2.4 about 32 minDeep Learning viewL2 p.26–31

Mediators and the systemic response

Every step so far was ordered by a chemical: amines and kinins open vessels in minutes, arachidonic acid products shape pain, leak and chemotaxis, complement tags and attracts, and cytokines carry the alarm to the brain, liver and marrow.

Fast mediators: histamine, bradykinin and nitric oxide

L2 p.4, 27, 29

The first mediators are either preformed (histamine sits in mast-cell granules) or made in seconds from precursors already present (bradykinin from plasma kininogen, nitric oxide from arginine). They act within minutes and are destroyed almost as quickly, which is why the earliest swelling of a bee sting or a scratch fades within half an hour.

The fast mediatorsL2 p.27, 29

  • Histamine

    Source
    Mast cells (main), basophils, platelets
    Released by
    IgE cross-linking, C3a/C5a, trauma, heat, cold
    Main actions
    H₁: arteriolar dilation, venular endothelial contraction (leak), itch, bronchoconstriction

  • Serotonin

    Source
    Platelets, enterochromaffin cells
    Released by
    Platelet aggregation
    Main actions
    Vasoconstriction; contributes to permeability

  • Bradykinin

    Source
    High-molecular-weight kininogen, cut by kallikrein (after factor XII activation)
    Released by
    Contact of plasma with collagen and negatively charged surfaces
    Main actions
    Vasodilation, venular permeability, pain, bronchoconstriction

  • Nitric oxide

    Source
    Endothelium (eNOS), macrophages (iNOS)
    Released by
    Arginine → citrulline by NO synthase
    Main actions
    Smooth-muscle relaxation (vasodilation), less platelet adhesion, microbicidal in macrophages

Arachidonic acid: two enzymes, many mediators, four drug targets

L2 p.26–27, 39

When a cell is stimulated, phospholipase A₂ cuts arachidonic acid out of membrane phospholipids. Two enzyme families then compete for it. Cyclooxygenases (COX-1, always present; COX-2, induced at sites of inflammation) make PGG₂ and PGH₂, which tissue-specific synthases turn into prostaglandins and thromboxane. 5-Lipoxygenase, mainly in leukocytes, makes 5-HPETE, then LTA₄, then LTB₄ or the cysteinyl leukotrienes LTC₄ → LTD₄ → LTE₄. Lipoxins are made when two cells cooperate: a neutrophil's LTA₄ is finished by a platelet's 12-lipoxygenase.

Teaching schematic

Membrane phospholipids

phospholipase A₂ ⊣ glucocorticoids

Arachidonic acid

Cyclooxygenase (COX-1, COX-2) ⊣ aspirin, NSAIDs

PGG₂ → PGH₂ → tissue synthases

  • PGE₂ vasodilation, pain, fever
  • PGI₂ vasodilation, platelets off
  • TXA₂ vasoconstriction, platelets on
  • PGD₂ mast cells: leak, bronchospasm
  • PGF₂α uterine, bronchial contraction

5-Lipoxygenase ⊣ zileuton

5-HPETE → LTA₄

  • LTB₄ neutrophil chemotaxis
  • LTC₄ → D₄ → E₄ bronchoconstriction, vasoconstriction, leak⊣ montelukast (receptor)
  • Lipoxins stop signal (with platelet 12-LOX)
Arachidonic acid metabolism with the actions of each product and the four drug targets on the lecture's chart.L2 p.26–27

What each product doesL2 p.26–27, 39

  • PGE₂

    Main source
    Macrophages, many cells
    Actions
    Vasodilation; potentiates edema; pain (sensitizes nerves to bradykinin); fever (hypothalamus)

  • PGI₂ (prostacyclin)

    Main source
    Endothelium
    Actions
    Vasodilation; inhibits platelet aggregation

  • TXA₂

    Main source
    Platelets
    Actions
    Vasoconstriction; platelet aggregation

  • PGD₂

    Main source
    Mast cells
    Actions
    Vasodilation, permeability; bronchoconstriction; attracts eosinophils and Th2 cells

  • PGF₂α

    Main source
    Uterus, many tissues
    Actions
    Contracts uterine and bronchial smooth muscle

  • LTB₄

    Main source
    Neutrophils, macrophages
    Actions
    Neutrophil chemotaxis and activation (adhesion)

  • LTC₄, LTD₄, LTE₄

    Main source
    Mast cells, eosinophils
    Actions
    Bronchoconstriction, vasoconstriction, venular permeability

  • Lipoxins (LXA₄, LXB₄)

    Main source
    Neutrophil + platelet together
    Actions
    Stop signals: inhibit neutrophil chemotaxis and transmigration; promote clearance of apoptotic cells

