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CHAPTER 3: INFLAMMATION, TISSUE REPAIR AND WOUND HEALING

Complete Semester Preparation Notes

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PART 1: FUNDAMENTALS OF INFLAMMATION

What is Inflammation?

• Without inflammation, infections would go unchecked, wounds would never heal, and injured tissue would remain permanently damaged.
• However, inflammation is a double-edged sword - excessive or dysregulated inflammation itself causes tissue damage and underlies many diseases.

The Five Cardinal Signs of Inflammation (PRISH)

Exam Tip (MCQ): Redness and heat result from vasodilation. Swelling results from increased vascular permeability. Pain is caused by bradykinin and prostaglandins.

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PART 2: ACUTE INFLAMMATION

Definition and Duration

• Rapid onset, short duration (minutes to days)
• Characterized by vascular leakage and neutrophil infiltration
• Aimed at quickly eliminating the causative agent

Causes of Acute Inflammation

1. Infections - bacteria, viruses, fungi, parasites (most common cause)
2. Physical agents - trauma, burns, radiation, frostbite
3. Chemical agents - caustic chemicals, toxins
4. Tissue necrosis - from any cause (ischemia, infarction)
5. Foreign bodies - sutures, splinters, implants
6. Immune reactions (hypersensitivity reactions)

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A. VASCULAR RESPONSES IN ACUTE INFLAMMATION

Step 1: Vasodilation

• First event after injury
• Arterioles and capillaries dilate, increasing blood flow to the area
• Key mediator: Histamine (from mast cells) + nitric oxide (NO)
• Result: Redness (rubor) and Warmth (calor)

Step 2: Increased Vascular Permeability

• Normally, endothelial cells form a tight barrier
• Inflammatory mediators cause endothelial cell contraction, creating gaps between cells in postcapillary venules
• Key mediators: Histamine, Bradykinin, Leukotrienes (C4, D4, E4), Substance P
• Result: Protein-rich fluid (exudate) leaks into the interstitium - causing swelling (tumor)
• Occurs within 15-30 minutes of mediator exposure

Exudate vs. Transudate (CRITICAL DISTINCTION)

• Pus (purulent exudate) = exudate rich in neutrophils + dead cell debris + microbes
• Edema = excess fluid in interstitial tissue (can be either exudate or transudate)

Step 3: Stasis (Slowing of Blood Flow)

• As fluid leaks out, blood becomes more viscous (hemoconcentration)
• Red blood cells pack tightly in small vessels = vascular congestion
• This slows blood flow, allowing leukocytes to move to vessel periphery

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B. CELLULAR RESPONSES - LEUKOCYTE RECRUITMENT

Sequence of Leukocyte Recruitment (MUST MEMORIZE):

1. Margination

• Normally, red blood cells flow in the center of vessels, with leukocytes on the periphery (axial flow)
• As blood flow slows (stasis), leukocytes move to the vessel periphery - this is called margination
• Definition: "The movement of leukocytes to the periphery of the vessel wall"

2. Rolling

• Leukocytes tumble along the endothelial surface
• Mediated by selectins:
  • E-selectin (on endothelium - expressed after cytokine activation)
  • P-selectin (on endothelium - stored in Weibel-Palade bodies, released within minutes by histamine)
  • L-selectin (on leukocytes)
• Selectins bind sialic acid-containing oligosaccharides (carbohydrate ligands)

3. Firm Adhesion (Sticking)

• Loose rolling converts to firm adhesion
• Mediated by integrins on leukocytes binding to ICAM-1 and VCAM-1 on endothelium
  • Integrins (e.g., LFA-1, Mac-1) are activated by chemokines
  • ICAM-1 (intercellular adhesion molecule-1) - ligand for LFA-1
  • VCAM-1 (vascular cell adhesion molecule-1) - ligand for VLA-4 on monocytes/lymphocytes
• Activated by cytokines: IL-1, TNF-α (increase ICAM and VCAM expression)

Exam Tip (MCQ Q22): The most important molecules for leukocyte adhesion are Selectins and Integrins.

