Inflammation & Wound Healing

🟢 Lite — Quick Review (1h–1d)

Rapid summary for last-minute revision before your exam.

Acute inflammation (<24 hrs): Neutrophils, vasodilation, increased vascular permeability → heat, redness, swelling, pain, loss of function. Cardinal signs: Rubor (redness), calor (heat), tumor (swelling), dolor (pain), functio laesa (loss of function).

Chronic inflammation (days–weeks): Lymphocytes, macrophages, plasma cells; tissue destruction + fibrosis; granuloma formation.

Wound healing:

• 1st intention: Clean surgical incision; minimal tissue loss; sutured; minimal scarring
• 2nd intention: Large tissue loss; healing from wound edges + base; granulation tissue; significant scar
• 3rd intention: Wound approximated but infected; healing by secondary intention

Types of healing: Regeneration (hepatocytes, epithelium) vs fibrosis/scarring (connective tissue).

⚡ Exam tip: “Granuloma with caseous necrosis” = TB. “Granuloma with asteroid bodies” = sarcoidosis. “Granuloma with schistosome eggs” = schistosomiasis.

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🟡 Standard — Regular Study (2d–2mo)

Standard content for students with a few days to months.

Acute Inflammation

Steps

1. Vasodilation (immediate, transient): Histamine, bradykinin, NO → arterioles dilate → redness (rubor) and heat (calor); mediated by histamine and prostaglandins
2. Increased vascular permeability (immediate or delayed):
   • Immediate transient: Histamine, bradykinin → endothelial cell contraction (widens intercellular gaps) → leak in venules (1–5 µm); lasts 15–30 min
   • Immediate sustained: Severe injury (burns, toxins) → direct endothelial damage → leakage from all vessels
   • Delayed sustained: Cytokines (IL-1, TNF-α, VEGF) → endothelial cell contraction → leak in venules and capillaries; takes 4–6 hours
3. Leukocyte extravasation: Rolling → adhesion → transmigration → chemotaxis
4. Phagocytosis: Opsonization (IgG, C3b), recognition, engulfment, killing

Leukocyte Extravasation Sequence

1. Margination: Leukocytes move to periphery of vessel
2. Rolling: Selectins (E-selectin, P-selectin) on endothelium bind carbohydrates on leukocytes → transient adhesion → leukocytes “roll”
3. Adhesion: Tight adhesion; ICAM-1, VCAM-1 on endothelium bind integrins (LFA-1 = CD11a/CD18; Mac-1 = CD11b/CD18) on leukocytes
4. Transmigration (diapedesis): Leukocytes squeeze between endothelial cells; CD31 (PECAM-1) on both leukocytes and endothelium facilitates this
5. Chemotaxis: Directed migration along chemical gradient; neutrophil attractants: bacterial products (N-formyl peptides), C5a, IL-8 (CXCL8), LTB4

Phagocytosis & Killing

Opsonization: IgG (Fab fragment binds antigen, Fc binds Fc receptor on neutrophils/macrophages), C3b (complement opsonin)

Killing mechanisms:

• Oxygen-dependent (respiratory burst):
  • NADPH oxidase generates superoxide (O₂⁻) → dismutates to H₂O₂
  • Myeloperoxidase (MPO) in neutrophils: H₂O₂ + Cl⁻ → HOCl (hypochlorous acid, bleach) → potent microbicide
  • Chronic Granulomatous Disease (CGD): Defect in NADPH oxidase → catalase-positive organisms (S. aureus, Aspergillus, Serratia, Nocardia, Burkholderia cepacia — mnemonic: “PLACESS”) cannot be killed
  • Nitroblue tetrazolium (NBT) test: Negative in CGD (no respiratory burst → no formazan blue color)
• Oxygen-independent: Lysozyme, lactoferrin, defensins, bactericidal permeability-increasing protein (BPI)

Neutrophil vs Monocyte/Macrophage

Feature	Neutrophils	Macrophages
First response	<6–12 hours	24–48 hours
Lifespan	Short (hours–days)	Long (months–years)
Primary role	Phagocytosis of bacteria	Phagocytosis of debris, chronic inflammation
Key enzymes	Myeloperoxidase	Lysosomal acid hydrolases
Not in healing	No role in tissue repair	Activate fibroblasts → fibrosis

Chronic Inflammation

Causes

• Persistent infections: TB, syphilis, viral infections, fungal infections
• Autoimmune diseases: Rheumatoid arthritis, SLE, IBD
• Prolonged exposure to toxic agents: Silica (silicosis), asbestos (asbestosis), hydrocarbons
• Transplant rejection

Histologic Features

• Infiltration by lymphocytes, plasma cells, macrophages (mononuclear infiltrate)
• Tissue destruction (by inflammatory cells)
• Fibrosis/scarring (attempted repair)
• Angiogenesis (new blood vessel formation; VEGF mediated)

Granulomatous Inflammation

Granuloma: Collection of epithelioid macrophages (activated macrophages with abundant pink cytoplasm) ± giant cells + lymphocytes + fibroblasts

Types of granulomas:

