Inflammation — Acute & Chronic
Pathology · General Pathology · lean revision notes
Inflammation — Acute & Chronic
Inflammation is the protective vascular and cellular response of living vascularised tissue to an injurious agent, designed to localise and eliminate the offending stimulus and initiate repair. It is a double-edged sword: essential for survival yet capable of causing host tissue damage. This single topic seeds more NEET PG MCQs than almost any other in General Pathology — chiefly through chemical mediators and granuloma morphology.
Definition & Overview
Inflammation literally means "to set on fire" (Latin inflammare). It can be acute (rapid onset, short duration — minutes to days, dominated by neutrophils and exudation) or chronic (longer duration — weeks to years, dominated by lymphocytes, plasma cells and macrophages, with simultaneous tissue destruction and repair).
The five cardinal signs of acute inflammation:
| Sign (Latin) | English | Underlying mechanism |
|---|---|---|
| Rubor | Redness | Vasodilatation → increased blood flow |
| Calor | Heat | Increased blood flow |
| Tumor | Swelling | Exudation of protein-rich fluid (oedema) |
| Dolor | Pain | Bradykinin, prostaglandins (PGE2) |
| Functio laesa | Loss of function | Added by Rudolf Virchow |
High-yield: The first four cardinal signs (rubor, calor, tumor, dolor) were described by Celsus. The fifth, functio laesa (loss of function), was added by Virchow.
Acute Inflammation
Acute inflammation has three major components: (1) vascular changes, (2) cellular events (leucocyte recruitment and activation), and (3) chemical mediators.
Vascular Events
The sequence (memorise the order):
Transient vasoconstriction (seconds) → vasodilatation (arterioles, mediated by histamine & NO) → increased vascular permeability → stasis → margination of leucocytes.
Increased vascular permeability produces a protein-rich exudate (the hallmark of acute inflammation), distinguishing it from a transudate.
| Feature | Exudate | Transudate |
|---|---|---|
| Cause | Inflammation (↑ permeability) | Hydrostatic/oncotic imbalance |
| Protein | High (>3 g/dL) | Low (<3 g/dL) |
| Specific gravity | >1.020 | <1.012 |
| LDH | High | Low |
| Cells | Many (neutrophils) | Few |
| Light's criteria (pleural) | Meets ≥1 criterion | Meets none |
High-yield: Light's criteria for exudative pleural effusion — fluid protein/serum protein >0.5, fluid LDH/serum LDH >0.6, or fluid LDH > two-thirds the upper limit of normal serum LDH.
Mechanisms of increased vascular permeability:
- Endothelial contraction — the commonest, immediate-transient response; histamine, bradykinin, leukotrienes; affects venules; short-lived (15–30 min).
- Endothelial retraction — cytokine-mediated (IL-1, TNF, IFN-γ); delayed and prolonged.
- Direct endothelial injury — burns, toxins; immediate-sustained response; affects all microvessels.
- Leucocyte-mediated injury — late.
- Increased transcytosis — VEGF-mediated.
- Leakage from new vessels — angiogenesis (regeneration phase).
Cellular Events — Leucocyte Recruitment
The neutrophil journey across the vessel wall — the classic ordered cascade:
Margination → Rolling → Adhesion → Transmigration (diapedesis) → Chemotaxis
| Step | Key adhesion molecules | Notes |
|---|---|---|
| Rolling | Selectins (E-, P-, L-selectin) bind sialyl-Lewis X | Weak, transient |
| Stable adhesion | Integrins (LFA-1, VLA-4) bind ICAM-1, VCAM-1 | Activated by chemokines |
| Transmigration | PECAM-1 (CD31) | Through interendothelial junctions |
High-yield: P-selectin is stored preformed in Weibel-Palade bodies of endothelium and alpha granules of platelets; histamine and thrombin mobilise it within minutes. E-selectin is synthesised de novo (cytokine-induced).
Leucocyte Adhesion Deficiency (LAD):
- LAD-1 — defect in β2-integrin (CD18) → impaired adhesion/transmigration. Delayed umbilical cord separation, recurrent bacterial infections, no pus despite leucocytosis.
- LAD-2 — defect in sialyl-Lewis X (fucosyl transferase) → impaired rolling; milder, with Bombay (hh) blood group and mental retardation.
Chemotactic agents (cause directional leucocyte movement): C5a, LTB4, IL-8 (CXCL8), and bacterial N-formyl-methionyl peptides.
High-yield: Most potent chemotactic agents = C5a, LTB4, IL-8, bacterial products. (Mnemonic: "C5a Loves IL-8 Bacteria".)
Phagocytosis
Three steps: Recognition & attachment → Engulfment → Killing/degradation.