4. Transmigration (Diapedesis)

• Leukocytes squeeze through gaps between endothelial cells (paracellular route) - mainly in postcapillary venules
• Key molecule: PECAM-1 (CD31) - expressed on both leukocytes and endothelial junctions, mediates "zippering through"
• Leukocytes then cross the basement membrane using collagenases

5. Chemotaxis

• Directed migration of leukocytes toward the site of injury along a chemical gradient
• Definition: "Directed movement of leukocytes toward chemical signals"

• Bacterial products (N-formyl methionine peptides - fMLP)
• C5a (complement fragment)
• Leukotriene B4 (LTB4)
• Chemokines (e.g., IL-8/CXCL8 for neutrophils; MCP-1/CCL2 for monocytes)

Exam Tip (MCQ Q12): Chemotaxis = directed movement toward chemical signals (NOT random movement, which is chemokinesis).

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C. LEUKOCYTE SEQUENCE AT INFLAMMATORY SITES

First Responders: Neutrophils (PMNs)

• Arrive first (within 6-24 hours) to acute inflammation sites
• Predominant cell in acute inflammation
• Short-lived (die within 24-48 hours)
• Functions: phagocytosis, killing via reactive oxygen species (ROS) and lysosomal enzymes, release of mediators

Second Wave: Macrophages

• Arrive after neutrophils (24-48 hours, peaking at 48-72 hours)
• Derived from monocytes that emigrate from blood
• Long-lived; replace neutrophils as dominant cell
• Functions: phagocytosis, antigen presentation, cytokine secretion (TNF-α, IL-1, IL-6, IL-12), growth factor release for repair
• NOT a source of collagen synthesis (that is fibroblasts)

Exam Tip (MCQ Q13): Macrophages do NOT synthesize collagen. Collagen is synthesized by fibroblasts.

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D. PHAGOCYTOSIS

1. Recognition and attachment - Opsonization: coating of microbe with opsonins (IgG antibodies, C3b complement) enhances recognition by Fc receptors and CR1 (complement receptor 1)
2. Engulfment - Pseudopods extend around the particle, forming a phagosome
3. Killing and degradation - Phagosome fuses with lysosome forming phagolysosome

• Reactive oxygen species (ROS) - via NADPH oxidase ("respiratory burst"): produces superoxide (O2•-), hydrogen peroxide (H2O2), hypochlorous acid (HOCl via myeloperoxidase)
• Nitric oxide (NO) - via iNOS in macrophages
• Lysosomal enzymes - elastase, lysozyme, defensins, cathepsins (bactericidal)

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E. CHEMICAL MEDIATORS OF INFLAMMATION

Cell-Derived Mediators (Preformed - Stored in Granules)

Cell-Derived Mediators (Newly Synthesized)

Exam Tip (MCQ Q5): Main mediator of increased vascular permeability = Histamine. Main mediator of vasodilation = Histamine + NO. Fever mediators = IL-1, TNF-α, IL-6 (act on hypothalamus via prostaglandins).

Plasma-Derived Mediators (Circulate as Precursors)

1. Complement System (C1-C9)

• Activated by 3 pathways: Classical (antibody-antigen), Lectin (MBL-mannose binding), Alternative (spontaneous on microbial surfaces)
• Key products:
  • C3a, C5a (Anaphylatoxins) - increase vascular permeability, degranulate mast cells; C5a is also a potent chemotactic agent for neutrophils
  • C3b - opsonin (coats bacteria for phagocytosis)
  • C5b-9 (MAC) - Membrane Attack Complex - lyses bacterial membranes

2. Kinin System

• Bradykinin - causes vasodilation, increased permeability, smooth muscle contraction, and PAIN
• Activated by Hageman factor (Factor XII)

3. Coagulation/Fibrinolysis System

• Thrombin - promotes inflammation, activates PAR receptors on endothelium
• Fibrin degradation products - increase vascular permeability
• Plasmin - activates complement, degrades fibrin

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F. OUTCOMES OF ACUTE INFLAMMATION

Acute Inflammation
       ↓
   ┌──────────────────────────────────────────────┐
   │                                              │
Resolution    Abscess     Fibrosis/Scarring    Chronic
(complete    Formation    (fibrous repair)    Inflammation
 healing)    (pus wall)

1. Resolution (Complete) - If injury is minor and limited, inflammation resolves completely. Mediators are broken down, edema absorbed, leukocytes die by apoptosis. Tissue restores normal structure.
2. Abscess Formation - Pus is walled off by fibrous tissue. A localized collection of pus = abscess (requires drainage).
3. Fibrosis (Scarring) - When tissue cannot regenerate (e.g., myocardium, neurons). Replaced by collagen scar tissue.
4. Progression to Chronic Inflammation - If the cause persists (e.g., TB, autoimmune reaction) or acute inflammation fails to resolve.

