8.2 Inflammation, Wound Healing & Soft-Tissue Infection
Key Takeaways
- Acute inflammation mediators: histamine/bradykinin (vasodilation, permeability, pain), prostaglandins (pain/fever via PGE2), leukotrienes (chemotaxis, bronchospasm), and cytokines IL-1/IL-6/TNF-α (acute-phase and leukocyte recruitment).
- Leukocyte extravasation sequence: margination → rolling (selectins) → firm adhesion (integrins/ICAM) → diapedesis (PECAM-1) → chemotaxis to C5a, LTB4, IL-8, bacterial products.
- Wound healing phases are hemostasis, inflammation, proliferation (granulation, re-epithelialization), and remodeling (type III → type I collagen); keloids extend beyond wound margins, hypertrophic scars do not.
- Soft-tissue infection patterns: erysipelas (superficial lymphatic, often strep), cellulitis (deeper dermis/subcutis), abscess (walled pus), necrotizing fasciitis (deep necrosis, surgical emergency), gas gangrene (*C. perfringens* α-toxin).
- Superantigens (TSST-1, streptococcal pyrogenic exotoxins) bridge MHC II and TCR Vβ nonspecifically → massive cytokine storm (toxic shock).
Acute Inflammation: Purpose and Cardinal Signs
Acute inflammation is the immediate vascular and cellular response to infection or injury. Goals are to deliver plasma proteins and leukocytes, contain the insult, and set up repair. Classical signs—rubor, calor, tumor, dolor, and loss of function—map directly onto mediator effects: vasodilation (redness/heat), increased permeability and cellular influx (swelling), and nociceptor sensitization (pain).
Chemical Mediators (High-Yield Table)
| Mediator | Source | Principal actions |
|---|---|---|
| Histamine | Mast cells, basophils, platelets | Arteriolar dilation; increased venular permeability; endothelial gap formation |
| Bradykinin | Kinin system (HMW kininogen → kallikrein) | Pain, permeability, vasodilation; links to coagulation contact pathway |
| Prostaglandins (PGE2, PGI2) | COX pathway from arachidonic acid | PGE2: pain sensitization, fever (hypothalamus); vasodilation |
| Leukotrienes (LTB4, LTC4/D4/E4) | LOX pathway | LTB4: neutrophil chemotaxis; cysteinyl LTs: vasoconstriction/bronchospasm, permeability |
| C5a, C3a | Complement | Anaphylatoxins; C5a potent chemotaxin |
| IL-1, IL-6, TNF-α | Macrophages, others | Endothelial activation, fever, acute-phase proteins (IL-6 → CRP, fibrinogen), leukocyte recruitment |
| Chemokines (e.g., IL-8/CXCL8) | Multiple cells | Directed neutrophil chemotaxis |
| NO | eNOS/iNOS | Vasodilation; antimicrobial in high amounts; can contribute to shock |
Arachidonic acid branch point: membrane phospholipids → PLA2 → arachidonic acid → COX (prostaglandins/thromboxane) vs LOX (leukotrienes). Steroids inhibit PLA2 via lipocortin/annexin pathways (broad anti-inflammatory); NSAIDs inhibit COX (analgesia/antipyresis but gastric/renal tradeoffs). TXA2 (platelets) promotes aggregation/vasoconstriction; PGI2 (endothelium) opposes—vascular tone balance tested in hemostasis as well as inflammation.
Vascular Events
Seconds to minutes after injury, arteriolar dilation increases blood flow. Histamine and other mediators open inter-endothelial gaps in postcapillary venules → plasma protein leak → exudate (high protein) and edema. Stasis helps neutrophils marginate along endothelium.
