Other Mediators of Inflammation

Slide 1 · Other Mediators of Inflammation

Platelet-activating factor · Coagulation products · Kinins · Neuropeptides

Inflammatory mediators: mechanisms and clinicopathologic interpretation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Classify platelet-activating factor, coagulation products, kinins, and neuropeptides by origin.

Trace their documented effects on vascular responses, platelets, pain, and inflammatory regulation.

Distinguish established mediator actions from tentative causal associations.

Origins

Mechanisms

Evidence

Slide 3 · Inflammatory mediators initiate and regulate responses

Inflammatory mediators are substances that initiate or control inflammation.

Different mediators evoke distinct, partly overlapping components of the response.

The biologic response depends on mediator production, targets, and termination.

Stimulus

Mediator release

Target-cell response

Slide 4 · Four additional mediator systems

Platelet-activating factor (PAF): Phospholipid-derived mediator.

Coagulation products: Thrombin, protease-activated receptors, and possible fibrinopeptide effects.

Kinins: Vasoactive peptides formed from plasma proteins.

Neuropeptides: Neural and leukocyte-associated regulatory peptides.

PAF

Coagulation products

Kinins

Neuropeptides

Slide 5 · Cellular and plasma-derived mediators differ

Cells may rapidly release stored products or synthesize mediators following stimulation.

Plasma protein pathways often require proteolytic activation of inactive precursors.

PAF and neuropeptides have cellular sources; Kinins derive from circulating substrates.

Cellular mediators

Plasma-derived mediators

Slide 6 · Tissue injury triggers mediator generation

Microbial products and substances released from injured or necrotic cells can initiate mediator responses.

Production is normally concentrated where initiating stimuli are present.

The same tissue injury may activate inflammatory and coagulation pathways.

Microbes / injured cells

Mediator systems

Localized response

Slide 7 · Mediator activity is deliberately transient

Most mediators have short half-lives or are rapidly degraded, scavenged, or inhibited.

Short-lived activity helps prevent persistence after removal of an offending stimulus.

Bradykinin is a clear example because kininase rapidly inactivates it.

Stimulus present

Active mediator

Inactivation

Slide 8 · One mediator can induce secondary mediators

A mediator can stimulate cells to release additional inflammatory signals.

Secondary mediators may amplify, modify, or oppose the original effect.

The source describes complement-driven histamine release and TNF-driven endothelial mediator production.

Initial signal

Second mediator

Amplified / altered effect

Slide 9 · Redundancy stabilizes inflammatory responses

Several mediators can converge on the same physiologic endpoint.

Vascular leakage and pain each have more than one mediator.

That redundancy makes the protective response robust.

Inflammatory endpoints

PAF

Bradykinin

Substance P

Slide 10 · Mechanistic orientation: Source to effect

Identify the origin of each mediator before attributing a function.

Distinguish directly described functions from hypothesized pathway effects.

Use the physiologic endpoint—edema, pain, airway response, or immunoregulation—to interpret each pathway.

Origin

Activation

Effector target

Outcome

Slide 11 · PAF is a phospholipid-derived mediator

Its original identification depended on platelet aggregation.

Subsequent work showed multiple inflammatory effects beyond platelets.

Its activities include effects on vascular tone, permeability, and airways.

PAF

Platelets

Vessels

Bronchi

Slide 12 · PAF is synthesized by several cell populations

Platelets, basophils, and mast cells can elaborate PAF.

Neutrophils and macrophages are also sources.

Endothelial cells contribute to the same mediator network.

Platelets

Basophils / mast cells

Neutrophils / macrophages

Endothelial cells

Slide 13 · PAF can be secreted or remain cell-bound

Both secreted and cell-bound PAF.

This distinction broadens the ways PAF may participate in inflammatory signaling.

The excerpt does not assign specific effects exclusively to either form.

Secreted PAF

Cell-bound PAF

Slide 14 · Platelet aggregation is the historical PAF effect

PAF was discovered as a factor inducing platelet aggregation.

This platelet effect is only one component of its reported biologic activity.

Its name should not obscure its non-platelet inflammatory actions.