- Opsonins: IgG (Fc), C3b, and collectins (mannose-binding lectin) coat microbes for recognition.
- Killing is mainly via oxygen-dependent mechanisms (respiratory burst).
- NADPH oxidase generates superoxide → H2O2 → myeloperoxidase (MPO) + H2O2 + halide (Cl⁻) → hypochlorous acid (HOCl) — the most potent bactericidal system.
High-yield: Chronic granulomatous disease (CGD) = defective NADPH oxidase → no respiratory burst. Diagnosed by negative NBT (nitroblue tetrazolium) test or DHR (dihydrorhodamine) flow cytometry. Infections with catalase-positive organisms (S. aureus, Aspergillus, Serratia, Burkholderia, Nocardia).
Chediak-Higashi syndrome — defective lysosome-phagosome fusion (LYST gene), giant granules in leucocytes, partial albinism, recurrent infections.
Chemical Mediators of Inflammation
This is the single most examined sub-topic. Mediators are cell-derived or plasma-derived (synthesised by the liver, circulate as precursors).
Cell-Derived Mediators
| Mediator | Source | Main actions |
|---|---|---|
| Histamine | Mast cells, basophils, platelets | Vasodilatation, ↑ permeability (the first mediator released) |
| Serotonin | Platelets | Vasoconstriction/permeability |
| Prostaglandins | COX pathway | Vasodilatation, pain, fever |
| Leukotrienes | LOX pathway | LTC4/D4/E4 = ↑ permeability, bronchospasm; LTB4 = chemotaxis |
| PAF | Leucocytes, endothelium | Bronchoconstriction, ↑ permeability (100–1000× histamine) |
| Cytokines (TNF, IL-1) | Macrophages | Endothelial activation, fever, acute-phase response |
| Chemokines (IL-8) | Many cells | Chemotaxis |
| Nitric oxide | Endothelium, macrophages | Vasodilatation, microbicidal |
| ROS | Neutrophils, macrophages | Microbial killing, tissue damage |
Arachidonic acid (AA) metabolism — central exam concept:
Membrane phospholipids → (phospholipase A2) → Arachidonic acid → two pathways:
- Cyclooxygenase (COX) pathway → prostaglandins (PGE2, PGD2, PGF2α), prostacyclin (PGI2), thromboxane A2 (TXA2).
- Lipoxygenase (LOX) pathway → leukotrienes (LTB4, LTC4, LTD4, LTE4) and lipoxins.
| Eicosanoid | Source | Action |
|---|---|---|
| TXA2 | Platelets | Vasoconstriction, platelet aggregation |
| PGI2 (prostacyclin) | Endothelium | Vasodilatation, inhibits aggregation |
| PGE2 | Many | Pain, fever, vasodilatation |
| LTB4 | Leucocytes | Chemotaxis, leucocyte activation |
| LTC4/D4/E4 | Mast cells | Bronchospasm, ↑ permeability (slow-reacting substance of anaphylaxis, SRS-A) |
| Lipoxins | Platelets + leucocytes (transcellular) | Anti-inflammatory — inhibit neutrophil chemotaxis |
High-yield: Corticosteroids inhibit phospholipase A2 (via lipocortin/annexin-1), blocking BOTH COX and LOX pathways. NSAIDs/aspirin inhibit only COX. Zileuton inhibits 5-lipoxygenase; montelukast/zafirlukast are leukotriene receptor (CysLT1) antagonists. Aspirin irreversibly acetylates COX → low-dose used for antiplatelet effect (blocks platelet TXA2).
High-yield: Lipoxins and resolvins are anti-inflammatory mediators that terminate the inflammatory response. A class switch from leukotriene to lipoxin synthesis signals resolution.
Plasma-Derived Mediators
Three interlinked cascades, all triggered by activated Hageman factor (Factor XII): kinin, clotting/fibrinolytic, and complement systems.
Kinin system: Factor XIIa → prekallikrein → kallikrein → cleaves HMW kininogen → bradykinin (vasodilatation, ↑ permeability, pain, bronchospasm).
Complement system — classic NEET PG favourite:
| Component | Function |
|---|---|
| C3a, C5a (anaphylatoxins) | ↑ permeability, mast cell degranulation, vasodilatation |
| C5a | Most potent chemotactic factor; activates LOX |
| C3b | Opsonisation |
| C5b-9 (MAC) | Membrane attack complex → cell lysis |
High-yield: C3a and C5a = anaphylatoxins. C5a = chemotaxis + anaphylatoxin. C3b = opsonisation. C5b-9 (MAC) = lysis. (Mnemonic: anaphylatoxin = 3a, 5a; chemotaxi = 5a; opso3bin.)