1. Foreign body granuloma: Non-immune; response to inert foreign material (suture, silica, asbestos, urate crystals, cholesterol crystals); giant cells are Langhans type (peripheral nuclei) but differ from TB granulomas
2. Immune granuloma: Type IV hypersensitivity; poorly degradable antigen persists → T cell-mediated (IFN-γ from CD4+ Th1 cells activates macrophages)

Key Examples:

• TB granuloma (caseating granuloma): Central caseous necrosis + epithelioid cells + Langhans giant cells (horseshoe nuclei) + peripheral lymphocytes + fibroblasts; contains M. tuberculosis (AFB may be scanty)
• Sarcoidosis: Non-caseating granulomas + asteroid bodies (eosinophilic inclusions in giant cells) + Schaumann bodies (laminated calcified concretions); bilateral hilar lymphadenopathy; lung involvement
• Crohn disease: Non-caseating granulomas; transmural inflammation; skip lesions
• Schistosomiasis: Granulomas with schistosome eggs; pipestem fibrosis (Symmers fibrosis)
• Cat-scratch disease: CSD granuloma with necrotizing stellate abscesses; Bartonella henselae
• Leprosy: Tuberculoid (paucibacillary, Th1 response, good immunity) vs Lepromatous (multibacillary, poor Th1 response, widespread disease)

Wound Healing

Phases of Wound Healing

1. Hemostasis (immediate): Platelet plug + fibrin clot; platelet-derived growth factor (PDGF) released
2. Inflammatory phase (Day 1–3):
   • Neutrophils predominate (first 24–48 hours); remove bacteria, debris
   • Macrophages appear by day 2–3; key cells for wound healing (secrete cytokines: IL-1, TNF-α, growth factors)
   • Lymphocytes appear by day 3–5
3. Proliferative phase (Day 3–3 weeks):
   • Granulation tissue: Fibroblasts + new blood vessels (angiogenesis, mediated by VEGF and FGF) + Type III collagen
   • Angiogenesis: Formation of new blood vessels from existing vessels; VEGF is key mediator
   • Fibroblasts: Migrate into wound; produce extracellular matrix (Type III collagen initially)
   • Myofibroblasts: Wound contraction (TGF-β mediated)
   • Epithelialization: Re-epithelialization from wound edges; basal cells migrate across wound bed; contact inhibition when confluence reached
4. Remodeling/Maturation (3 weeks–1–2 years):
   • Type III collagen → Type I collagen (scar strengthening)
   • Wound tensile strength: 3% at 1 week, 30% at 3 weeks, 80% at 3 months (max)
   • Scar: Pale, avascular, acellular; mature scar has Type I collagen (organized)

Factors Affecting Wound Healing

Local: Infection (most important), hypoxia (poor blood supply), radiation, denervation, foreign bodies, mechanical forces

Systemic: Age (elderly = slower), nutrition (protein, vitamin C, zinc), diabetes mellitus (impaired healing + increased infection), steroids (inhibit inflammation and fibroblast function), immunosuppression, smoking (vasoconstriction → hypoxia), malignancy

Complications of Wound Healing

• Infection: Most common complication; purulent discharge
• Dehiscence: Surgical wound breakdown; risk factors: wound infection, poor surgical technique, increased intra-abdominal pressure
• Hypertrophic scar: Raised scar within wound boundaries; more common in children, burns; regresses partially
• Keloid: Raised scar that extends beyond wound boundaries; more common in dark-skinned individuals; familial; Tx: intralesional steroids, pressure therapy, radiotherapy; RECURS despite treatment
• Contractures: Scarring that shortens tissue; most common after burns; limits joint movement
• Adhesions: Fibrous bands between serosal surfaces; most common in peritoneal cavity after surgery or peritonitis

Wound Strength

• Day 0: Tensile strength = 0 (transected)
• Week 1: ~3% (fibrin clot)
• Week 3: ~30% (Type III collagen cross-linking)
• Month 3: ~80% (Type I collagen replaces Type III; remodeling)
• Scar never reaches >80% of original tissue strength

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🔴 Extended — Deep Study (3mo+)

Comprehensive coverage for students on a longer study timeline.

Chemical Mediators of Inflammation

Vasoactive Amines

• Histamine: Stored in mast cells, basophils, platelets; released by IgE-mediated degranulation, complement (C3a, C5a), physical injury
• Actions: Vasodilation (H2 receptors), increased vascular permeability (H1 receptors → endothelial cell contraction), itch, pain
• Serotonin (5-HT): Platelets, enterochromaffin cells; vasoconstriction at high doses; vasodilation at low doses; potentiates platelet aggregation

Arachidonic Acid Metabolites

• Cyclooxygenase (COX) pathway → Prostaglandins (PGD₂, PGE₂, PGF₂α, PGI₂ = prostacyclin) and Thromboxane A₂ (TXA₂)
  • PGE₂: Vasodilation, fever, pain, protects gastric mucosa
  • PGI₂ (prostacyclin): Vasodilation, inhibits platelet aggregation (produced by endothelium)
  • TXA₂: Vasoconstriction, promotes platelet aggregation (produced by platelets)
  • Aspirin: Irreversibly inhibits COX-1 and COX-2 → ↓TXA₂ (antiplatelet) + ↓PGI₂ (both lost; net effect = antiplatelet); gastric ulceration (lost PGE₂ protection)
• Lipoxygenase (LOX) pathway → Leukotrienes (LTB₄, LTC₄, LTD₄, LTE₄)
  • LTB₄: Potent neutrophil chemotaxis
  • LTC₄, LTD₄, LTE₄: Bronchoconstriction, increased vascular permeability, mucus secretion (components of slow-reacting substance of anaphylaxis, SRS-A)