PAF

Platelet response

Aggregation

Slide 15 · PAF can cause vasoconstriction

Vasoconstriction among the actions of PAF.

This finding must be read alongside the low-concentration vasodilator effect.

PAF should not be memorized as having a single fixed effect on vascular tone.

Vasoconstriction

Low-dose vasodilation

Slide 16 · PAF can cause bronchoconstriction

Bronchoconstriction is an explicitly described action of PAF.

It extends mediator biology to airway smooth-muscle responses.

The source does not quantify the magnitude or assign a particular disease-specific role.

PAF

Airway response

Bronchoconstriction

Slide 17 · Low concentrations of PAF induce vasodilation

At low concentrations, PAF produces vasodilation.

This is a concentration-qualified effect, not a universal statement for all exposure levels.

Qualitative arrows should not be mistaken for a measured dose-response curve.

Low concentration

Vasodilation

Slide 18 · PAF can increase venular permeability

Low concentrations of PAF increase venular permeability.

Increased permeability facilitates the movement of fluid out of small vessels.

Vascular leakage is shared with several other inflammatory mediators.

PAF at low concentration

Venular permeability ↑

Fluid movement

Slide 19 · PAF actions depend on context

Both constrictor actions and low-concentration vasodilation.

Concentration matters when summarizing a mediator’s vascular effect.

No numerical threshold for these contrasting responses is given.

Platelet aggregation

Vascular tone

Airway tone

Venular permeability

Slide 20 · PAF connects multiple inflammatory compartments

Platelets: Aggregation.

Blood vessels: Effects on tone and venular permeability.

Airways: Bronchoconstriction.

PAF

Platelet

Vessel

Airway

Slide 21 · PAF antagonists have not proved clinically useful

PAF has several striking experimentally characterized effects.

Nevertheless, PAF antagonists have not been useful in the inflammatory diseases tested.

Molecular activity alone does not guarantee clinical benefit from blocking a target.

Biologic effects established

Clinical benefit not demonstrated

Slide 22 · Application: Identify the PAF-related pattern

A conceptual mediator produces platelet aggregation and bronchoconstriction.

At low concentration it also increases venular permeability.

The combination is compatible with the properties assigned to PAF.

Clinical reasoning • hypothetical example

Platelet aggregation

Bronchoconstriction

Permeability ↑

Slide 23 · Injury can recruit coagulation and inflammation

Many injuries simultaneously produce clotting and inflammation.

Co-occurrence is not itself evidence that coagulation products drive inflammation.

This distinction is central to the textbook’s discussion.

Coagulation

Inflammation

Slide 24 · Thrombin cleaves fibrinogen to form fibrin

Thrombin is the protease that acts on fibrinogen.

Fibrin forms the structural basis of the clot.

The described enzymatic step is established independently of proposed inflammatory effects.

Thrombin + fibrinogen

Proteolytic cleavage

Fibrin → clot

Slide 25 · Fibrin and fibrinopeptides are not synonymous

Fibrin is the clot-forming product of fibrinogen cleavage.

Fibrinopeptides are cleavage products proposed to influence inflammation.

Distinguish the established clotting function from the less certain inflammatory activity.

Fibrin: Clot formation

Fibrinopeptides: Possible inflammation

Slide 26 · Protease-activated receptors link enzymes to cells

Protease-activated receptors (PARs) are present on leukocytes.

Thrombin can activate these receptors.

This offers a possible molecular connection between coagulation proteases and inflammatory cells.

Thrombin

Leukocyte PAR

Potential inflammatory signaling

Slide 27 · Leukocytes express thrombin-responsive PARs

PAR expression makes leukocytes potential targets of coagulation proteases.

The presence of a receptor and activation by thrombin support mechanistic plausibility.

The net contribution to inflammation in vivo remains insufficiently established in the source.

Thrombin

PAR on leukocyte

Potential inflammatory signaling

Slide 28 · Platelet activation is likely the major PAR function

PARs probably play their major role in platelet activation during clotting.

This role should be distinguished from PAR expression on leukocytes.

A receptor may be shared across cell types without identical physiologic importance.

