2.1 about 24 minDeep Learning viewL2 p.2–8

From injury to acute inflammation

Something harmful is recognized, and within minutes the local vessels change: arterioles dilate, venules leak, flow slows. Those vascular changes explain four of the five cardinal signs and set the stage for neutrophils.

What sets inflammation off

L2 p.2, 6

Inflammation is the response of vascularized tissue that brings plasma proteins and leukocytes out of the blood to where they are needed, so they can dilute, destroy or wall off a harmful agent and start repair. Acute inflammation is the fast version: it begins within seconds to minutes, lasts hours to days, and is dominated by fluid exudate and neutrophils. It is part of innate immunity, so it responds the same way to the first encounter as to the tenth.

Four kinds of trigger, one kind of alarmL2 p.2, 40Ref. · Robbins, inflammation

  • Infection

    What the tissue senses
    Microbial molecules (PAMPs) such as LPS, flagellin and bacterial nucleic acids, through Toll-like receptors
    Example
    A thorn carrying Staphylococcus aureus

  • Tissue necrosis

    What the tissue senses
    Molecules released by dead cells (DAMPs): ATP, uric acid, HMGB1, mitochondrial DNA
    Example
    Myocardial infarct, burn

  • Foreign bodies and crystals

    What the tissue senses
    Material that cannot be digested; crystals activate the NLRP3 inflammasome
    Example
    Splinter, suture, urate crystals in gout

  • Immune reactions

    What the tissue senses
    Antigen recognized by antibody or T cells
    Example
    Hypersensitivity and autoimmune disease (Chapter 3)

The first responders are sentinel cells already in the tissue: macrophages, dendritic cells and mast cells. Their receptors recognize the trigger. Toll-like receptors switch on genes for cytokines such as TNF; the inflammasome, a cytosolic complex, activates caspase-1, which cuts pro-IL-1β into active IL-1. Mast cells release preformed histamine within seconds. These mediators act on the nearest small vessels, and everything visible follows from that.

The whole chapter in one line

  1. Stimulus recognized by sentinel cells
  2. Mediators released
  3. Vessels dilate and leak (2.1)
  4. Leukocytes recruited (2.2)
  5. Agent killed and removed (2.3)
  6. Response switched off (2.5)
  7. Tissue regenerates or scars (2.7)

Acute versus chronic inflammation, as the lecture contrasts them

Acute

  • Onset in seconds to minutes; lasts hours to a few days
  • Neutrophils, edema
  • Usually mild, self-limited tissue injury
  • Prominent local signs

Chronic (2.6)

  • Slow onset; weeks to years
  • Macrophages and lymphocytes, plasma cells
  • Tissue destruction, angiogenesis and fibrosis at the same time
  • Local signs often subtle
L2 p.2, 6, 40

Lecture image

H&E section crowded with neutrophils with multilobed nuclei in pale, edematous stroma
Acute inflammation: the stroma is pale and widened by edema fluid, and crowded with neutrophils, recognized by their multilobed nuclei.L2 p.6

Five cardinal signs, five mechanisms

L2 p.3–4

Celsus described four signs of inflammation (rubor, calor, tumor, dolor), and Virchow added a fifth (functio laesa). Each sign is a visible consequence of a specific vascular or neural event, so knowing the mechanism tells you which mediator to blame and which drug will help.

Each sign has its own vessel or nerveL2 p.3–4

  • Rubor (redness)

    Mechanism
    Arterioles and precapillary sphincters dilate; more capillaries fill with blood (hyperemia)
    Main mediators
    Histamine, nitric oxide, PGI₂, PGE₂

  • Calor (heat)

    Mechanism
    More warm core blood reaches the surface; systemic fever adds to it
    Main mediators
    Same vasodilators; IL-1 and TNF for fever

  • Tumor (swelling)

    Mechanism
    Postcapillary venules leak protein-rich fluid into the interstitium (exudate)
    Main mediators
    Histamine, bradykinin, LTC₄/D₄/E₄, C3a/C5a

  • Dolor (pain)

    Mechanism
    PGE₂ sensitizes nerve endings to bradykinin; swelling raises tissue pressure
    Main mediators
    PGE₂ + bradykinin

  • Functio laesa (loss of function)

    Mechanism
    Pain and swelling limit use; tissue damage
    Main mediators
    Consequence of the others

The vascular sequence

L2 p.5, 7

The lecture lists the vascular events in order: vasoconstriction of arterioles → vasodilation of arterioles → increased permeability of venules → edema. Each step causes the next.

