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Inflammation — A Detailed Overview

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1. Definition and Purpose

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2. Classification: Acute vs. Chronic

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3. Acute Inflammation

3.1 Three Cardinal Components

1. Vasodilation of small vessels → redness and warmth
2. Increased vascular permeability → exudate formation
3. Leukocyte emigration from the microcirculation to the site of injury

3.2 Vascular Changes

• Endothelial cell contraction creating interendothelial gaps — triggered by histamine, bradykinin, leukotrienes; occurs within 15–30 minutes and is short lived
• Direct endothelial injury (e.g., burns) — immediate and sustained leakage

An exudate is a protein-rich extravascular fluid containing cellular debris, indicating increased vascular permeability. A transudate is a protein-poor ultrafiltrate formed without increased permeability (osmotic/hydrostatic imbalance). Pus (purulent exudate) is rich in neutrophils and dead cell debris.

3.3 Leukocyte Recruitment — The Multistep Process

1. Margination — Leukocytes move to vessel periphery as flow slows
2. Rolling — Loose adhesion via selectins (P- and E-selectin on activated endothelium; L-selectin on leukocytes); leukocytes tumble along the endothelial surface
3. Firm adhesion — Triggered by chemokines activating leukocyte integrins (LFA-1, Mac-1) which bind ICAM-1 on endothelium
4. Transmigration (diapedesis) — Leukocytes squeeze through inter-endothelial junctions mediated by PECAM-1 (CD31)
5. Migration in tissues — Directed movement toward the site of injury along a chemical gradient (chemotaxis) — key chemoattractants: C5a, LTB4, IL-8 (CXCL8), bacterial peptides (f-Met-Leu-Phe)

3.4 Leukocyte Functions at the Site of Injury

Phagocytosis

1. Recognition and attachment — Enhanced by opsonins (IgG, C3b)
2. Engulfment — Pseudopod formation and phagosome creation
3. Killing and degradation — Via reactive oxygen species (ROS) and lysosomal enzymes

Intracellular Killing Mechanisms

• Oxygen-dependent (respiratory burst): NADPH oxidase generates superoxide (O₂⁻) → hydrogen peroxide (H₂O₂) → hypochlorous acid (HOCl) via myeloperoxidase (MPO) — most potent bactericidal mechanism
• Oxygen-independent: Lysozyme, lactoferrin, defensins, elastase, cathepsins (from granules)

Neutrophil Extracellular Traps (NETs)

Leukocyte-Mediated Tissue Injury

• Defending against resistant organisms (e.g., mycobacteria)
• Directed against self antigens (autoimmune) or harmless antigens (allergy)
• Encountering indigestible material (e.g., urate crystals, silica)

3.5 Outcomes of Acute Inflammation

1. Complete resolution — Debris cleared by macrophages; edema reabsorbed via lymphatics; tissue returns to normal (when injury is limited and parenchymal cells can regenerate)
2. Healing by connective tissue replacement (fibrosis/scar) — When tissue is incapable of regeneration, or abundant fibrin exudate cannot be cleared
3. Progression to chronic inflammation — When injurious agent persists or normal healing is disrupted

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4. Mediators of Inflammation

• Derived from plasma (synthesized in liver as inactive precursors, activated at the site) or from cells (mast cells, platelets, macrophages, neutrophils, endothelium)
• Most have short half-lives — they are degraded, inactivated, or become exhausted
• Triggering one mediator often activates others (cascade/amplification)

Key Mediators

The arachidonic acid cascade is central: membrane phospholipids → arachidonic acid (via phospholipase A₂) → COX pathway (prostaglandins, thromboxane) or LOX pathway (leukotrienes). NSAIDs inhibit COX; corticosteroids inhibit phospholipase A₂ (upstream of both).

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5. Chronic Inflammation

5.1 Definition

• Following unresolved acute inflammation
• De novo as a smoldering process

5.2 Causes

• Persistent infections (mycobacteria, certain fungi, viruses, parasites)
• Hypersensitivity/autoimmune diseases (rheumatoid arthritis, multiple sclerosis, asthma)
• Prolonged toxic exposure — inhaled silica (silicosis), cholesterol/lipids (atherosclerosis)

5.3 Morphologic Features

1. Infiltration with mononuclear cells — macrophages, lymphocytes, plasma cells
2. Tissue destruction (induced by the inflammatory cells)
3. Attempts at repair — angiogenesis + connective tissue replacement (fibrosis)

5.4 Key Cells in Chronic Inflammation

Macrophages (dominant cell)

• Derived from blood monocytes or tissue-resident populations (Kupffer cells, microglia, alveolar macrophages)
• Two polarization states:
  • M1 (classical activation): Triggered by IFN-γ, microbial products → produces NO, ROS, pro-inflammatory cytokines (TNF, IL-1, IL-12) → kills microbes
  • M2 (alternative activation): Triggered by IL-4, IL-13 (from Th2 cells) → promotes tissue repair, fibrosis, angiogenesis; secretes TGF-β, VEGF

Lymphocytes

• T helper 1 (Th1) cells → IFN-γ → activate macrophages
• Th2 cells → IL-4, IL-5, IL-13 → activate eosinophils, stimulate IgE (allergic reactions)
• Th17 cells → IL-17 → neutrophil recruitment, antimicrobial peptides
• B cells → mature to plasma cells → antibody secretion

Plasma Cells — produce antibodies directed at persistent antigens

Eosinophils — prominent in parasitic infections and allergies

Mast Cells — key in allergic reactions and surveillance

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6. Granulomatous Inflammation

• Formed when injurious agents (microbes, foreign bodies) cannot be eliminated by standard phagocytosis
• Giant cells may form by macrophage fusion (Langerhans cells in TB, foreign-body giant cells)
• Central caseous necrosis = soft, cheese-like necrosis (characteristic of tuberculosis)

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7. Systemic Effects of Inflammation — Acute Phase Response

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8. Anti-Inflammatory Drug Targets (Clinical Correlations)

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9. Summary Flow

Injurious stimulus (infection, trauma, necrosis)
         ↓
Recognition by PRRs (TLRs, NLRs) on tissue macrophages
         ↓
Release of vasoactive amines (histamine) + cytokines (TNF, IL-1)
         ↓
VASCULAR CHANGES: vasodilation → ↑ permeability → exudation
         ↓
CELLULAR CHANGES: margination → rolling (selectins) → 
  firm adhesion (integrins/ICAM) → transmigration (PECAM-1) → 
  chemotaxis → phagocytosis + killing (ROS, MPO, enzymes)
         ↓
    ┌──────────────┐
    ↓              ↓
RESOLUTION   CHRONIC INFLAMMATION
(macrophage   (macrophages + lymphocytes
 clearance)    + tissue damage + fibrosis)
                    ↓
             GRANULOMA (if agent
              cannot be cleared)

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• Robbins & Kumar Basic Pathology, 10th ed. — Chapter 2 (Inflammation and Repair), pp. 44–70
• Robbins, Cotran & Kumar Pathologic Basis of Disease — Chapter 3