Inflammation — Acute and Chronic Inflammation, Healing and Repair
🟢 Lite — Quick Review (1h–1d)
Rapid summary for last-minute revision before your exam.
Inflammation is a core pathology topic — questions in INI CET frequently test knowledge of the mechanisms of acute and chronic inflammation, the cells involved, the chemical mediators, and the outcomes of healing. Focus on the cardinal signs of inflammation, the difference between exudate and transudate, and the stages of healing.
High-Yield Facts for INI CET:
- Cardinal signs of inflammation: Calor (heat), Dolor (pain), Tumor (swelling), Rubor (redness), Functio laesa (loss of function)
- Exudate: High protein (>3g/dL), high LDH, high cell content — indicates inflammation; Transudate: Low protein (<3g/dL), low LDH — indicates systemic cause (heart failure, cirrhosis)
- Acute inflammation: Neutrophils (PMNs) predominate; Chronic inflammation: Lymphocytes, plasma cells, macrophages (MONO); Giant cells in granulomas
- Healing: Granulation tissue → fibroblasts + new vessels + macrophages → scar; wound strength: 30% at 1 week, 80% at 3 months; collagen remodelling continues for years
⚡ Exam tip: Neutrophils arrive first in acute inflammation (within minutes to hours); macrophages arrive by 24-48 hours; lymphocytes come later in chronic inflammation. If you see eosinophils prominently, think parasitic infection, allergic reaction, or Hodgkin’s lymphoma.
🟡 Standard — Regular Study (2d–2mo)
Standard content for students with a few days to months.
Acute Inflammation:
Sequence of Events
- Vasodilation: Immediate; mediated by histamine, NO, prostaglandins (PGI2, PGE2); causes redness (rubor) and warmth (calor)
- Increased permeability: Endothelial cell contraction (histamine, bradykinin, leukotrienes) → gaps between cells → oedema (swelling — tumor); also direct injury and leukocyte-dependent injury
- Emigration of leukocytes: Margination (move to periphery) → rolling (selectin-mediated) → adhesion (integrin-mediated) → transmigration (diapedesis) through vessel wall → chemotaxis
Chemical Mediators
Vasoactive amines:
- Histamine: Released from mast cells, basophils, platelets; causes vasodilation, increased permeability; blocked by antihistamines (H1 blockers for allergies)
- Serotonin: From platelets; similar effects to histamine
Arachidonic acid metabolites (eicosanoids):
- COX pathway (cyclooxygenase): PGH2 → PGE2, PGD2 (inflammatory), PGI2 (vasodilation, inhibits platelet aggregation — prostacyclin from endothelium), TXA2 (vasoconstriction, platelet aggregation — from platelets); NSAIDs block COX → reduced prostaglandins → anti-inflammatory effect
- LOX pathway (lipoxygenase): 5-HPETE → LTB4 (potent neutrophil chemotactic agent), LTC4, LTD4, LTE4 (slow-reacting substance of anaphylaxis — bronchoconstriction, increased vascular permeability)
Cytokines:
- IL-1, TNF-alpha: Fever (acts on hypothalamus), acute phase reactants, endothelial activation, neutrophil recruitment
- IL-6: Acute phase reactants; pyogenic (causes abscess formation)
Complement system:
- Classic (antibody-dependent), alternative (spontaneous), lectin (MBL) pathways → C3a (anaphylatoxin — histamine release), C3b (opsonisation), C5a (neutrophil chemotaxis and activation), MAC (membrane attack complex — C5b-C9 → lysis)
- C3 is central to all pathways
Kallikrein-Kinin system:
- Kininogen → kallikrein → bradykinin → increases vascular permeability, causes pain
Coagulation cascade:
- Thrombin → fibrin mesh; also has inflammatory effects — activates endothelial cells, attracts neutrophils
Key inflammatory cells and their roles:
Neutrophils (PMNs):
- First responders; 1-2 days of acute inflammation; arrive within minutes to hours
- Phagocytose bacteria and debris; release lysosomal enzymes (causes bystander tissue damage)
- Multi-lobed nucleus (2-5 lobes); azurophilic granules (lysosomes containing myeloperoxidase, defensins)
- Lunge, migrate, phagocytose, kill (respiratory burst → superoxide → hydrogen peroxide → hypochlorous acid)
- Bacterial infection: High neutrophil count (neutrophilia); toxic granulation (large dark granules — indicates severe infection); band cells (left shift — immature neutrophils released)
