Acute inflammation: vascular changes and neutrophil recruitment/activation

1. Vasodilatation
2. Increased vascular permeability with exudation
3. Emigration of leukocytes, predominantly neutrophils, to the site of injury

1. Vascular changes in acute inflammation

A. Transient vasoconstriction

• Immediately after injury there may be a brief, reflex arteriolar vasoconstriction, lasting only seconds.
• It is followed rapidly by vasodilatation.

B. Vasodilatation

• Arterioles dilate and previously closed capillary beds open.
• Important mediators:
  • Histamine: principal early mediator
  • Nitric oxide (NO)
  • Prostaglandins, especially PGI₂ and PGE₂
• Consequences:
  • Increased local blood flow, or hyperemia
  • Produces redness (rubor) and warmth (calor).

C. Increased vascular permeability and exudation

Exudate versus transudate

Mechanisms of increased vascular permeability

1. Endothelial cell contraction
   • Most common mechanism.
   • Endothelial cells contract and create intercellular gaps, mainly in postcapillary venules.
   • Mediators: histamine, bradykinin, leukotrienes.
   • Begins rapidly, within minutes, and is usually brief, called immediate transient response.
2. Endothelial junctional retraction
   • Cytoskeletal reorganization causes widening of interendothelial junctions.
   • Mediated by TNF and IL-1.
   • Begins later and is more prolonged than endothelial contraction.
3. Direct endothelial injury
   • Due to severe burns, trauma, toxins, or infections.
   • Causes endothelial necrosis and detachment.
   • Leakage is immediate and sustained until thrombosis or repair occurs.
4. Leukocyte-mediated endothelial injury
   • Adherent activated neutrophils may release reactive oxygen species and proteolytic enzymes.
   • This damages endothelium and increases leakage.
5. Increased transcytosis
   • Movement of fluid and proteins through endothelial cells via vesiculovacuolar channels.
   • Enhanced by mediators such as VEGF.
6. Leakage from newly formed vessels
   • New vessels in healing tissue are immature and have incomplete endothelial junctions.

D. Stasis

• Hemoconcentration
• Increased blood viscosity
• Slower blood flow, termed stasis

2. Recruitment of neutrophils

A. Margination

• In normal laminar blood flow, red cells occupy the axial center of the vessel and leukocytes remain near the periphery.
• With stasis, leukocytes move toward the endothelial surface, called margination.

B. Rolling

• Leukocytes attach loosely to endothelium, repeatedly detach, and roll along the vessel wall.
• Rolling is mediated by selectins.

Selectins in rolling

• Selectins bind sialylated carbohydrate ligands, particularly sialyl-Lewis X, on leukocytes or endothelium.

C. Neutrophil activation

• Chemokines displayed on endothelial surfaces bind receptors on rolling neutrophils.
• Major neutrophil chemokine: IL-8 (CXCL8).
• This signaling converts neutrophil integrins from a low-affinity to a high-affinity state.

D. Firm adhesion

• Activated neutrophil integrins bind strongly to endothelial adhesion molecules.

• TNF and IL-1 increase endothelial expression of ICAM-1 and VCAM-1.
• Firm adhesion arrests the neutrophil on the endothelial surface.

E. Transmigration or diapedesis

• Neutrophils pass between endothelial cells, predominantly through postcapillary venules.
• This is mediated by PECAM-1 (CD31), expressed on both leukocytes and endothelial cells.
• Neutrophils then cross the basement membrane by secreting collagenases and other proteases.

F. Chemotaxis

Exogenous

• Bacterial products, especially N-formylmethionyl peptides

Endogenous

• C5a of complement
• Leukotriene B4 (LTB4)
• Chemokines, especially IL-8/CXCL8
• Products of necrotic cells

3. Activation and effector functions of neutrophils

• Microbial products through pattern-recognition receptors, including Toll-like receptors
• Cytokines and chemokines
• Complement products, especially C5a
• Opsonized microbes binding to Fc and complement receptors
• Products released from necrotic cells

A. Phagocytosis

Steps

1. Recognition and attachment
2. Engulfment, forming a phagosome
3. Fusion with lysosomes to form a phagolysosome
4. Killing and degradation of the ingested organism

Opsonins

• IgG antibody, recognized by Fc receptors
• C3b, recognized by complement receptors
• Plasma lectins

B. Intracellular killing

Oxygen-dependent killing: respiratory burst

• NADPH oxidase generates superoxide anion.
• Superoxide is converted to hydrogen peroxide.
• In neutrophils, myeloperoxidase (MPO) uses H₂O₂ and chloride to produce hypochlorous acid (HOCl), a potent microbicidal agent.

Oxygen-independent killing

• Lysozyme
• Defensins
• Lactoferrin
• Proteases, including elastase and cathepsins
• Acid hydrolases

C. Degranulation and extracellular injury

• Activated neutrophils may release granule enzymes, ROS, and inflammatory mediators into extracellular tissues.
• These substances help destroy microbes but can also cause collateral tissue damage.

D. Neutrophil extracellular traps (NETs)

• Activated neutrophils can extrude nuclear chromatin decorated with granule proteins.
• These web-like structures, called NETs, trap extracellular microbes.
• Excessive NET formation may contribute to endothelial injury and thrombosis.

Flowchart for revision

Tissue injury or microbial invasion
        ↓
Histamine, NO, prostaglandins, TNF, IL-1, chemokines
        ↓
Vasodilatation + increased permeability
        ↓
Exudation, edema, hemoconcentration, stasis
        ↓
Margination
        ↓
Rolling: E-selectin, P-selectin, L-selectin
        ↓
Neutrophil activation: chemokines, especially IL-8
        ↓
Firm adhesion: β2 integrins binding ICAM-1
        ↓
Diapedesis: PECAM-1/CD31
        ↓
Chemotaxis: C5a, LTB4, IL-8, bacterial N-formyl peptides
        ↓
Phagocytosis, oxidative burst, degranulation, NET formation
        ↓
Microbial killing and removal of necrotic tissue