Where drugs cut inL2 p.26–27

  • Glucocorticoids

    Target
    Phospholipase A₂ (via annexin A1) and COX-2/cytokine gene transcription
    Result
    Both arms reduced at the source

  • Aspirin

    Target
    Irreversibly acetylates COX-1 and COX-2
    Result
    Prostaglandins ↓; platelet TXA₂ ↓ for the platelet's lifespan

  • Other NSAIDs (ibuprofen, naproxen)

    Target
    Reversibly inhibit COX
    Result
    Prostaglandins ↓ (pain, fever, swelling)

  • Celecoxib

    Target
    COX-2 selectively
    Result
    Less gastric injury; spares platelet TXA₂, so thrombotic risk rises

  • Zileuton

    Target
    5-Lipoxygenase
    Result
    LTB₄ and LTC₄/D₄/E₄ synthesis ↓

  • Montelukast, zafirlukast

    Target
    Cysteinyl-leukotriene receptor (CysLT₁)
    Result
    LTC₄/D₄/E₄ cannot act (asthma)

Core activity · The Missing Arrow

The Missing Arrow

Complete the causal chain. Place the missing step by dragging a card onto a gap, or tap a card and then tap the gap. Some gaps need an event; others need the mechanism that links one event to the next.

Gram-negative bacteria multiply in a kidney (pyelonephritis). Follow the alarm from a tissue macrophage to the fever and the blood tests.

  1. LPS binds Toll-like receptor 4 on tissue macrophages
  2. cytokine genes are switched on (NF-κB)
  6. IL-6 reaches hepatocytes
  9. The ESR rises over the next days

Cards

Tap or drag a card. Placing a used card moves it.

Complement: split products with three jobs

L2 p.16, 27

Complement is a cascade of plasma proteins made by the liver. Three routes start it: the classical pathway (C1q binds antibody on an antigen), the alternative pathway (C3 activates spontaneously and is stabilized on microbial surfaces) and the lectin pathway (mannose-binding lectin binds microbial sugars). All three converge on a C3 convertase that splits C3, and then a C5 convertase that splits C5.

Teaching schematic

Classical (antibody) · alternative (microbe surface) · lectin (MBL) → C3 convertase → C5 convertase

  1. C3

    C3a small, diffuses

    anaphylatoxin: mast cells release histamine

    C3b large, stays on the microbe

    opsonin: coats the microbe

  2. C5

    C5a small, diffuses

    anaphylatoxin + neutrophil chemotaxis

    C5b → C5b–9 large, stays on the microbe

    membrane attack complex: lysis

C3 and C5 split into a small fragment that diffuses away and acts on cells, and a large fragment that stays on the microbe.L2 p.27

Three jobsL2 p.27

  • C3a, C5a (anaphylatoxins)

    Job
    Inflammation
    Effect
    Mast cells release histamine → vasodilation and leak

  • C5a

    Job
    Recruitment
    Effect
    Neutrophil chemotaxis, integrin activation, lipoxygenase activation

  • C3b (iC3b)

    Job
    Opsonization
    Effect
    Coats microbes for phagocytes (CR1, CR3)

  • C5b–C9 (membrane attack complex)

    Job
    Lysis
    Effect
    Pores in thin-walled microbes, especially Neisseria

Cytokines: the long-range signals

L2 p.27–29

Cytokines are proteins secreted mainly by activated macrophages, lymphocytes and endothelium. Locally they activate endothelium and leukocytes; in blood they act on the brain, liver and marrow. TNF and IL-1 are the central pair of acute inflammation, and IL-6 carries the message to the liver.

The lecture's cytokine table, by functionL2 p.27–29

  • TNF

    Main source
    Macrophages, T cells, mast cells
    Key actions
    Endothelial activation (E-selectin, ICAM-1, VCAM-1); neutrophil activation; fever; acute-phase proteins; cachexia; apoptosis; shock at high levels; maintains granulomas (2.6)

  • IL-1

    Main source
    Macrophages (main), endothelium, epithelium
    Key actions
    Endothelial activation; fever via hypothalamic PGE₂; acute-phase proteins; activates fibroblasts. Made by the inflammasome (caspase-1)

  • IL-6

    Main source
    Macrophages, endothelium, T cells
    Key actions
    Main signal for hepatic acute-phase proteins (CRP, fibrinogen, hepcidin); fever; Th17; B-cell growth

  • IL-8 (CXCL8)

    Main source
    Macrophages, endothelium, epithelium
    Key actions
    Neutrophil chemotaxis and activation (integrins, burst, degranulation)