Platelet PAR: Likely dominant

Leukocyte PAR: Possible link

Slide 29 · Fibrinopeptides may stimulate inflammation

Some evidence supports inflammatory activity of fibrin cleavage products.

This is described as suggestive rather than conclusively established.

Avoid presenting the association as a universally accepted causal pathway.

Fibrinogen cleavage

Fibrinopeptides

Possible inflammation

Slide 30 · Coagulation-related causality remains unresolved

Tissue injury is a common cause of both clotting and inflammation.

It is not established whether coagulation products themselves stimulate inflammation in some settings.

The mechanistic diagram therefore separates known reactions from proposed effects.

Injury → clotting

Established

Injury → inflammation

Compare evidence

Products → inflammation ?

Slide 31 · Interpret the strength of coagulation evidence

Statement

Status

Interpretation

Thrombin → fibrin

Established

Clotting reaction

Thrombin → leukocyte PAR

Established

Receptor activation

Products → inflammation

Unresolved

No firm causal conclusion

Slide 32 · Do not infer inflammation from a clot alone

The same damaged tissue can activate coagulation and inflammation in parallel.

Detecting a clot does not identify the dominant inflammatory mediator.

Mechanistic reasoning requires a causal chain, not just simultaneous observations.

Clinical reasoning • hypothetical example

Shared injury

Two parallel outcomes

Causality unproven

Slide 33 · Application: Classify coagulation claims

Claim A: Thrombin produces fibrin from fibrinogen.

Claim B: Thrombin activates PARs expressed on leukocytes.

Claim C: Coagulation products are necessarily the cause of inflammation after every injury.

Clinical reasoning • hypothetical example

A: Established

B: Established

C: Unsupported

Slide 34 · Kinins are plasma-derived vasoactive peptides

Kinins arise from plasma proteins called kininogens.

Proteolytic enzymes called kallikreins generate active kinin peptides.

Bradykinin is the principal example emphasized by Robbins.

Plasma kininogen

Kallikrein action

Bradykinin

Slide 35 · Kininogens supply inactive precursors

The source identifies high-molecular-weight kininogen as a plasma glycoprotein precursor.

Precursor cleavage is the key activation step.

This contrasts with release of an already active granule-stored mediator.

Inactive plasma precursor

Proteolytically generated peptide

Slide 36 · Kallikrein generates bradykinin

Kallikrein cleaves high-molecular-weight kininogen.

The cleavage reaction produces bradykinin.

This is a direct example of inflammation-related proteolytic mediator generation.

High-MW kininogen

Kallikrein cleavage

Bradykinin

Slide 37 · Bradykinin dilates blood vessels

Vasodilation is among the textbook-described actions of bradykinin.

Increased local blood flow is one way mediator activity contributes to vascular reactions.

Bradykinin therefore overlaps functionally with histamine.

Bradykinin

Vasodilation

Vascular response

Slide 38 · Bradykinin increases vascular permeability

Bradykinin directly increases vascular permeability.

This action provides a mechanistic contribution to inflammatory fluid leakage.

The endpoint is shared by histamine, PAF, and substance P.

Permeability ↑

Bradykinin

PAF

Substance P

Slide 39 · Bradykinin contracts smooth muscle

Smooth-muscle contraction is listed among bradykinin actions.

Do not confuse smooth-muscle contraction with the vascular dilation also caused by the same mediator.

Biologic actions vary with tissue and physiologic context.

Vasodilation

Smooth-muscle contraction

Slide 40 · Bradykinin mediates pain

Bradykinin produces pain when injected into the skin.

The textbook’s summary also lists it among principal pain mediators.

Pain can be mediated chemically even without direct proof of infection.

Bradykinin

Cutaneous nociceptive effect

Pain

Slide 41 · Bradykinin resembles histamine functionally

Both mediators contribute to vascular dilation and increased permeability.

The textbook explicitly calls bradykinin’s effects similar to histamine.

Similarity of effects does not imply identical biochemical origin.

Bradykinin: Plasma peptide

Histamine: Vasoactive amine

Slide 42 · Kininase rapidly ends bradykinin action

Bradykinin is short-lived because kininase rapidly inactivates it.

Enzymatic clearance provides a concrete mechanism for mediator control.