Exam Tip (MCQ Q30): Failure of resolution of acute inflammation leads to Chronic Inflammation.

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PART 3: CHRONIC INFLAMMATION

Definition

• Prolonged inflammation (weeks, months, years)
• Characterized by simultaneous ongoing inflammation, tissue destruction, and tissue repair/healing
• Unlike acute inflammation, chronic inflammation represents a dysregulated, sustained response

Causes of Chronic Inflammation

1. Persistent infections - organisms resistant to phagocytosis (Mycobacterium tuberculosis, Treponema pallidum, fungi) - MOST COMMON CAUSE
2. Autoimmune diseases - rheumatoid arthritis, inflammatory bowel disease, lupus (immune reactions against self)
3. Prolonged exposure to irritants - silica (silicosis), asbestosis, atherosclerosis
4. Acute inflammation that fails to resolve

Exam Tip (MCQ Q14): Main cause of chronic inflammation = Persistent infection

Cellular Features of Chronic Inflammation

Dominant Cell: Macrophages

• Key cell in chronic inflammation (just as neutrophils are key in acute)
• Accumulate at the site, activated by cytokines (IFN-γ) and microbial products
• Can differentiate into epithelioid cells (in granulomatous inflammation)
• Can fuse to form multinucleated giant cells

Other Cells Present:

• Lymphocytes (T and B cells) - both CD4+ helper T cells and CD8+ cytotoxic T cells
• Plasma cells - secrete antibodies
• Eosinophils - in parasitic infections and allergic reactions
• Mast cells

Exam Tip (MCQ Q6 & Q7): Chronic inflammation = mononuclear cell infiltration, predominant cell = macrophages

Tissue Damage in Chronic Inflammation

• Caused by: Lysosomal enzymes from macrophages and Reactive Oxygen Species (ROS)
• NOT caused by RBCs, platelets, or antibodies alone

Exam Tip (MCQ Q25): Tissue damage in chronic inflammation = Enzymes and reactive oxygen species

Outcomes of Chronic Inflammation

• Fibrosis (scarring)
• Amyloidosis
• Increased cancer risk (e.g., colorectal cancer in IBD, hepatocellular carcinoma in chronic hepatitis)
• Destruction of specific tissues

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GRANULOMATOUS INFLAMMATION

Definition

Granuloma Components:

1. Epithelioid cells - activated macrophages with abundant pale cytoplasm, resemble epithelial cells (hence the name)
2. Multinucleated giant cells - formed by fusion of multiple epithelioid macrophages
   • Langhans giant cells - nuclei arranged in horseshoe/periphery pattern (TB)
   • Foreign body giant cells - nuclei scattered centrally
3. Lymphocytes - surrounding the epithelioid cells
4. Central necrosis (caseous necrosis) - in TB granulomas; cheese-like appearance
5. Fibrosis - surrounding older granulomas

Formation Trigger:

• Agents that cannot be eliminated by normal phagocytosis
• Key cytokine: IFN-γ (from T lymphocytes) activates macrophages to become epithelioid cells
• IL-12 (from macrophages) drives T helper cell differentiation toward Th1 → produce IFN-γ

Causes of Granulomatous Inflammation:

Exam Tip (MCQ Q15 & Q26): Granulomatous inflammation = epithelioid macrophages. TB is the classic condition.