Leukocyte Extravasation: Ordered Steps
Exams love the sequence and the molecular pairs.
| Step | Process | Key molecules |
|---|---|---|
| 1. Margination / rolling | Leukocytes loosely tether and roll along endothelium | Endothelial E/P-selectin (upregulated by histamine, TNF, IL-1); leukocyte L-selectin and sialylated ligands (Sialyl-Lewis X) |
| 2. Firm adhesion | High-affinity stop | Leukocyte integrins (LFA-1/Mac-1) activated by chemokines; bind endothelial ICAM-1/VCAM-1 |
| 3. Diapedesis (transmigration) | Squeeze between/through endothelium | PECAM-1 (CD31) and related junctional molecules |
| 4. Chemotaxis | Directed migration in tissue | Gradient of C5a, LTB4, IL-8, fMLP (bacterial peptides) |
| 5. Phagocytosis / killing | Opsonins enhance uptake; ROS/enzymes kill | C3b, IgG opsonins; NADPH oxidase (CGD if deficient); myeloperoxidase system |
Clinical correlations: Leukocyte adhesion deficiency (integrin/selectin pathway defects) → high blood neutrophils with poor pus formation and delayed umbilical stump separation (classic LAD-I). Chronic granulomatous disease → defective oxidative burst → catalase-positive organism infections and granulomas.
Chronic Inflammation and Granulomas
When the inciting agent persists (mycobacteria, fungi, foreign body, some autoimmune disease), inflammation becomes chronic: lymphocytes, plasma cells, and macrophages dominate; tissue destruction and attempted repair coexist with fibrosis and angiogenesis.
Granulomatous inflammation is a patterned chronic response: aggregates of activated macrophages (epithelioid cells) ± multinucleated giant cells, often rimmed by lymphocytes. Caseating granulomas (central necrosis) suggest TB and some fungi; non-caseating suggest sarcoidosis, Crohn disease, foreign body. IFN-γ from Th1 cells activates macrophages; TNF helps maintain granuloma structure—anti-TNF therapy can reactivate latent TB.
Wound Healing Phases
Repair restores tissue integrity by regeneration (same cell type) and/or scar (collagenous replacement when architecture or permanent cells are lost).
| Phase | Timing (approx.) | Key events |
|---|---|---|
| Hemostasis | Immediate | Platelet plug, fibrin clot; scaffold and growth-factor release (PDGF, TGF-β, etc.) |
| Inflammation | Hours–days | Neutrophils clear bacteria/debris; macrophages orchestrate transition to repair (M1 → M2-type programs) |
| Proliferation | Days–weeks | Angiogenesis; fibroblast migration; granulation tissue (new vessels + fibroblasts + loose ECM); re-epithelialization; myofibroblasts begin contraction |
| Remodeling (maturation) | Weeks–months+ | Collagen remodeling: early type III collagen replaced by stronger type I; cross-linking; vascular regression; scar tensile strength rises toward—but often not to—original (~70–80% max in skin) |
Growth factors: EGF/TGF-α (epithelial proliferation), VEGF (angiogenesis), FGF (fibroblasts/angiogenesis), PDGF (fibroblast recruitment), TGF-β (fibrosis, collagen production, anti-inflammatory remodeling)—excess TGF-β signaling is a fibrosis theme across organs.
Keloid vs Hypertrophic Scar
| Feature | Hypertrophic scar | Keloid |
|---|---|---|
| Growth relative to wound | Stays within original margins | Extends beyond original wound borders |
| Natural history | May regress partially over time | Persists/expands; high recurrence after excision |
| Histology concept | Parallel collagen | Thick, haphazard hyalinized collagen bundles |
| Risk | Tension, delayed healing | Genetic predisposition (higher in darker skin phototypes), earlobes/chest/shoulders common |
Both reflect excessive fibroproliferative healing; the beyond-margins rule is the classic discriminator.
Soft-Tissue Infection Patterns
Anatomic depth and organism virulence determine syndrome and urgency.