This reflects the general principle that inflammatory mediators do not persist indefinitely.

Bradykinin active

Kininase

Inactivated mediator

Slide 43 · Bradykinin may participate in anaphylaxis

Robbins implicates bradykinin in some allergic reactions, including anaphylaxis.

The wording does not establish that bradykinin is the sole or dominant mediator.

Multiple mediators can contribute to a single clinical reaction.

Associated with allergic reaction

Not a single-mediator explanation

Slide 44 · Application: Edema accompanied by pain

A hypothetical injury produces localized edema and pain.

One plausible mediator with both actions is bradykinin.

The finding alone cannot uniquely identify bradykinin because mediator effects overlap.

Clinical reasoning • hypothetical example

Vascular leakage

Pain

Bradykinin compatible

Slide 45 · Neuropeptides link nervous and immune systems

Neuropeptides are small regulatory peptides secreted by sensory nerves and leukocytes.

They may participate in initiation and regulation of inflammatory reactions.

Their effects establish a route for neural–immune communication.

Sensory nerves / leukocytes

Neuropeptide signal

Inflammatory target

Slide 46 · Substance P and neurokinin A are examples

Substance P and neurokinin A as neuropeptides.

They are produced in central and peripheral nervous systems.

Substance P has explicitly described functions in pain and vascular permeability.

Substance P

Neurokinin A

Slide 47 · Sensory nerves are a neuropeptide source

Nerve endings can secrete peptides involved in local inflammation.

This creates an interface between tissue sensation and vascular reactions.

The source also recognizes leukocyte-derived neuropeptides.

Sensory nerve

Released peptide

Tissue response

Slide 48 · Leukocytes also supply neuropeptides

Leukocytes are among the cells capable of secreting neuropeptides.

Immune and neural compartments thus share mediators rather than functioning in isolation.

The source does not provide quantitative contributions from each source.

Neural origin

Leukocyte origin

Slide 49 · Substance P-containing fibers occur in lung and gut

Substance P-containing nerves are especially prominent in the lungs and gastrointestinal tract.

These sites illustrate the anatomic proximity of neural signaling and barrier tissues.

Presence of such fibers should not be treated as a disease-specific diagnostic finding.

Lung

Gastrointestinal tract

Nerve fibers

Local tissue response

Slide 50 · Substance P participates in pain transmission

Transmission of pain signals is an inflammatory-relevant action of substance P.

Robbins also lists substance P in its mediator table for pain.

Neuropeptide activity connects sensory signaling to tissue responses.

Substance P

Pain signaling

Perceived pain

Slide 51 · Substance P can increase vascular permeability

Substance P also increases vascular permeability.

Neurogenic mediators therefore contribute to a vascular endpoint shared with plasma-derived kinins.

The source does not assign a universal quantitative contribution to tissue edema.

Substance P

Microvascular response

Permeability ↑

Slide 52 · Leukocytes bear receptors for neuropeptides

Leukocytes express receptors for numerous neuropeptides.

Nerve-derived signals can therefore be received by immune-effector cells.

This supports neural regulation of inflammation without identifying a single universal response.

Neuropeptide

Leukocyte receptor

Potential immune modulation

Slide 53 · Neural and immune cells share peptide signals

Neuropeptides may originate from either nerves or leukocytes.

Leukocyte receptors provide an additional route for neural mediators to act.

These features motivate a network, rather than a one-cell-one-mediator, model.

Sensory neuron

Neuropeptide

Leukocyte

Tissue

Slide 54 · Efferent vagal activity can suppress inflammation

Activation of the efferent vagus nerve inhibits production of proinflammatory cytokines.

TNF is the explicit example given.

This is a regulatory mechanism rather than another pathway of edema or pain.

Efferent vagus activation

Cytokine production ↓

Inflammation restraint

Slide 55 · TNF suppression demonstrates a neural brake

TNF participates in leukocyte recruitment and endothelial activation.

The excerpt describes vagal activity inhibiting TNF production.

Thus neural signaling can oppose as well as promote inflammatory responses.