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PART 4: SYSTEMIC EFFECTS OF INFLAMMATION

Acute Phase Response

1. Fever - cytokines act on hypothalamus → increase prostaglandin E2 → raise set point temperature
2. Leukocytosis - increased WBC count
   • Bacterial infections → neutrophilia (increased neutrophils)
   • Viral infections → lymphocytosis (increased lymphocytes)
   • Parasitic/allergic → eosinophilia
3. Elevated ESR (Erythrocyte Sedimentation Rate) - fibrinogen causes RBCs to stack (rouleaux)
4. Elevated CRP (C-reactive protein) - acute phase protein, made by liver; marker of inflammation
5. Hypoalbuminemia - albumin production decreases
6. Anorexia, malaise, fatigue

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PART 5: TISSUE REPAIR AND WOUND HEALING

Overview

Tissue Repair
     ↓
┌──────────────────┐
│                  │
Regeneration      Fibrosis (Scarring)
(original cells   (scar tissue replaces
 replace lost      normal tissue - when
  tissue)         regeneration impossible)

Cell Proliferative Capacity - Types of Cells

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Regeneration

• Complete restoration of normal tissue architecture
• Requires: Intact basement membrane/ECM scaffold + cells with proliferative capacity
• Driven by growth factors binding to cell receptors

Key Growth Factors:

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Fibrosis (Scarring)

• Occurs when regeneration is NOT possible (permanent cells) OR when ECM scaffold is destroyed
• Fibroblasts (key cells) are activated by TGF-β, PDGF, FGF
• Fibroblasts synthesize collagen (type I and III) and other ECM components
• Fibrosis = excessive collagen deposition (key MCQ fact)
• Pathological fibrosis: liver cirrhosis, pulmonary fibrosis, cardiac fibrosis after MI

Exam Tip (MCQ Q17): Fibrosis results from excess collagen deposition

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PART 6: GRANULATION TISSUE

Definition

Components of Granulation Tissue:

1. New capillaries (Angiogenesis) - thin-walled, leaky new blood vessels (give the pinkish "granular" appearance)
2. Proliferating fibroblasts - synthesize collagen and ECM
3. Inflammatory cells (macrophages)
4. Myofibroblasts - modified fibroblasts with contractile ability (important in wound contraction)
5. Loose ECM (hyaluronic acid, fibronectin)

Angiogenesis (Formation of New Blood Vessels)

• Key process in granulation tissue and tumor growth
• Stimulated by: VEGF (primary), FGF-2, PDGF
• Process: existing vessels sprout new capillaries → grow toward gradient

Exam Tip (MCQ Q8 & Q18): Granulation tissue = new capillaries + fibroblasts. Angiogenesis = formation of new blood vessels (NOT scar tissue, NOT collagen breakdown).

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PART 7: WOUND HEALING

The Three Phases of Wound Healing

Phase 1: Inflammatory Phase (Day 0-3)

• Occurs immediately after injury
• Hemostasis: platelets aggregate, fibrin clot forms
• Vasodilation and increased permeability (vascular response)
• Neutrophils arrive first (within hours), then macrophages (24-48 hours)
• Macrophages are the dominant cell here and orchestrate repair
• Debridement of dead tissue and bacteria
• Release of growth factors to initiate repair

Phase 2: Proliferative Phase (Day 3-21)

• Angiogenesis - new blood vessel formation (VEGF-driven)
• Fibroblast proliferation and migration into wound
• Collagen synthesis - initially type III collagen, then replaced by type I
• Granulation tissue formation (hallmark of this phase)
• Re-epithelialization - epithelial cells migrate from wound edges
• Wound contraction - myofibroblasts contract to reduce wound size

Exam Tip (MCQ Q27): Proliferative phase = angiogenesis and fibroblast proliferation

Phase 3: Remodeling Phase (Day 21 - 1 year+)

• Collagen remodeling: type III collagen replaced by type I collagen (stronger)
• Matrix metalloproteinases (MMPs) degrade old collagen; new collagen is deposited
• Tensile strength increases: reaches ~70-80% of original strength maximum (never 100%)
• Vascularity decreases - granulation tissue becomes an avascular scar
• Scar matures and becomes pale

Exam Tip (MCQ Q10): Collagen remodeling occurs in the Remodeling phase

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Wound Healing by Primary vs. Secondary Intention

Exam Tip (MCQ Q9 & Q19): Primary intention = clean surgical wounds. Secondary intention = large tissue loss.

