14.2 Acute and Chronic Inflammation, Chemical Mediators, and Tissue Healing

14.2 Acute and Chronic Inflammation, Chemical Mediators, and Tissue Healing

Inflammation is the vascular and cellular response of living tissue to injury, infection, or necrosis. Designed to eliminate noxious agents, clear necrotic debris, and initiate tissue repair, inflammation is broadly divided into acute and chronic phases. Mastering the chemical mediators, leukocyte kinetics, and regenerative tissue mechanics is essential for understanding pathology across all organ systems.

Acute Inflammation: Vascular and Cellular Dynamics

Acute inflammation is a rapid, early defense response dominated by neutrophils. It unfolds through coordinated vascular changes followed by leukocyte extravasation.

Tissue Injury / Pathogen Exposure
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Transient Arteriolar Vasoconstriction (Seconds)
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Vasodilation & Hyperemia (Histamine, Nitric Oxide)
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Increased Vascular Permeability (Histamine, LTC4/D4/E4)
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Endothelial Contraction in Postcapillary Venules
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Stasis & Leukocyte Margination

Vascular Phase Events

1. Transient Vasoconstriction: Neurogenic reflex lasting only seconds.
2. Vasodilation: Arteriolar smooth muscle relaxation driven by histamine and nitric oxide (NO), leading to increased localized blood flow (rubor and calor).
3. Increased Vascular Permeability: Endothelial cell contraction forms intercellular gaps in postcapillary venules. Mediated by histamine, bradykinin, and leukotrienes C4, D4, and E4. Protein-rich fluid leaks into interstitium causing edema (tumor).
4. Stasis and Margination: Fluid loss concentrates red blood cells, slowing microvascular flow (stasis) and pushing leukocytes toward the vessel margins.

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Leukocyte Extravasation: The Multistep Cascade

Extravasation of circulating white blood cells into injured tissue proceeds through four distinct, highly regulated molecular steps:

Clinical Pearl \u2014 LAD-1 Deficiency: Leukocyte Adhesion Deficiency Type 1 is an autosomal recessive defect in the CD18 integrin subunit (beta-2 integrins). Patients present with delayed separation of the umbilical cord, recurrent bacterial infections without pus formation, and severe peripheral blood neutrophilia (neutrophils cannot extravasate).

Cellular Kinetics of Acute Inflammation

• First 6 to 24 Hours: Neutrophils (PMNs) predominate due to their rapid response and high blood concentrations, but they undergo apoptosis after 24\u201348 hours.
• 24 to 48 Hours: Macrophages (monocytes) peak, taking over phagocytosis, clearing dead neutrophils, and secreting growth factors to govern repair.

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Chemical Mediators of Inflammation

Inflammatory processes are orchestrated by endogenous chemical signals derived from plasma proteins or cellular secretion.

                     Arachidonic Acid (Membrane Phospholipids)
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                           Phospholipase A2 (Inhibited by Steroids)
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         Cyclooxygenase (COX-1/COX-2)                5-Lipoxygenase (5-LOX)
         (Inhibited by NSAIDs/Aspirin)                      \u2502
                    \u2502                                       \u25bc
        \u250c\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u253c\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2510                     Leukotrienes
        \u25bc           \u25bc           \u25bc                           \u2502
      PGE2        PGI2        TXA2           \u250c\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2534\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2510
     Fever /  Vasodilation / Vasoconstriction/ \u25bc                             \u25bc
      Pain     Inhibits Aggr.  Promotes Aggr. LTB4                    LTC4, LTD4, LTE4
                                              Neutrophil Chemotaxis   Bronchospasm / Permeability

Key Vasoactive and Eicosanoid Mediators

• Histamine: Preformed in mast cell granules; causes rapid vasodilation and endothelial gap formation in postcapillary venules.
• Arachidonic Acid (AA) Metabolites: Freed from cell membranes by Phospholipase A2 (inhibited by glucocorticoids).
  • Cyclooxygenase (COX) Pathway:
    • Prostaglandin E2 (PGE2): Mediates fever (acts on hypothalamus) and increases pain sensitivity.
    • Prostacyclin (PGI2): Synthesized by endothelium; causes vasodilation and inhibits platelet aggregation.
    • Thromboxane A2 (TXA2): Synthesized by platelets; causes vasoconstriction and promotes platelet aggregation.
  • Lipoxygenase (LOX) Pathway:
    • Leukotriene B4 (LTB4): Potent chemoattractant and activator for neutrophils.
    • Leukotrienes LTC4, LTD4, LTE4: Slow-reacting substances of anaphylaxis; cause severe bronchospasm and marked vascular permeability.