Substance P: Permeability / pain

Vagal activity: TNF suppression

Slide 56 · Vagus stimulation has been tested in rheumatoid arthritis

The vagal antiinflammatory observation prompted clinical trials in rheumatoid arthritis.

The excerpt mentions trials but provides no outcomes or efficacy estimates.

Clinical testing should not be conflated with established treatment efficacy.

Mechanistic observation

Established

Clinical trial motivation

Compare evidence

Outcome not specified

Slide 57 · Neural mediators can have opposing directions

Substance P may increase vascular permeability and contribute to pain.

Efferent vagal activation can inhibit proinflammatory TNF production.

The effect of neural signals depends on the pathway being activated.

Proinflammatory activity

Antiinflammatory activity

Slide 58 · Application: Interpret a neural antiinflammatory claim

An intervention activates efferent vagal pathways in an experimental model.

A reduction in TNF production is consistent with the mechanism described.

The observation alone does not establish clinical efficacy for rheumatoid arthritis.

Clinical reasoning • hypothetical example

Vagal activation

TNF production ↓

Efficacy still separate

Slide 59 · Integrating mediator origin and principal effects

Mediator

Origin

Selected actions

PAF

Multiple cell types

Aggregation; vascular/airway actions

Coagulation products

Coagulation cascade

Clot; possible inflammatory link

Bradykinin

Kininogen cleavage

Dilation; leakage; pain

Neuropeptides

Nerves / leukocytes

Pain; leakage; TNF modulation

Slide 60 · Multiple mediators increase permeability

PAF at low concentrations increases venular permeability.

Bradykinin and substance P also increase vascular permeability.

Shared endpoints are not proof that the mediators act through identical biochemical pathways.

Permeability ↑

PAF (low concentration)

Bradykinin

Substance P

Slide 61 · Pain has chemically distinct mediators

Bradykinin is pain-producing and is generated by proteolysis.

Substance P contributes to neural pain transmission.

Robbins’ summary also identifies prostaglandins as major pain mediators.

Pain

Bradykinin

Substance P

Prostaglandins

Slide 62 · A mediator may have several target effects

PAF acts on platelets, vascular tone, permeability, and airways.

Bradykinin affects vascular responses, smooth muscle, and pain.

Multiple physiologic effects make single-output definitions incomplete.

One mediator

Multiple physiologic outputs

Slide 63 · Not all proposed links are equally established

PAF, bradykinin, and substance P have stated biologic effects.

Coagulation-product causation of inflammation remains uncertain in the source.

Vagus stimulation trials are mentioned without demonstrated therapeutic outcomes.

Documented action

Established

Mechanistic proposal

Compare evidence

Clinical efficacy not supplied

Slide 64 · Clinicopathologic reasoning: Edema and pain

Edema indicates increased fluid movement, not a unique mediator identity.

Pain may involve bradykinin, substance P, or prostaglandins.

Link observed findings to possible mechanisms while respecting overlap and uncertainty.

Clinical reasoning • hypothetical example

Observed edema

Observed pain

Multiple compatible mediators

Slide 65 · Knowledge check: Match mediators to claims

Which mediator is produced by kallikrein cleavage of kininogen?

Which mediator is derived from phospholipids and induces platelet aggregation?

Which neural pathway is described as inhibiting TNF production?

Kinin pathway

Platelet response

Cytokine restraint

Slide 66 · Knowledge check: Mechanistic answers

Kallikrein cleavage of high-molecular-weight kininogen generates bradykinin.

Platelet-activating factor (PAF) can induce platelet aggregation.

Activation of the efferent vagus nerve inhibits TNF production.

Bradykinin

PAF

Efferent vagus

Distinct mechanisms

Slide 67 · Integrated principles

Mediator origin predicts the route of production but not one exclusive effect.

Vascular leakage and pain are shared outputs of several chemically distinct mediators.

Distinguish documented actions, plausible pathways, and clinically proven target benefits.

Origin

Biologic effect

Evidence strength

Clinical relevance

Slide 68 · Primary reference

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

Section: Other Mediators of Inflammation; parent sections on mediator principles and cytokines.

Related contextual material: mediator principles, cytokines, and the summary of inflammatory mediator actions.