| Entity | Depth / pattern | Typical organisms & notes |
|---|---|---|
| Impetigo | Epidermis; honey-crust | S. aureus, S. pyogenes; bullous form often staphylococcal toxin |
| Erysipelas | Superficial dermis + lymphatics; sharply raised bright red plaque | Often group A strep; face/legs common |
| Cellulitis | Deeper dermis ± subcutis; poorly demarcated erythema | Strep and staph most common; risk with breaks in skin, edema, diabetes |
| Abscess | Walled-off purulent collection | S. aureus including MRSA; I&D is definitive for drainable pus |
| Necrotizing fasciitis | Deep fascia; rapid spread along planes | Type I polymicrobial (diabetes, perineum—Fournier); Type II often group A strep ± staph; pain out of proportion, crepitus, systemic toxicity → surgical emergency |
| Gas gangrene (clostridial myonecrosis) | Muscle necrosis with gas | Clostridium perfringens: traumatic inoculation; α-toxin (lecithinase/phospholipase C) lyses cell membranes; severe pain, gas, shock |
Pathogenesis pearls: S. pyogenes spreads with enzymes (hyaluronidase, streptokinase) and can trigger toxin-mediated disease. S. aureus produces abscesses via coagulase and numerous toxins. Imaging and labs support but do not delay surgery when necrotizing infection is suspected—time to debridement drives survival.
Superantigens and Toxic Shock
Conventional antigens are processed into peptides presented in MHC grooves to specific TCRs. Superantigens bind outside the peptide groove, linking MHC class II on APCs to the Vβ chain of many TCRs, activating up to ~20% of T cells nonspecifically.
| Toxin | Source | Classic syndrome |
|---|---|---|
| TSST-1 | S. aureus | Toxic shock syndrome (classically tampon-associated or packing; also other foci): fever, rash, desquamation, hypotension, multi-organ involvement |
| Streptococcal pyrogenic exotoxins (Spe) | S. pyogenes | Streptococcal toxic shock; often with invasive soft-tissue infection |
| Enterotoxins | S. aureus | Food poisoning (preformed toxin—different timing) and some TSS-like illness |
Massive IL-1, IL-2, TNF, IFN-γ release produces capillary leak and shock. Management is source control, supportive care, and appropriate antimicrobials; clindamycin is often added in toxin-mediated strep/staph disease because it inhibits bacterial protein synthesis (toxin production).
Burns: Classification and Physiology
Burn depth determines healing capacity and clinical urgency.
| Depth | Layers | Clinical features | Healing concept |
|---|---|---|---|
| Superficial (1st) | Epidermis | Erythema, pain, no blisters (sunburn-type) | Regenerates from intact basal layer |
| Partial-thickness (2nd) | Epidermis + dermis (superficial or deep) | Blisters, very painful if superficial (nerve endings intact) | Superficial partial heals from adnexal epithelium; deep partial may scar |
| Full-thickness (3rd) | Through dermis | Leathery, white/brown/charred; painless in center (nerves destroyed) | Cannot regenerate epidermis from adnexa—needs grafting for large areas |
| Fourth-degree | Into fascia/muscle/bone | Severe destruction | Reconstructive complexity high |
Systemic physiology of major burns: massive fluid shifts from increased permeability and evaporative loss → burn shock; hypermetabolic state; loss of barrier → infection (Pseudomonas, staph); circumferential full-thickness burns risk compartment syndrome (escharotomy). Parkland-type fluid formulas and smoke inhalation (CO, cyanide, airway edema) appear in acute-care vignettes.
Putting Mechanisms Together on CBSE Items
A stem with wheal and itch minutes after allergen points to mast-cell histamine. Fever and elevated CRP after infection implicate IL-1/IL-6/TNF acute-phase signaling. Absent pus with neutrophilia suggests adhesion defects. Wound that becomes a raised scar beyond borders is a keloid. Pain out of proportion with rapid systemic toxicity is necrotizing infection until proven otherwise. Fever, diffuse rash, shock with retained packing or invasive strep should trigger superantigen toxic shock reasoning. Burns that are painless and leathery are full-thickness—nerve endings are gone.
Master the mediator table, the extravasation ladder, healing timeline with collagen type switch, depth-based infection syndromes, and toxin mechanisms—these recur across pathology, microbiology, and physiology items.
During acute dermal infection, neutrophils roll along postcapillary venule endothelium before stopping. Which molecular interaction primarily mediates this rolling step?
A patient develops fever, diffuse macular rash, hypotension, and multi-organ dysfunction associated with a retained nasal packing colonized by Staphylococcus aureus producing TSST-1. What is the primary immunologic mechanism of TSST-1?
Six months after earlobe piercing, a patient has a firm scar that grows beyond the original wound margins and shows thick haphazard collagen on histology. Which statement is most accurate?