  • IL-12

    Main source
    Macrophages, dendritic cells
    Key actions
    Th1 differentiation; IFN-γ from NK and T cells

  • IFN-γ

    Main source
    Th1 cells, NK cells, CD8⁺ T cells
    Key actions
    Activates macrophages (killing, MHC II, epithelioid change); granulomas

  • IL-2

    Main source
    Helper T cells
    Key actions
    T-cell (and NK) proliferation; memory and effector cells

  • IL-3

    Main source
    T cells
    Key actions
    Growth of all hematopoietic lineages in the marrow

  • IL-4

    Main source
    Th2 cells, mast cells
    Key actions
    IgE class switching; Th2 differentiation; alternative macrophage activation

  • IL-5

    Main source
    Th2 cells
    Key actions
    Eosinophil production and activation; B-cell growth, IgA

  • IL-10

    Main source
    Regulatory T cells, macrophages
    Key actions
    Anti-inflammatory: suppresses IL-12, MHC II and costimulators on macrophages and dendritic cells

A memory aid that fits the slide: “hot T-bone stEAK”

  • IL-1: hot (fever)
  • IL-2: T cells
  • IL-3: bone marrow
  • IL-4: IgE
  • IL-5: IgA (and eosinophils)
  • IL-6: aKute-phase proteins

The acute-phase response

L2 p.27–30

When enough IL-1, TNF and IL-6 reach the blood, the whole body responds. Three organs matter most.

Teaching schematic

Site of inflammation: macrophages, endothelium, T cells release IL-1, TNF, IL-6 into the blood

  • Hypothalamus · IL-1, TNF

    COX-2 → PGE₂ → set point ↑

    Fever

  • Liver · IL-6 (+ IL-1, TNF)

    Positive reactants ↑ (CRP, fibrinogen, SAA, hepcidin, ferritin, ceruloplasmin); negative ↓ (albumin, transferrin)

    Acute-phase response

  • Bone marrow · IL-1, TNF, CSFs

    Storage pool released; production ↑

    Leukocytosis, left shift

  • Muscle and fat · TNF

    Protein and fat breakdown, anorexia

    Cachexia (chronic)

Cytokines from the site of inflammation act on the hypothalamus (fever), the liver (acute-phase proteins) and the bone marrow (leukocytosis).L2 p.27–29
  • Fever: IL-1 and TNF act on hypothalamic endothelium, which induces COX-2 and makes PGE₂. PGE₂ raises the thermoregulatory set point through cAMP, so the body conserves and generates heat (vasoconstriction, shivering). Aspirin, NSAIDs and acetaminophen lower fever by blocking prostaglandin synthesis.
  • Acute-phase proteins: IL-6 (with IL-1 and TNF) reprograms hepatocytes: some plasma proteins rise (positive reactants) and others fall (negative reactants).
  • Leukocytosis: IL-1 and TNF release neutrophils from the marrow storage pool, often with immature band forms (left shift); colony-stimulating factors increase production. Bacteria favour neutrophilia, viruses lymphocytosis, parasites and allergy eosinophilia; some infections (typhoid, many viruses) lower the count.
  • Also: tachycardia, chills, anorexia, sleepiness and malaise; in severe infection, sepsis and septic shock (Chapter 4: Shock).
L2 p.27

Acute-phase reactantsL2 p.29–30Midterm sim. p.5

  • C-reactive protein

    Direction
    ↑ (fast)
    Function
    Opsonin; fixes complement
    Why it matters
    Rises within ~6 h, falls promptly: a monitor of activity

  • Fibrinogen

    Direction
    ↑
    Function
    Clotting factor
    Why it matters
    Promotes rouleaux → raised ESR

  • Serum amyloid A

    Direction
    ↑
    Function
    Recruits immune cells; lipid transport
    Why it matters
    Prolonged elevation → secondary (AA) amyloidosis

  • Hepcidin

    Direction
    ↑
    Function
    Degrades ferroportin: less iron absorbed and released from macrophages
    Why it matters
    Anemia of chronic disease

  • Ferritin

    Direction
    ↑
    Function
    Stores iron away from microbes
    Why it matters
    Can be normal or high despite iron deficiency

  • Haptoglobin

    Direction
    ↑
    Function
    Binds free hemoglobin
    Why it matters
    —

  • Ceruloplasmin

    Direction
    ↑
    Function
    Carries copper; ferroxidase; antioxidant
    Why it matters
    Simulation Q14

  • α₂-Macroglobulin

    Direction
    ↑ (modest in humans)
    Function
    Broad protease inhibitor
    Why it matters
    Simulation Q14