Macrophages:
- Arrive by 24-48 hours; persist in chronic inflammation
- Origins: Blood monocytes → tissue macrophages (different names: Kupffer cells in liver, alveolar macrophages in lungs, microglia in brain, histiocytes in connective tissue)
- Phagocytose debris, present antigen (MHC II → T cells), release cytokines (IL-1, TNF, growth factors)
- Chronic inflammation: Macrophages are the dominant cells; epithelioid cells (activated macrophages that look epithelial — found in granulomas); giant cells (fused macrophages — Langhans-type in TB, foreign body giant cells)
- Giant cells: Langhans (peripheral nuclei — TB), foreign body (scattered nuclei — foreign material), Touton (central ring of nuclei surrounded by foamy cytoplasm — xanthomatous)
Eosinophils:
- Increased in parasitic infections (eosinophil granules contain major basic protein — toxic to parasites), allergic reactions, Hodgkin’s lymphoma, drug reactions
- Bilobed nucleus; large eosinophilic granules (crystalloids — Charcot-Leyden crystals in bronchial asthma; made of eosinophil cationic protein)
Lymphocytes:
- Chronic inflammation; T cells (cellular immunity), B cells (humoral immunity); plasma cells (active antibody secretion)
- Small lymphocytes with condensed chromatin; scant cytoplasm; transform to larger immunoblasts when activated
- Seen in: Viral infections, chronic bacterial infections (TB, syphilis), autoimmune diseases, transplant rejection
Mast cells:
- Tissue cells; contain basophilic granules (heparin + histamine); involved in Type I hypersensitivity (immediate — anaphylaxis, asthma)
- Degranulation releases histamine, leukotrienes, prostaglandins
- Also involved in parasitic infections and wound healing
Platelets:
- Release PDGF (platelet-derived growth factor) and TGF-beta → fibroblast proliferation; important in repair
🔴 Extended — Deep Study (3mo+)
Comprehensive coverage for students on a longer study timeline.
Outcomes of Acute Inflammation:
- Resolution: Complete restoration to normal tissue; occurs if the injurious agent is eliminated and the tissue can regenerate; requires intact basement membrane and sufficient cell proliferation capacity
- Suppuration: Abscess formation (localised collection of purulent exudate — neutrophils + necrotic debris + fluid); pus contains dead neutrophils (pus cells), dead tissue, bacteria
- Chronic inflammation: If the injurious agent cannot be eliminated; persisting inflammation → tissue damage and fibrosis
- Scarring: Replacement of damaged tissue with dense collagen; occurs in tissues that cannot regenerate; granulation tissue → myofibroblasts contract → scar
- Systemic effects: Fever (IL-1, TNF acting on hypothalamus), leukocytosis (IL-1 stimulates neutrophil release), acute phase proteins (CRP, fibrinogen, serum amyloid A — produced by liver under IL-6 stimulation)
Exudate vs Transudate:
| Feature | Exudate | Transudate |
|---|---|---|
| Protein | >3 g/dL | <3 g/dL |
| LDH | High (similar to serum) | Low |
| Cell count | High (WBC >500/μL) | Low |
| Specific gravity | >1.018 | <1.018 |
| Appearance | Cloudy, yellow | Clear |
| Cause | Inflammation | Systemic (heart failure, cirrhosis, nephrotic syndrome) |
Cell Types in Different Inflammatory Exudates:
- Neutrophilic: Acute bacterial infection
- Eosinophilic: Parasites, allergy, drug reactions, Hodgkin’s lymphoma
- Lymphocytic: Chronic inflammation, viral infections, TB
- Plasmacytic: Chronic infections, plasma cell dyscrasias
- Hemorrhagic: Vascular injury, trauma, malignancy
- Fibrinous: Severe inflammation (uraemia, rheumatic fever, pneumonia) — forms membrane on serosal surfaces
Chronic Inflammation:
Causes
- Persistent infections: TB, syphilis, fungal infections, certain parasites (leishmaniasis)
- Immune-mediated diseases: Autoimmune (RA, SLE, type 1 DM), hypersensitivity reactions (bronchial asthma, allergic rhinitis)
- Prolonged exposure to irritants: Silicosis, atherosclerosis (lipid-induced inflammation in vessel wall)
- Unknown: Sarcoidosis (non-caseating granulomas; unknown aetiology)