High-yield: C1 esterase inhibitor deficiency → hereditary angioedema (recurrent non-pitting, non-itchy oedema). DAF (CD55) / CD59 deficiency (GPI anchor defect) → paroxysmal nocturnal haemoglobinuria (PNH) due to complement-mediated lysis.
Mediators of specific effects — rapid table:
| Effect | Principal mediators |
|---|---|
| Vasodilatation | Histamine, NO, PGI2, PGE2, PGD2 |
| ↑ Vascular permeability | Histamine, bradykinin, C3a/C5a, LTC4/D4/E4, PAF |
| Chemotaxis | C5a, LTB4, IL-8, bacterial products |
| Fever | IL-1, IL-6, TNF, prostaglandins (PGE2) |
| Pain | Bradykinin, PGE2 |
| Tissue damage | ROS, lysosomal enzymes, NO |
Morphological Patterns of Acute Inflammation
- Serous — outpouring of thin fluid (e.g., skin blister, viral pleuritis effusion).
- Fibrinous — fibrin-rich exudate on serosal surfaces (e.g., bread-and-butter pericarditis in rheumatic fever/uraemia).
- Suppurative/purulent — pus formation (neutrophils, necrotic debris); abscess = localised collection. Caused by pyogenic organisms (Staphylococcus).
- Ulcer — local excavation of an epithelial surface (e.g., peptic ulcer).
- Membranous (pseudomembranous) — e.g., diphtheria, C. difficile colitis.
Outcomes of Acute Inflammation
Acute inflammation can lead to:
(1) Complete resolution (best outcome — restitution to normal) → (2) Healing by fibrosis/scarring (when substantial tissue destruction) → (3) Abscess formation → (4) Progression to chronic inflammation.
Chronic Inflammation
Inflammation of prolonged duration (weeks–years) in which active inflammation, tissue destruction, and attempts at repair proceed simultaneously.
Causes:
- Persistent infection (TB, syphilis, fungi) — often granulomatous.
- Hypersensitivity/autoimmune disease (RA, SLE).
- Prolonged exposure to toxic agents (silica → silicosis, atherosclerosis lipids).
Cells of chronic inflammation:
- Macrophages — the dominant cell; derived from blood monocytes. Activated by IFN-γ (M1, classical) or IL-4/IL-13 (M2, alternative — repair, fibrosis).
- Lymphocytes (T and B), plasma cells (antibody production), eosinophils (parasitic infections, IgE-mediated — recruited by eotaxin), mast cells.
High-yield: Plasma cells secreting antibody and lymphocytes are hallmark of chronic inflammation; eosinophils dominate in parasitic infestations and allergic (Type I) reactions.
Granulomatous Inflammation
A distinctive pattern of chronic inflammation characterised by collections of activated macrophages (epithelioid cells), often with multinucleated giant cells, surrounded by a rim of lymphocytes.
- Epithelioid cells = activated macrophages with abundant pink cytoplasm resembling epithelium.
- Giant cells: Langhans type (nuclei in horseshoe/periphery — TB) vs foreign-body type (nuclei haphazard).
| Type | Granuloma feature | Disease |
|---|---|---|
| Caseating | Central caseous necrosis | Tuberculosis, some fungi |
| Non-caseating | No central necrosis | Sarcoidosis, Crohn's, leprosy (tuberculoid), berylliosis |
High-yield: Granuloma formation is driven by CD4+ Th1 cells → IFN-γ → macrophage activation; TNF maintains the granuloma (hence anti-TNF therapy reactivates latent TB). Type IV (delayed) hypersensitivity underlies granuloma formation.
Characteristic inclusions in sarcoidosis: Schaumann bodies (laminated calcium/protein) and asteroid bodies (stellate inclusions) — non-specific but classic.
High-yield: Mnemonic for granulomatous diseases — "My TB CaSeS": Mycobacteria (TB, leprosy), Treponema/Syphilis, Berylliosis/Brucella, Cat-scratch disease, Sarcoidosis, Schistosomiasis, Crohn's, Silicosis, fungi.
Systemic Effects of Inflammation (Acute-Phase Response)
Driven by IL-1, IL-6, TNF:
- Fever — pyrogens (LPS) → IL-1/IL-6/TNF → ↑ PGE2 in hypothalamus (anterior, OVLT) → ↑ thermal set point.
- Leucocytosis — neutrophilia (bacterial), lymphocytosis (viral), eosinophilia (parasites/allergy).
- Acute-phase proteins (liver, IL-6-driven): CRP, fibrinogen, serum amyloid A (SAA), hepcidin.
High-yield: Fibrinogen causes rouleaux formation of RBCs → raised ESR. CRP is the most sensitive acute-phase reactant and is used as a cardiovascular risk marker (hs-CRP). Persistent SAA elevation → secondary (AA) amyloidosis.
