Acute Inflammation

What Is Acute Inflammation?

The Three Core Components

1. Dilation of small vessels
2. Increased vascular permeability
3. Emigration of leukocytes from the circulation

Component 1: Vascular Reactions

Vasodilation

• One of the earliest events
• Caused primarily by histamine (released from mast cells) and later prostaglandins and nitric oxide
• Produces redness and warmth at the site
• Slows blood flow - setting the stage for leukocyte margination

Increased Vascular Permeability (Leakage)

• Histamine, bradykinin, leukotrienes C4/D4/E4 cause endothelial cells to contract, creating gaps between them
• This happens within 15-30 minutes and is usually short-lived
• In burns, direct endothelial injury causes immediate and sustained leakage

Component 2: Leukocyte Recruitment

Step-by-Step Process

• As blood flow slows (stasis), red cells migrate centrally
• Leukocytes are pushed peripherally toward the vessel wall

• Leukocytes loosely attach to activated endothelium and tumble along it
• Mediated by selectins: E-selectin and P-selectin on endothelium bind carbohydrate ligands on leukocytes; L-selectin on leukocytes binds endothelial ligands
• P-selectin is stored in Weibel-Palade bodies and moves to the surface within minutes of histamine/thrombin stimulation

• Chemokines (e.g., CXCL8/IL-8, CCL2) displayed on the endothelial surface activate leukocyte integrins, converting them from low-affinity to high-affinity state
• Activated integrins (LFA-1, Mac-1) bind ICAM-1 on endothelium - producing stable adhesion

• Leukocytes squeeze between endothelial cells
• Mediated by PECAM-1 (CD31), expressed on both leukocytes and endothelial junctions

• Leukocytes migrate through extracellular matrix toward the source of injury along a chemical gradient
• Key chemoattractants: C5a (complement), LTB4 (leukotriene B4), IL-8/CXCL8, and bacterial products (fMLP)

Clinical relevance: Leukocyte adhesion deficiency (LAD) is a genetic defect in integrin expression (CD18). Affected patients have recurrent bacterial infections, no pus formation, and markedly elevated blood neutrophil counts.

Phagocytosis and Killing

1. Recognize microbes (aided by opsonins - IgG, C3b)
2. Engulf them into phagosomes
3. Kill them via:
   • Reactive oxygen species (ROS) generated by NADPH oxidase ("oxidative burst")
   • Nitric oxide (NO) via iNOS
   • Lysosomal enzymes (elastase, myeloperoxidase, defensins)

Component 3: Mediators of Inflammation

The Major Mediator Families

• Preformed, stored in mast cell granules
• Released immediately upon injury or allergen exposure
• Cause rapid vasodilation and increased permeability

• Produced from cell membrane phospholipids via phospholipase A2
• Two branches:
  • COX pathway → Prostaglandins (vasodilation, pain, fever) and Thromboxane A2
  • Lipoxygenase pathway → Leukotrienes (LTB4 = chemotaxis; LTC4/D4/E4 = permeability, bronchoconstriction)
• NSAIDs block COX → reduce prostaglandins → reduce fever, pain, swelling
• Corticosteroids block phospholipase A2 → suppress the entire pathway

• Produced by activated macrophages and dendritic cells
• Increase endothelial expression of adhesion molecules (E/P-selectin, ICAM-1)
• Drive the acute-phase response: fever, neutrophilia, acute-phase protein synthesis (CRP, fibrinogen, serum amyloid A) by the liver
• At very high levels (sepsis): hypotension, reduced cardiac contractility, DIC

• C3a and C5a are anaphylatoxins - stimulate mast cell degranulation → permeability
• C5a is a potent chemoattractant for neutrophils
• C5b-9 (membrane attack complex) lyses microbes directly

• Produced from kininogens by kallikrein
• Causes vasodilation, increased permeability, smooth muscle contraction, and pain

Morphologic Patterns of Acute Inflammation

Outcomes of Acute Inflammation

1. Complete resolution - the ideal outcome. The injurious agent is eliminated, edema fluid drains via lymphatics, dead cells/debris removed by macrophages, parenchymal cells regenerate. Occurs when injury is limited and tissue can regenerate.
2. Healing by fibrosis (scarring) - when there is extensive tissue destruction, or tissues incapable of regeneration (e.g., cardiac muscle), or abundant fibrin that cannot be cleared. Connective tissue replaces the damaged area.
3. Progression to chronic inflammation - when the acute response cannot resolve the injurious agent (e.g., mycobacteria, persistent irritants) or healing is impaired. Characterized by mononuclear cell infiltrate (lymphocytes, macrophages), angiogenesis, and fibrosis.

Memory Summary

STIMULUS (infection/injury)
        ↓
RECOGNITION (TLRs, complement activation)
        ↓
MEDIATOR RELEASE (histamine, eicosanoids, TNF, IL-1, complement)
        ↓
VASCULAR RESPONSE                    LEUKOCYTE RESPONSE
  Vasodilation (redness, heat)         Margination → Rolling (selectins)
  ↑ Permeability (edema, pus)          → Firm adhesion (integrins/ICAM-1)
                                        → Transmigration (PECAM-1)
                                        → Chemotaxis (C5a, IL-8, LTB4)
                                        → Phagocytosis & killing (ROS, enzymes)
        ↓
OUTCOMES: Resolution / Fibrosis / Chronic inflammation