Cytokines

• IL-1: Fever (acts on hypothalamus → ↑COX → ↑PGE₂), acute phase reactants, endothelial activation
• TNF-α: Fever, cachexia, endothelial activation, shock, neutrophil recruitment
• IL-6: Acute phase reactants (hepatocytes → CRP, fibrinogen, serum amyloid A)
• IL-8 (CXCL8): Neutrophil chemotaxis (major chemokine for neutrophils)

Complement System

• C3a, C5a (anaphylatoxins): Mast cell degranulation → histamine release → vasodilation + increased permeability
• C3b: Opsonization (most important opsonin)
• C5a: Neutrophil chemotaxis + activation
• MAC (membrane attack complex): C5b–C9 → creates pores in bacterial cell membrane → lysis

Kinin System

• Bradykinin: Vasodilation, increased vascular permeability, pain (slow-acting), causes bronchoconstriction
• Generated from kininogen by kallikrein (activated by Hageman factor = Factor XII)
• Aspirin/NSAIDs inhibit bradykinin generation (part of their anti-inflammatory effect)

Nitric Oxide (NO)

• Produced by endothelial nitric oxide synthase (eNOS) → vasodilation; Anti-inflammatory (inhibits platelet aggregation, leukocyte adhesion)
• Produced by inducible nitric oxide synthase (iNOS) during inflammation → antimicrobial (reactive nitrogen species)

Healing of Specific Tissues

Liver Regeneration

• Hepatocytes can divide (quiescent → proliferate); can regenerate up to 70% of liver mass
• Oval cells (bipotent progenitor cells) activate when hepatocyte proliferation is impaired
• Liver architecture restored without scarring (if basement membrane is intact)
• Repeated injury → cirrhosis (fibrosis + regenerative nodules = regenerative failure)

Bone Healing

• Inflammatory phase: Hematoma formation between fracture ends; inflammatory infiltrate
• Soft callus formation (Days 7–14): Fibroblasts + chondrocytes produce Type II collagen (cartilaginous callus)
• Hard callus formation (Weeks 3–12): Osteoblasts produce woven bone (Type I collagen + hydroxyapatite); bridging callus
• Remodeling: Woven bone → lamellar bone; restored architecture

Myocardial Infarction Healing

• 0–4 hours: No visible changes; wavy fibers
• 4–12 hours: Early coagulative necrosis; edema; marginal RBC extravasation
• 12–24 hours: Coagulative necrosis begins; pyknosis, early neutrophil infiltration
• 1–3 days: Loss of nuclei; heavy neutrophil infiltration; yellow softening
• 3–7 days: Macrophages arrive; disintegration of dead myocytes; early granulation tissue at margins
• 1–3 weeks: Granulation tissue (capillaries + fibroblasts + macrophages); red, soft
• Weeks to months: Progressive fibrosis; grey-white scar tissue (dense collagen)

Nerve Regeneration

• CNS (brain, spinal cord): NO significant regeneration; oligodendrocytes produce inhibitory proteins (Nogo, MAG); glial scar
• PNS: Axons can regenerate; Schwann cells proliferate; Büngner bands guide regrowth; functional recovery possible if gap is small

Chronic Inflammation & Cancer

• Chronic irritation/inflammation → DNA damage → mutations → cancer (part of inflammation-oncology link)
• Examples: Chronic UC → colorectal cancer; chronic pancreatitis → pancreatic cancer; H. pylori → gastric cancer; chronic hepatitis B/C → hepatocellular carcinoma; asbestos → mesothelioma + lung cancer; schistosomiasis (S. haematobium) → bladder cancer

Key NEET PG Pearls

1. Cardinal signs of inflammation: Rubor (redness), calor (heat), tumor (swelling), dolor (pain), functio laesa (loss of function)
2. Neutrophils arrive first (<24 hrs); macrophages by day 2–3; lymphocytes by day 3–5
3. VEGF is the key growth factor for angiogenesis; PDGF is key for fibroblast proliferation
4. C3b = most important complement opsonin; C5a = neutrophil chemotaxis and activation
5. LTB₄ = potent neutrophil chemotactic factor (arachidonic acid via 5-lipoxygenase)
6. Granuloma with central caseous necrosis + Langhans giant cells = TB
7. Granuloma with asteroid bodies = Sarcoidosis; Schaumann bodies also seen
8. CGD: Defective NADPH oxidase → catalase-positive organisms; negative NBT test
9. Keloid: Extends beyond wound margins; dark-skinned individuals; recurrent; Hypertrophic scar: Within margins
10. Type III collagen → Type I collagen remodeling = wound strengthening; tensile strength never exceeds 80% of original

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