Morphology
- Mononuclear infiltrate: Lymphocytes, plasma cells, macrophages
- Fibrosis: Due to fibroblast activation by cytokines (PDGF, TGF-beta, IL-1)
- Tissue destruction: From persistent inflammatory cells
- Angiogenesis: New vessel formation (from proliferating endothelial cells); allows delivery of inflammatory cells + nutrients for repair
Granulomatous Inflammation:
Granuloma: Collection of epithelioid macrophages surrounded by lymphocytes + occasional giant cells; a form of chronic inflammation where macrophages attempt to wall off an offending agent they cannot eliminate
Types of granulomas:
- Infection-related: TB (caseating granulomas — central caseous necrosis), syphilis (gumma — plasma cells + giant cells + fibrosis), leprosy, schistosomiasis, cat scratch disease, fungal infections
- Non-infectious: Sarcoidosis (non-caseating, may have Schaumann bodies — laminated calcifications, asteroid bodies — stellate inclusions in giant cells), Crohn’s disease (transmural granulomas), foreign body granulomas (silica, suturing material, beryllium)
- In granulomatous vasculitis: Wegener’s granulomatosis (now Granulomatosis with Polyangiitis) — necrotising granulomas in respiratory tract + necrotising vasculitis + necrotizing glomerulonephritis; c-ANCA positive
TB Granuloma (caseating granuloma):
- Central caseous necrosis (cheese-like); surrounded by:
- Epithelioid macrophages (activated, elongated, look like epithelial cells)
- Langhans giant cells (peripheral nuclei — horseshoe pattern; formed by fusion of macrophages)
- Lymphocytes (T cells — CD4+)
- Peripheral fibrosis
- Acid-fast bacilli (Mycobacterium tuberculosis) may be visible on Ziehl-Neelsen stain; use fluorescent auramine O stain for better sensitivity
Foreign Body Granuloma:
- Non-caseating; foreign body giant cells (scattered nuclei rather than peripheral)
- In response to: Sutures, silica, asbestos, beryllium, schistosome eggs, pollen, implanted devices
- Beryllium granulomas → chronic berylliosis (Type IV hypersensitivity — Be acts as a hapten)
Healing and Repair:
Wound Healing — Steps
Phase 1 — Haemostasis (immediate):
- Platelet aggregation → fibrin clot formation (coagulation cascade)
- Platelet release: PDGF, TGF-beta, EGF → initiate repair
- Fibrin clot acts as scaffold for migrating cells
Phase 2 — Inflammation (Day 1-3):
- Neutrophils arrive (0-24h): Debris removal; release proteases and ROS; peak at 24-48h
- Macrophages dominate (1-3 days): Continue debris removal; release cytokines (IL-1, TNF) that stimulate fibroblast proliferation; release growth factors (PDGF, TGF-beta, EGF, FGF)
- Lymphocytes arrive (later): Modulate wound healing (TGF-beta promotes fibrosis)
Phase 3 — Proliferation (Day 3-3 weeks):
- Angiogenesis: New blood vessel formation; endothelial cells proliferate in response to VEGF (vascular endothelial growth factor) and basic FGF; vessels are leaky (immature) → granulation tissue is oedematous
- Fibroblast proliferation: Fibroblasts migrate into wound; synthesise collagen and extracellular matrix (fibronectin, tenascin); initially Type III collagen (immature, thin); later replaced by Type I collagen
- Granulation tissue formation: Characteristic appearance under microscope — numerous new vessels (red), fibroblasts (spindle-shaped), macrophages, loose collagen; fragile, bleeds easily
- Wound contraction: Myofibroblasts (fibroblasts that acquire smooth muscle features — alpha-smooth muscle actin) contract → wound edges come together; can cause distortion (contracture) if excessive
- Epithelialisation: Re-epithelialisation from wound edges; basal cells migrate across wound bed; contact inhibition stops migration when cells meet; epithelial cells release cytokines that promote wound healing
- Keratinocyte growth factor (KGF): Stimulates epithelial migration
Phase 4 — Remodelling (3 weeks to years):
- Collagen remodelling: Type III collagen replaced by Type I (stronger); cross-linking increases; wound tensile strength increases
- Myofibroblasts disappear (apoptosis) → scar contraction
- Scar matures: Becas扁平 and pale; cellularity decreases; vascular regression → avascular scar