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PART 8: FACTORS AFFECTING WOUND HEALING

Local Factors (Impair Healing)

1. Infection - most important local factor that impairs healing; bacteria prolong inflammation, produce toxins, destroy tissue
2. Poor blood supply - ischemia deprives tissue of oxygen and nutrients
3. Foreign bodies - sutures, glass, soil impair healing
4. Wound size and location - larger wounds = slower healing
5. Radiation - damages blood vessels, impairs cell division

Systemic Factors (Impair Healing)

1. Diabetes mellitus - impairs neutrophil function, causes vascular disease, peripheral neuropathy prevents recognition of injury, high glucose impairs collagen synthesis
2. Malnutrition - protein deficiency impairs collagen synthesis; vitamin C deficiency (scurvy) = defective hydroxylation of proline/lysine in collagen
3. Glucocorticoids (steroids) - inhibit collagen synthesis, reduce inflammatory response
4. Anemia - reduces oxygen delivery to wound
5. Old age - reduced regenerative capacity
6. Immunosuppression - increases infection risk

Exam Tip (MCQ Q16 & Q29): Factor that IMPAIRS healing = Infection (local), Diabetes mellitus (systemic).

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PART 9: COMPLICATIONS OF WOUND HEALING

1. Wound Dehiscence

• Reopening/bursting open of a wound
• Common in abdominal wounds
• Caused by infection, poor suturing, increased abdominal pressure, malnutrition

2. Keloid Formation

• Excessive collagen deposition beyond wound margins (extends beyond original wound)
• Occurs more commonly in dark-skinned individuals
• Composed of thick bands of type I collagen
• Appears as a raised, irregular, firm scar
• Tendency to recur after excision

3. Hypertrophic Scar

• Excess collagen within wound margins (does NOT extend beyond)
• Usually regresses over time (unlike keloid)
• Less severe than keloid

Exam Tip (MCQ Q28): Keloid = excessive collagen deposition

4. Contractures

• Excessive wound contraction by myofibroblasts
• Serious problem across joints - restricts movement
• Common after burns

5. Chronic Non-Healing Wounds

• Diabetic foot ulcers, venous stasis ulcers, pressure sores
• Persistent inflammation, inadequate blood supply, infection

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PART 10: COMPARING ACUTE vs. CHRONIC INFLAMMATION

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PART 11: DIAGRAM EXPLANATIONS

Diagram 1: Overview of Inflammation Process

Diagram 2: Leukocyte Recruitment (Steps at the Vessel Wall)

1. Normal blood flow (RBCs in center, leukocytes at periphery)
2. Stasis develops as fluid leaks out
3. Margination - leukocytes crowd the vessel wall
4. Rolling - loose attachment via selectins (P-selectin, E-selectin on endothelium; L-selectin on leukocytes)
5. Firm adhesion - integrins (LFA-1 on leukocytes) bind ICAM-1 on endothelium
6. Transmigration/Diapedesis - leukocytes squeeze through junctions (PECAM-1 mediates this)
7. Chemotaxis - migration toward the source of chemoattractants (C5a, LTB4, IL-8, bacterial peptides)

Diagram 3: Chemical Mediators Summary

• Mast cells release histamine (early, rapid response)
• Arachidonic acid pathway - COX branch → prostaglandins; LOX branch → leukotrienes
• Plasma proteins - complement activation cascade (C3a, C5a, MAC), kinin system (bradykinin)
• All converge to produce: vasodilation, increased permeability, chemotaxis, pain, fever

Diagram 4: Exudate vs Transudate

• Normal capillary: hydrostatic pressure (~32 mmHg arterial end, 12 mmHg venous end) is balanced by colloid osmotic pressure (~25 mmHg)
• Exudate: endothelial gaps allow large proteins through → high protein → pulls more fluid out
• Transudate: increased hydrostatic pressure (heart failure) OR decreased colloid osmotic pressure (hypoalbuminemia/liver disease) → low protein fluid accumulates

Diagram 5: Granuloma Structure

• Center: caseous necrosis (in TB) - cheesy, acellular zone
• Inner zone: Epithelioid macrophages - activated, pale cytoplasm
• Langhans giant cells - horseshoe arrangement of nuclei at periphery of cell
• Middle zone: CD4+ T lymphocytes (secrete IFN-γ which maintains granuloma)
• Outer zone: fibroblasts → fibrosis (in older granulomas)

Diagram 6: Outcomes of Acute Inflammation

• Resolution → Normal tissue
• Abscess → Pus collection
• Fibrosis → Scar tissue
• Chronic inflammation → Persistent disease

Diagram 7: Phases of Wound Healing (Timeline)