  • α₁-Antitrypsin

    Direction
    ↑
    Function
    Inhibits neutrophil elastase
    Why it matters
    Limits collateral damage (2.3)

  • Procalcitonin

    Direction
    ↑
    Function
    —
    Why it matters
    High in bacterial, normal in viral infection

  • Albumin

    Direction
    ↓
    Function
    Main oncotic protein
    Why it matters
    Amino acids redirected to positive reactants

  • Transferrin

    Direction
    ↓
    Function
    Carries iron
    Why it matters
    Internalized by macrophages to sequester iron

  • Transthyretin (prealbumin)

    Direction
    ↓
    Function
    Carries thyroxine and retinol
    Why it matters
    Falls in inflammation as well as malnutrition

CRP versus ESR

L2 p.30–31

CRP is measured directly: an acute-phase protein whose level rises within about 6 hours, peaks in 1–2 days and, with a half-life of about a day, falls quickly once the stimulus ends. ESR is indirect: the distance (mm) that red cells fall in one hour in a vertical tube of anticoagulated blood.

Why red cells fall faster in inflammation: their membranes carry a negative surface charge that keeps them apart. Large, asymmetric plasma proteins, chiefly fibrinogen (and immunoglobulins), reduce that repulsion and bridge neighbouring cells, so the red cells stack into rouleaux. A stack has more mass for its surface area, meets less drag and sinks faster. Fibrinogen has a half-life of about 4 days and immunoglobulins of weeks, so the ESR rises slowly and stays high long after CRP has fallen.

Lecture image

Blood smear with red cells stacked like coins (rouleaux)
Rouleaux: red cells stacked like coins, the reason the ESR rises when fibrinogen or immunoglobulins increase.L2 p.31

Teaching schematic

CRP and ESR after an inflammatory stimulusday 0day 3day 7day 14day 21treatedCRPESRrelative level
Typical time course after a single inflammatory stimulus that is treated on day 3: CRP rises and falls within days; ESR lags behind and returns slowly over weeks.L2 p.30–31

Two markers, two time scalesL2 p.30–31

  • What is measured

    CRP
    The protein itself
    ESR
    Speed of red-cell settling

  • Rise

    CRP
    Within ~6 h
    ESR
    Over days

  • Fall after recovery

    CRP
    Within days
    ESR
    Over weeks

  • Affected by red cells and age

    CRP
    No
    ESR
    Yes: anemia, pregnancy, older age and female sex raise it; polycythemia, sickle cells and spherocytes lower it

  • Best for

    CRP
    Acute changes; response to treatment
    ESR
    Slow, chronic disease activity (e.g. polymyalgia rheumatica, giant cell arteritis)

Worked calculation · Is this ESR raised for her age?

Age
70 years (woman)
Measured ESR
36 mm/h

Formula

Approximate upper limit (Westergren): men = age ÷ 2; women = (age + 10) ÷ 2

Ref. · Miller age-adjusted rule

Knowledge check · 2.4

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 6 correct
  1. Q1Cysteinyl leukotrienesL2 p.27Midterm sim. p.4

    An 8-year-old girl with asthma, allergies and exercise-induced wheeze presents in respiratory distress.

    Which mediator of inflammation is the most powerful stimulator of bronchoconstriction and vasoconstriction in this patient?

  2. Q2Acute-phase reactantsL2 p.29–30Midterm sim. p.5

    A 25-year-old woman has two weeks of fever and chest pain, a red macular facial rash, tender wrist and elbow joints, mild anemia and thrombocytopenia. Her serum ceruloplasmin, fibrinogen, α₂-macroglobulin, serum amyloid A and C-reactive protein are all increased.

    Together, these markers belong to which family of proteins?

  3. Q3Leukotriene drug targetsL2 p.26–27

    A 35-year-old woman with asthma and nasal polyps wheezes within an hour of taking ibuprofen for a headache.

    Which drug would reduce the synthesis of the mediators responsible?

  4. Q4CRP versus ESR kineticsL2 p.30–31

    A 30-year-old woman is treated for pyelonephritis. On day 5 she is afebrile and well. Her CRP has fallen from 180 to 20 mg/L, but her ESR is still 60 mm/h.

    What best explains the difference?

  5. Q5Rouleaux and ESR: image interpretationL2 p.31

    A 68-year-old man has back pain and anemia. His ESR is 110 mm/h, and his blood smear shows the pattern in the image.

    Lecture image

    Blood smear with red cells stacked like coins (rouleaux)

    Which change in his plasma best explains the smear and the ESR?

  6. Q6Complement split productsL2 p.16, 27

    Which complement fragment both attracts neutrophils and makes mast cells release histamine?

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