Major Inflammatory Cytokines

• TNF-alpha & IL-1: Secreted by activated macrophages. Induce endothelial cell expression of adhesion molecules (selectins/ICAM-1), trigger systemic acute-phase reactions (fever, lethargy), and stimulate hepatic synthesis of acute-phase reactants (C-reactive protein [CRP], fibrinogen, serum amyloid A [SAA]).
• Interleukin-6 (IL-6): Stimulates hepatic production of acute-phase proteins and erythrocyte sedimentation rate (ESR) elevation.

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Chronic Inflammation and Granuloma Formation

Chronic inflammation is prolonged inflammation (weeks to years) characterized by simultaneous active inflammation, tissue destruction, and repair efforts.

Key Cellular Drivers

• Macrophages: Primary effector cells. Classical activation (M1 pathway, stimulated by IFN-gamma) yields pro-inflammatory, microbicidal macrophages. Alternative activation (M2 pathway, stimulated by IL-4 and IL-13) yields anti-inflammatory macrophages that promote tissue repair and fibrogenesis.
• T Lymphocytes & Plasma Cells: Produce cytokines (IFN-gamma) and antibodies to maintain immune activation.

Granulomatous Inflammation

A specialized subtype of chronic inflammation featuring microscopic aggregates of transformed, expanded macrophages called epithelioid histiocytes and fused Langhans multinucleated giant cells (horseradish-shaped nuclei), bordered by a peripheral rim of lymphocytes.

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Tissue Repair, Wound Healing, and Complications

Tissue restoration following injury occurs via regeneration (proliferation of uninjured parenchymal cells) or repair (deposition of collagen forming a fibrous scar).

The Four Phases of Cutaneous Wound Healing

1. Hemostasis Phase (Immediate): Platelet aggregation and activation of the coagulation cascade form a fibrin clot to arrest hemorrhage.
2. Inflammatory Phase (Days 1\u20133): Neutrophils infiltrate to clear bacteria, followed by macrophages that phagocytose debris and secrete growth factors (TGF-beta, VEGF, FGF).
3. Proliferative Phase (Days 3\u2013Weeks): Formation of granulation tissue (characterized by proliferating fibroblasts, delicate capillary angiogenesis, and loose Type III collagen deposition). Myofibroblasts mediate wound contraction.
4. Remodeling Phase (Weeks to Months): Matrix metalloproteinases (MMPs / collagenases, dependent on zinc) break down temporary matrix, replacing weak Type III collagen with high-tensile-strength Type I collagen. Tensile strength reaches ~80% of normal by 3 months.

       Phase 1: Hemostasis           Phase 2: Inflammation         Phase 3: Proliferation        Phase 4: Remodeling
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    \u2502 Fibrin Clot Formation  \u2502\u2500\u2500\u2500>\u2502 Neutrophil / Macrophage\u2502\u2500\u2500\u2500>\u2502 Granulation Tissue,    \u2502\u2500\u2500\u2500>\u2502 MMP-Mediated Replacement\u2502
    \u2502 & Platelet Plug        \u2502    \u2502 Infiltration           \u2502    \u2502 Fibroblasts, Type III  \u2502    \u2502 of Type III Collagen   \u2502
    \u2514\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2518    \u2514\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2518    \u2502 Collagen & Angiogenesis\u2502    \u2502 with Type I Collagen   \u2502
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Complications of Wound Healing: Hypertrophic Scar vs. Keloid

• Hypertrophic Scar: Excessive deposition of Type III collagen organized parallel to the epidermis. Crucially, the scar remains confined strictly within the original wound boundaries and often regresses over time.
• Keloid: Excessive deposition of broad, disorganized bands of Type I and Type III collagen. Keloids grow beyond the original wound boundaries into surrounding uninjured tissue, rarely regress, and show a strong genetic predisposition in individuals of African, Asian, or Hispanic descent.