

Chapter 3: Inflammation and Repair — Mediators of Inflammation and related sections.

Teaching diagrams are original editable schematics; no textbook figures reproduced.