• 0-3 days: Inflammatory phase - clot, neutrophils, then macrophages
• 3-21 days: Proliferative phase - granulation tissue, angiogenesis, collagen (type III), re-epithelialization
• 21+ days: Remodeling phase - type III → type I collagen, increased tensile strength, scar maturation

Diagram 8: Primary vs Secondary Intention

• Primary: wound edges closed → minimal gap → thin scar
• Secondary: large open wound → extensive granulation tissue → wound contraction → large scar

Diagram 9: Healing by Primary Intention (Step by Step)

• Day 1: Clot in incision, neutrophil infiltration
• Day 2-3: Macrophages replace neutrophils, early granulation tissue forms
• Day 5-7: Granulation tissue fills the gap, new capillaries
• Week 2-4: Collagen accumulates, vascularity decreases
• 1 month+: Scar - collagen remodeled, no inflammation

Diagram 10: Factors Affecting Wound Healing (Mind Map/Summary Diagram)

• Local: infection (most important), blood supply, foreign bodies, radiation
• Systemic: diabetes, nutrition (protein, Vit C, zinc), steroids, immunosuppression, old age

Diagram 11: Keloid vs Hypertrophic Scar

• Keloid: scar extends BEYOND wound margins; does not regress
• Hypertrophic: scar stays WITHIN wound margins; may regress

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PART 12: COMPLETE MCQ ANSWER KEY WITH EXPLANATIONS

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TAKE-HOME SUMMARY (Exam High-Yield Points)

• Rapid, short-lived, neutrophil-dominated
• Vascular changes: vasodilation (histamine, NO) + increased permeability (histamine, bradykinin, leukotrienes)
• Cellular steps: Rolling → Adhesion → Transmigration → Chemotaxis
• Selectins (rolling), Integrins + ICAM/VCAM (adhesion), PECAM-1 (transmigration)
• Can resolve, form abscess, fibrose, or progress to chronic

• Prolonged, macrophage + lymphocyte-dominated
• Simultaneous injury and repair
• Caused by persistent infection (TB), autoimmune disease, irritants
• Tissue damage by: ROS + lysosomal enzymes
• Granulomas = epithelioid macrophages (TB, sarcoidosis, Crohn's, fungal)

• Labile cells → regeneration; permanent cells (neurons, cardiac) → scarring only
• Granulation tissue = new capillaries + fibroblasts (driven by VEGF, FGF, PDGF)
• Key fibrosis driver: TGF-β → activates fibroblasts → collagen synthesis

1. Inflammatory (0-3 days): clot, neutrophils, macrophages
2. Proliferative (3-21 days): granulation tissue, angiogenesis, type III collagen
3. Remodeling (21+ days): type III → type I collagen, tensile strength↑, scar matures

• Primary intention = clean/surgical wound = minimal scar
• Secondary intention = large tissue loss = big scar, wound contraction
• Keloid = scar beyond wound edges = excessive collagen
• Diabetes = major systemic impairment; Infection = major local impairment

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What These Notes Cover (Page by Page)

• Pages 1-16 (Pre-test MCQs): All 30 MCQs with their correct answers and detailed explanations included in the MCQ Answer Key table at the end
• Page 17 (Title slide): Chapter topic
• Page 18 (Learning Objectives): All 5 objectives are addressed throughout the notes
• Pages 19-62 (All diagram/image slides): Each type of diagram is explained in Part 11 - Diagram Explanations section, covering: leukocyte recruitment steps at vessel wall, mediator cascade, exudate vs transudate, granuloma structure (concentric zones), phases of wound healing timeline, primary vs secondary intention comparison, keloid vs hypertrophic scar, and outcomes of inflammation
• Pages 63-64 (Take-home messages): Integrated into the final summary
• Pages 65-79 (Post-test MCQs): Same 30 questions - all answered with explanations

Key Exam Tips Highlighted Throughout

• First cell in acute inflammation = Neutrophils
• Dominant cell in chronic inflammation = Macrophages
• Sequence of leukocyte recruitment = Rolling → Adhesion → Transmigration
• Main permeability mediator = Histamine
• Granuloma hallmark cell = Epithelioid macrophages
• Collagen remodeling phase = Remodeling phase
• Keloid = excessive collagen beyond wound edges
• Macrophages do NOT make collagen - fibroblasts do