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Inflammation — Acute & Chronic

Based on Robbins, Cotran & Kumar: Pathologic Basis of Disease

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What is Inflammation?

Without inflammation, infections would go unchecked, wounds would never heal, and injured tissues might remain permanent festering sores. — Robbins, Cotran & Kumar

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The 5 Cardinal Signs of Inflammation

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Steps in Any Inflammatory Reaction (Fig. 3.1 — Robbins)

1. Recognition — Sentinel cells (macrophages, dendritic cells) in tissues detect microbes or damaged cells using pattern-recognition receptors
2. Recruitment — Leukocytes and plasma proteins rush from blood to the injured site
3. Removal — Phagocytic cells engulf and destroy the offending agent
4. Regulation — Anti-inflammatory signals shut the reaction down
5. Repair — Damaged tissue is replaced (regeneration or scarring)

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ACUTE INFLAMMATION

Definition

1. Dilation of small blood vessels → increased blood flow
2. Increased vascular permeability → plasma proteins leak out
3. Emigration of leukocytes (mainly neutrophils) → into the tissue

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1. Vascular Changes

Vasodilation

• Triggered by histamine, and other mediators
• Involves mainly postcapillary venules
• Causes heat and redness at the site
• Quickly followed by increased vascular permeability

Increased Vascular Permeability (Leakage)

• Protein-rich fluid pours into the extravascular tissues
• Fluid + protein loss → blood flow slows (stasis)
• Red cells pack together → vascular congestion (histologically visible)

Key Terms:

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2. Leukocyte Recruitment — "The March to Battle"

Step-by-Step:

• Leukocytes tumble loosely along the endothelium
• Mediated by selectins (E-selectin and P-selectin on endothelium; L-selectin on leukocytes)
• Like a ball rolling along velcro — slow but not yet stuck

• Chemokines (e.g., IL-8) displayed on endothelial surfaces activate leukocytes
• This increases the "stickiness" of integrin molecules on the leukocyte surface

• Leukocyte integrins (e.g., LFA-1, MAC-1) bind to ICAM-1 on endothelium
• Leukocyte stops rolling and sticks firmly

• Leukocyte squeezes through gaps between endothelial cells (mainly in postcapillary venules)
• Secretes collagenases to pierce the basement membrane
• Enters the extravascular space

• Leukocyte migrates toward the site of injury along a chemical gradient
• Chemoattractants: C5a (complement), LTB4 (leukotriene), IL-8 (chemokine), bacterial peptides (N-formylmethionine)
• All bind G protein-coupled receptors → actin polymerization → directed movement

Clinical Pearl: Genetic defects in leukocyte adhesion molecules → Leukocyte Adhesion Deficiency (LAD) → recurrent severe bacterial infections with markedly elevated neutrophil counts but impaired pus formation.

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3. Phagocytosis — "Eating the Enemy"

• Phagocytes recognize microbes via:
  • Mannose receptors (bind microbial sugar patterns)
  • Scavenger receptors (bind modified LDL and microbes)
  • Opsonin receptors — greatly enhance phagocytosis; opsonins are IgG antibodies and C3b (complement fragment) that coat the microbe like a "flag"

• Cytoplasmic extensions flow around the microbe → phagosome forms
• Phagosome fuses with lysosome → phagolysosome

• Reactive Oxygen Species (ROS): NADPH oxidase converts O₂ → superoxide (O₂⁻) → the "respiratory burst"
• Nitric Oxide (NO): from iNOS; reacts with ROS to form peroxynitrite — also bactericidal
• Lysosomal enzymes: elastase, cathepsins, etc.
• Neutrophil Extracellular Traps (NETs): chromatin + granule proteins released extracellularly to trap and kill microbes outside the cell

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4. Mediators of Acute Inflammation

A. Vasoactive Amines

B. Arachidonic Acid (AA) Metabolites

• PGE₂, PGI₂ → vasodilation, increased permeability, fever, pain
• TXA₂ (thromboxane) → vasoconstriction, platelet aggregation
• NSAIDs (aspirin, ibuprofen) block COX → antipyretic, anti-inflammatory

• LTB4 → potent neutrophil chemoattractant
• LTC4, LTD4, LTE4 → bronchoconstriction (important in asthma), increased permeability
• Lipoxins (also from this pathway) → anti-inflammatory, suppress neutrophil chemotaxis

C. Cytokines & Chemokines

D. Complement System

• C3a, C5a → increase vascular permeability; C5a is also a powerful chemoattractant
• C3b → opsonin (coats microbes for phagocytosis)
• C5b-9 (MAC) → membrane attack complex — directly lyses microbes

E. Other Mediators

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5. Morphologic Patterns of Acute Inflammation

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6. Outcomes of Acute Inflammation

• Normal healing when injury is limited and parenchymal cells can regenerate
• Macrophages remove debris, lymphatics drain edema

• When tissue is extensively destroyed or incapable of regeneration
• Fibrin exudate not cleared → fibroblasts grow in → connective tissue scar
• Example: fibrinous pericarditis → constrictive pericarditis (obliterated pericardial space)