Teaching schematic

  1. 1. Brief vasoconstriction

    Seconds; neurogenic reflex

  2. 2. Arteriolar dilation

    Histamine, NO, PGs → more capillaries open: red, hot

  3. 3. Venular leak

    Endothelial contraction opens gaps → exudate: swelling

  4. 4. Stasis and margination

    Concentrated, slow blood; leukocytes move to the wall

The same microcirculation in four moments: a brief constriction, arteriolar dilation (hyperemia), venular leak, and stasis with leukocytes drifting to the wall.L2 p.5, 7, 11
  1. Transient vasoconstriction (seconds): a neurogenic reflex and endothelin. It is why a scratched patch of skin briefly blanches.
  2. Arteriolar vasodilation: histamine, nitric oxide and prostaglandins relax arteriolar smooth muscle and precapillary sphincters. Flow increases and the capillary bed floods: redness and heat.
  3. Increased permeability of postcapillary venules: histamine, bradykinin and leukotrienes make endothelial cells contract and open gaps between them. Protein-rich fluid escapes: swelling. This contraction response is fast and short-lived (15–30 minutes); cytokines (TNF, IL-1) later loosen junctions for longer.
  4. Stasis: losing fluid concentrates red cells, so blood becomes more viscous and flow slows in the small vessels.
  5. Margination: in slow flow, leukocytes leave the central stream and settle along the endothelium, ready to adhere (2.2).
L2 p.4, 7, 11

Other ways vessels leakRef. · Robbins, vascular changes

  • Endothelial contraction (histamine, bradykinin, leukotrienes)

    Time course
    Immediate, transient; venules
    Example
    Insect bite, early inflammation

  • Junction reorganization by cytokines

    Time course
    Delayed (hours), longer
    Example
    TNF and IL-1 in bacterial infection

  • Direct endothelial injury

    Time course
    Immediate and sustained; all microvessels
    Example
    Severe burns, toxins

  • Leukocyte-mediated injury

    Time course
    Late
    Example
    Neutrophil proteases and oxygen radicals

  • Leaky new vessels

    Time course
    During repair
    Example
    Granulation tissue (VEGF) (2.7)

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.

A bee stings the back of a hand. Complete the chain from the first mediator to leukocytes lining the venule wall.

Two gaps ask for a mechanism (how one event causes the next); three ask for an event (what you would see).

  1. Mast cells around the sting degranulate and release histamine
  4. histamine also makes endothelial cells of postcapillary venules contract
  7. Flow slows in the small vessels: stasis
  8. in slow flow, leukocytes drift out of the central stream

Cards

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

Exudate versus transudate

L2 p.4, 10

Fluid leaves a capillary when the hydrostatic pressure pushing it out exceeds the oncotic pressure of plasma proteins holding it in; lymphatics return the small normal excess. Swelling can therefore come from two very different faults.

Teaching schematic

Transudate: intact wallWater and small solutes only
Transudate: pressure imbalance, intact wall. Low protein.
Exudate: leaky wallProtein, fibrin, cells out
Exudate: gaps in the wall. High protein, fibrin, leukocytes.
Left: an intact wall with abnormal pressures lets water and small solutes through (transudate). Right: gaps in the wall let proteins, fibrinogen and cells out as well (exudate).L2 p.10

How to tell them apartRef. · Robbins; Light criteria

  • Cause

    Transudate
    Imbalance of pressures across an intact wall
    Exudate
    Increased vascular permeability (inflammation)

  • Typical settings

    Transudate
    Heart failure (hydrostatic ↑), cirrhosis or nephrotic syndrome (oncotic ↓)
    Exudate
    Infection, abscess, pleuritis, burns

  • Protein

    Transudate
    Low
    Exudate
    High

  • Specific gravity

    Transudate
    < 1.012
    Exudate
    > 1.020

  • Cells and fibrin

    Transudate
    Few cells; does not clot
    Exudate
    Leukocytes, debris; fibrin may clot

  • Pleural fluid (Light criteria)

    Transudate
    Fluid/serum protein ≤ 0.5 and LDH ≤ 0.6
    Exudate
    Protein ratio > 0.5 or LDH ratio > 0.6

Once protein leaks, it adds a second force: protein in the interstitium raises interstitial oncotic pressure and draws still more water out. Pus is a purulent exudate, rich in neutrophils, dead cells and microbes.

Worked case · Two pleural effusions

Patient A has pneumonia and a pleural effusion with protein 4.6 g/dL (serum 6.8) and many neutrophils. Patient B has long-standing heart failure and an effusion with protein 1.8 g/dL (serum 6.6) and few cells.