Diagnosis & Investigations
- CRP (rises in 6–8 h, peaks ~48 h) — faster and more specific than ESR.
- ESR — non-specific, influenced by fibrinogen, anaemia; raised in chronic inflammation.
- Procalcitonin — specific for bacterial sepsis.
- WBC count with differential — pattern points to cause.
- Biopsy/histopathology — investigation of choice to characterise the inflammatory pattern (e.g., caseating granuloma → TB).
- NBT/DHR test — for CGD; flow cytometry for CD18 — for LAD-1.
Management / Drugs of Choice
- NSAIDs (ibuprofen, paracetamol for antipyresis) — inhibit COX; analgesia, antipyresis.
- Aspirin — irreversible COX inhibitor; low dose = antiplatelet.
- Corticosteroids — most potent; inhibit phospholipase A2 (block both pathways) plus broad anti-inflammatory gene effects.
- Leukotriene modifiers — montelukast (receptor antagonist), zileuton (5-LOX inhibitor) for asthma.
- Anti-TNF biologics (infliximab, etanercept, adalimumab) — RA, Crohn's; screen for latent TB before starting.
- Anti-histamines — allergic inflammation.
- Colchicine — inhibits microtubules/neutrophil migration; gout, familial Mediterranean fever.
Complications
- Progression to chronic inflammation and fibrosis (loss of function).
- Abscess and tissue destruction.
- Sepsis / SIRS — systemic dysregulated response.
- Secondary (AA) amyloidosis in chronic inflammation (RA, TB, IBD).
- Scarring/contractures, stricture formation.
Key Differentials
| Feature | Acute inflammation | Chronic inflammation |
|---|---|---|
| Onset/duration | Fast, short | Slow, prolonged |
| Predominant cell | Neutrophil | Macrophage, lymphocyte, plasma cell |
| Vascular change | Prominent (exudate) | Less prominent |
| Tissue destruction | Mild | Marked (with repair) |
| Fibrosis | Usually absent | Characteristic |
| Cardinal example | Acute appendicitis | TB, RA |
Distinguish exudate vs transudate (table above), resolution vs repair, and caseating vs non-caseating granuloma — all are repeatedly tested differentials.
Recently asked / exam angle
- Mediator-matching MCQs are perennial: "Most potent chemotactic agent?" (C5a / LTB4 / IL-8), "First mediator of acute inflammation?" (Histamine), "Mediator of fever?" (IL-1, PGE2), "Mediator of pain?" (bradykinin, PGE2).
- Arachidonic acid pathway: drug-target questions — steroids block phospholipase A2; NSAIDs block COX; zileuton blocks 5-LOX.
- Cell adhesion: P-selectin in Weibel-Palade bodies; LAD-1 (CD18) with delayed cord separation and absent pus.
- CGD: catalase-positive organisms, negative NBT/DHR test.
- Granuloma: Th1/IFN-γ/TNF axis, Langhans giant cell in TB, caseating vs non-caseating, anti-TNF reactivating TB.
- Complement: anaphylatoxins (C3a/C5a), opsonin (C3b), MAC (C5b-9); C1 inhibitor deficiency → hereditary angioedema; CD55/CD59 → PNH.
- Acute-phase reactants: CRP, fibrinogen, hepcidin; SAA → amyloidosis; procalcitonin for bacterial sepsis.
- Image-based: epithelioid granuloma, Langhans giant cell, asteroid/Schaumann bodies.
Rapid revision
- Cardinal signs — Celsus gave four; Virchow added functio laesa.
- Histamine = first mediator; from mast cells, basophils, platelets.
- Vascular sequence: vasoconstriction → vasodilatation → ↑ permeability → stasis → margination.
- Exudate = high protein, SG >1.020 (hallmark of acute inflammation); transudate = low protein.
- Leucocyte cascade: rolling (selectins) → adhesion (integrins) → transmigration (PECAM-1/CD31).
- P-selectin stored in Weibel-Palade bodies; mobilised by histamine/thrombin.
- Most potent chemotaxins: C5a, LTB4, IL-8, bacterial peptides.
- Steroids → phospholipase A2 (block both COX & LOX); NSAIDs → COX only; zileuton → 5-LOX.
- TXA2 = vasoconstriction + platelet aggregation; PGI2 = opposite; lipoxins = anti-inflammatory.
- C3a/C5a = anaphylatoxins; C3b = opsonin; C5b-9 = MAC; C5a = chemotaxis.
- CGD = NADPH oxidase defect → negative NBT test → catalase-positive infections.
- Caseating granuloma = TB; non-caseating = sarcoidosis/Crohn's; driven by Th1/IFN-γ/TNF, type IV hypersensitivity; Langhans giant cell in TB.