• When the injurious agent persists and cannot be eliminated
• Neutrophils are replaced by macrophages, lymphocytes, plasma cells

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CHRONIC INFLAMMATION

Definition

Chronic inflammation is a response of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist. — Robbins, Cotran & Kumar

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Causes of Chronic Inflammation

1. Persistent infections — microorganisms that resist elimination (mycobacteria causing TB, certain fungi, helminths, some viruses). These often trigger delayed-type hypersensitivity (T-cell mediated).
2. Hypersensitivity / Immune-mediated diseases:
   • Autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis) — self-antigens drive perpetual T and B cell reactions
   • Allergic diseases (e.g., bronchial asthma) — unregulated immune responses against harmless environmental antigens
   • Inflammatory bowel disease — dysregulated response against gut microbes
3. Toxic / Prolonged exposure:
   • Silica inhalation → silicosis (non-degradable particles → persistent stimulus)
   • Cholesterol deposition → atherosclerosis (chronic inflammation of arterial wall)

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Morphologic Features — "What It Looks Like"

1. Mononuclear cell infiltration — macrophages, lymphocytes, plasma cells (NOT mainly neutrophils)
2. Tissue destruction — caused by the persisting agent AND by the inflammatory cells themselves
3. Attempted healing — angiogenesis (new blood vessels) + fibrosis (connective tissue deposition)

These three processes — inflammation, destruction, and repair — all happen at the same time in chronic inflammation.

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Cells of Chronic Inflammation

1. Macrophages (The Dominant Cell)

• Derived from bone marrow monocytes (circulating) or tissue-resident precursors (e.g., Kupffer cells in liver, microglia in brain, alveolar macrophages in lung)
• Two activation states:
  • M1 (classically activated): Activated by IFN-γ (from T cells) + microbial products → kill microbes, produce pro-inflammatory cytokines (TNF, IL-1, IL-12, ROS, NO) → "angry soldiers"
  • M2 (alternatively activated): Activated by IL-4, IL-13 (Th2 cytokines) → tissue repair, secrete growth factors (TGF-β, VEGF), produce anti-inflammatory mediators → "cleanup crew"

2. Lymphocytes

• CD4+ T cells (helper) are central orchestrators:
  • Th1 cells → produce IFN-γ → activate M1 macrophages (defense against bacteria/viruses and autoimmune damage)
  • Th2 cells → produce IL-4, IL-13 → activate M2 macrophages, eosinophils (parasites, allergies)
  • Th17 cells → produce IL-17 → recruit neutrophils; involved in autoimmune diseases
• Lymphocytes and macrophages interact bidirectionally — each amplifies the other → perpetuates the cycle of inflammation

3. Plasma Cells

• Differentiated B lymphocytes
• Produce antibodies against persistent foreign antigens or self-antigens

4. Eosinophils

• Prominent in Th2-mediated reactions (parasitic infections, allergies)
• Contain major basic protein (MBP) — toxic to helminths but also damages host tissue

5. Mast Cells

• Widely distributed in connective tissue
• Bear FcεRI receptor (binds IgE)
• Central to immediate hypersensitivity (Type I); also contribute to chronic inflammation
• Release histamine, prostaglandins, cytokines

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Granulomatous Inflammation — A Special Pattern of Chronic Inflammation

What is it?

How it forms:

• A persistent, indigestible stimulus (e.g., TB bacillus, silica) cannot be cleared by ordinary phagocytosis
• T cells release IFN-γ → activates macrophages → they become epithelioid cells
• Epithelioid cells fuse → multinucleated giant cells (Langhans or foreign-body type)

Two types:

Classic TB granuloma:

• Central caseous necrosis (cheese-like, creamy) — diagnostic of TB
• Surrounded by epithelioid macrophages + Langhans giant cells
• Outer rim of lymphocytes + fibrosis

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Macrophage–Lymphocyte Crosstalk (Fig. 3.20 — Robbins)

Microbe/Antigen
       ↓
  Macrophage presents antigen → T cell activation
       ↓                              ↓
  IL-12 (activates Th1)         IFN-γ (activates macrophage)
       ↑__________________________|
           Bidirectional loop → SUSTAINED CHRONIC INFLAMMATION

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Tertiary Lymphoid Structures

• Synovium of rheumatoid arthritis
• Thyroid in Hashimoto thyroiditis
• Tumour infiltrates

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SYSTEMIC EFFECTS OF INFLAMMATION (Acute-Phase Response)

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Quick Comparison: Acute vs Chronic Inflammation

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Summary (Robbins' Key Concepts)

• Rapid response; dominated by vascular changes and neutrophils
• Purpose: eliminate the injurious agent quickly
• Outcomes: complete resolution → scarring → chronic inflammation

• Prolonged; simultaneous injury + repair
• Caused by persistent infections, immune-mediated diseases, toxic agents
• Dominated by macrophages and lymphocytes; bidirectional amplification loop
• Special pattern: granulomatous inflammation (epithelioid macrophages + giant cells)
• Ends in fibrosis if not resolved

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