Which effusion comes from a leaky wall, and which from pressure?

Ref. · Light criteria

Core activity · Almost Twins

Almost Twins

Two look-alikes side by side. Decide what they share, then pick the clue that separates them and say why it works.

Look-alike A

Exudate

Exudate: leaky wallProtein, fibrin, cells out
Pleural fluid in pneumonia (schematic).
  • Excess fluid outside the vessels
  • High protein, leukocytes, fibrin; specific gravity > 1.020
  • Leaky wall: inflammation opens endothelial gaps

Step 1 · What they share

What do they share?

Select every feature that both show.

Inflammation without microbes: the infarct

L1 p.31–35Ch. II cases p.9, 11

Teaching schematic

Cells in an infarct over time012 h1 d3 d7 d2 wk2 moHeartNeutrophilsMacrophagesGranulation tissueScarBrainNeutrophilsMicroglia / macrophagesAstrocytes (gliosis)
Which cell dominates when, in a myocardial infarct and in a brain infarct. Times are approximate.L1 p.33, 35Ref. · Robbins, infarct morphology

Cells in an infarct over timeCh. II cases p.9, 11Midterm sim. p.3Ref. · Robbins

  • First hours

    Heart (coagulative necrosis)
    Little to see; wavy fibers at the border
    Brain (liquefactive necrosis)
    Little to see

  • 12–24 h

    Heart (coagulative necrosis)
    Coagulative necrosis; neutrophils begin to arrive
    Brain (liquefactive necrosis)
    Red (eosinophilic) neurons; neutrophils from about 24 h

  • 1–3 days

    Heart (coagulative necrosis)
    Nuclei lost, neutrophils peak
    Brain (liquefactive necrosis)
    Neutrophils, edema

  • 3–7 days

    Heart (coagulative necrosis)
    Neutrophils die; macrophages remove dead myocytes
    Brain (liquefactive necrosis)
    Microglia and macrophages take over

  • 1–2 weeks

    Heart (coagulative necrosis)
    Granulation tissue from the margins
    Brain (liquefactive necrosis)
    Foamy, lipid-laden macrophages; tissue liquefies

  • Weeks to months

    Heart (coagulative necrosis)
    Collagen deposition → dense scar by about 2 months
    Brain (liquefactive necrosis)
    Reactive astrocytes wall off a cyst (gliosis)

Core activity · One Fact Changes

One Fact Changes

Answer a case and name the decisive clue. Then exactly one fact changes. Decide whether the answer moves, and why.

1 · The original case

A 64-year-old man with diabetes has crushing chest pain. His occluded left anterior descending artery cannot be opened in time. He dies of an arrhythmia 2 days later. The anterior wall is examined microscopically.

What dominates the infarcted myocardium?

Which fact decided it?

Knowledge check · 2.1

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

0 of 5 correct
  1. Q1Pain: PGE₂ + bradykininL2 p.4Ch. II cases p.3

    A 22-year-old man has marked right lower quadrant pain over the past day, with rebound tenderness. At laparoscopy the appendix is swollen, erythematous and partly covered by yellowish exudate; microscopy shows numerous neutrophils.

    The pain is predominantly the result of which two chemical mediators?

  2. Q2Swelling: increased vascular permeabilityL2 p.4, 7Midterm sim. p.3

    A 5-year-old boy punctures his thumb with a rusty nail. Four hours later the thumb is red and swollen.

    The initial swelling of the thumb is primarily due to which mechanism?

  3. Q3Inflammatory edema: endothelial gapsL2 p.4, 15Ch. II cases p.15

    A 22-year-old woman cut her foot on a rock three days ago. Her temperature is 37.7 °C. The lateral foot has a fluctuant, erythematous lesion surrounded by edema.

    What is most likely the primary mechanism of the edema?

  4. Q4Infarct timeline: neutrophils at 1–3 daysL1 p.33Ch. II cases p.11

    A 62-year-old man is admitted with an hour of severe chest pain radiating to his left arm and is diagnosed with a myocardial infarction. Treatment fails, and he dies 2 days after admission.

    What would most likely be seen in the infarcted myocardium at the time of death?

  5. Q5Neutrophils first: image recognitionL2 p.6

    This section is from an appendix removed 18 hours after symptoms began.

    Lecture image

    H&E section crowded with neutrophils with multilobed nuclei in pale, edematous stroma

    Why are the multilobed cells, rather than macrophages, the dominant cell at this time?

Chapter startNext2.2 Recruitment