- Tensile strength: 30% at 1 week, 50% at 3 weeks, 80% at 3 months; never returns to 100% (remains at ~80% maximum)
- Scar is metabolically active for years — collagen continues to be remodelled
Healing by Primary Intention (Surgical wound):
- Edges approximated (sutured); minimal tissue loss; minimal inflammation; heal quickly with minimal scar
- Steps: Haemostasis → inflammation (less) → proliferation → remodelling
Healing by Secondary Intention (Open wound):
- Large tissue defect; wound contracts; large scar; longer healing time; more inflammation
- Granulation tissue fills defect; epithelialisation occurs from edges; wound contraction reduces size
Factors Affecting Wound Healing:
Local:
- Infection (most common cause of delayed healing)
- Poor blood supply/ischaemia (atherosclerosis, venous stasis)
- Foreign bodies (suture material, dirt, glass)
- Mechanical stress (movement delays healing)
- Size and depth of wound
- Necrotic tissue
- Ionising radiation
Systemic:
- Age (elderly heal slower)
- Malnutrition (protein deficiency impairs healing — Kwashiorkor → poor wound healing, fragile skin)
- Vitamin C deficiency (scurvy — impaired collagen synthesis; can’t hydroxylate proline and lysine)
- Zinc deficiency (impaired epithelialisation and collagen synthesis)
- Diabetes mellitus (impaired healing due to microvascular disease, neutrophil dysfunction)
- Immunosuppression (steroids impair healing by reducing inflammation and fibroblast proliferation)
- Smoking (delays healing — vasoconstriction from nicotine; carbon monoxide reduces oxygen delivery)
Complications of Wound Healing:
- Infection: Wound infection → dehiscence; common organisms: Staph aureus, Streptococcus pyogenes, Pseudomonas
- Dehiscence: Wound breaks open; risk factors: sutured under tension, infection, malnutrition, coughing
- Keloid: Excessive collagen deposition beyond wound margins; more common in dark-skinned individuals; familial tendency; treatment: intralesional steroids, pressure, silicone gel, radiotherapy (prevent recurrence); not to be confused with hypertrophic scar (stays within wound)
- Hypertrophic scar: Excessive but stays within wound boundary; treatment: steroid injection
- Contracture: Excessive wound contraction; may limit joint movement (burns — flexion contractures)
- Adhesions: Fibrous bands between structures; in peritoneal cavity → can cause bowel obstruction
- Ulceration: Poorly healing wound breaks down → chronic ulcer
- Gaping: Wound edges separate due to inadequate suturing or infection
Tissue Regeneration vs Repair:
- Regeneration: Restoration of original tissue architecture; occurs if basement membrane is intact and parenchymal cells can proliferate (liver, kidney, skin); labile cells (epithelial, hematopoietic) proliferate constantly; stable cells (hepatocytes, fibroblasts) can proliferate on demand; permanent cells (neurons, cardiac myocytes) cannot divide (if permanent cells die → scarring)
- Repair: Tissue replacement with collagen (scarring); occurs when parenchymal cells cannot regenerate (extensive damage, permanent cells); granulation tissue → scar
Collagen Synthesis:
- Pro-alpha chains synthesised in rough ER → hydroxylation of proline and lysine (requires vitamin C as cofactor) → glycosylation → triple helix formation (tropocollagen) → secreted → cross-linking (requires copper as cofactor for lysyl oxidase) → collagen fibrils
- Types: Type I — skin, bone, tendon; Type II — cartilage; Type III — granulation tissue, blood vessels; Type IV — basement membrane; Type V — fetal tissue
Growth Factors in Wound Healing:
- PDGF (platelet, macrophages): Fibroblast proliferation, angiogenesis, macrophage activation
- TGF-beta (platelets, macrophages): Fibroblast chemotaxis, collagen synthesis, scar formation
- EGF (platelets, macrophages): Epithelial migration, fibroblast proliferation
- VEGF: Angiogenesis
- FGF: Angiogenesis, fibroblast proliferation, granulation tissue formation
- KGF (fibroblasts): Epithelial cell proliferation
- TNF-alpha, IL-1: Stimulate fibroblast and inflammatory cell activity