Acute Inflammation - Long Pathology Answer

Definition

Cardinal Signs (Celsus + Virchow)

Three Major Components of Acute Inflammation

1. Dilation of small vessels leading to increased blood flow
2. Increased permeability of the microvasculature, enabling plasma proteins and leukocytes to leave circulation
3. Emigration of leukocytes from the microcirculation, their accumulation at the site of injury, and activation to eliminate the offending agent

I. Vascular Reactions

A. Changes in Vascular Flow and Caliber

1. Vasodilation - the earliest manifestation of acute inflammation
   • Induced by mediators (mainly histamine) acting on vascular smooth muscle
   • Involves primarily postcapillary venules
   • Causes increased blood flow → redness and heat
2. Increased vascular permeability quickly follows vasodilation
   • Principal mechanism: contraction of endothelial cells, creating interendothelial gaps
   • Elicited by histamine, bradykinin, leukotrienes
   • Occurs rapidly (within 15-30 minutes), usually short-lived
   • In burns: direct endothelial injury causes immediate, sustained leakage
3. Stasis - loss of fluid and increased vessel diameter lead to:
   • Slower blood flow
   • Increased concentration of red cells in small vessels → engorgement (vascular congestion)
   • Leukocytes (principally neutrophils) accumulate along the endothelium (margination)

B. Exudate vs. Transudate

II. Leukocyte Recruitment (Cellular Events)

Step 1: Margination

• Due to slowing of blood flow (stasis), leukocytes move from the center of the vascular lumen and accumulate along the endothelium.

Step 2: Rolling

• Mediated by selectins:
  • P-selectin: stored in Weibel-Palade bodies of endothelium and platelets; rapidly redistributed to surface after histamine/thrombin stimulation
  • E-selectin: induced by TNF and IL-1 (takes hours)
  • L-selectin: on leukocytes; binds to addressins on endothelium

Step 3: Adhesion (Firm attachment)

• Mediated by integrins on leukocytes binding to ICAM-1 and VCAM-1 on endothelium
• Integrins are activated by chemokines on the endothelial surface, causing conformational change and high-affinity binding

Step 4: Transmigration (Diapedesis)

• Leukocytes migrate through endothelial gaps, mainly in postcapillary venules
• Mediated by PECAM-1 (CD31) expressed on leukocytes and endothelium
• Leukocytes then traverse the basement membrane using collagenases

Step 5: Chemotaxis

• Leukocytes migrate along a chemical gradient toward the site of injury
• Chemoattractants include:
  • Exogenous: bacterial products (N-formyl-methionine peptides)
  • Endogenous: C5a, LTB₄, IL-8 (CXCL8), and other chemokines

The sequence of cellular events: Margination → Rolling → Adhesion → Transmigration → Chemotaxis

III. Phagocytosis and Leukocyte Functions

Phagocytosis

1. Recognition and attachment - phagocyte receptors recognize microbes; greatly enhanced by opsonization (coating with IgG antibodies and C3b complement fragments)
2. Engulfment - pseudopods extend around the particle, forming a phagosome
3. Killing and degradation - phagosome fuses with lysosome → phagolysosome

Intracellular Killing

• Reactive oxygen species (ROS) - produced by the respiratory burst (NADPH oxidase assembly): O₂⁻ → H₂O₂ → hypochlorous acid (HOCl, via myeloperoxidase [MPO])
• Reactive nitrogen species - nitric oxide (NO) produced by iNOS; toxic to microbes
• Lysosomal enzymes - elastase, cathepsins, defensins, lysozyme, lactoferrin

Neutrophil Extracellular Traps (NETs)

• Extracellular fibrillar networks of nuclear chromatin that concentrate antimicrobial substances
• Trap and kill bacteria and fungi
• Produced in response to pathogens, chemokines, ROS
• Nuclear material (histones, DNA) in NETs may contribute to autoimmune diseases (e.g., SLE)

Leukocyte-Mediated Tissue Injury

• Activated leukocytes release their destructive products into the extracellular space
• Controlled by antiproteases: α₁-antitrypsin (major inhibitor of neutrophil elastase) and α₂-macroglobulin
• Deficiency of α₁-antitrypsin → emphysema (uncontrolled elastase destroys lung elastic fibers)

IV. Mediators of Inflammation

A. Vasoactive Amines

B. Arachidonic Acid Metabolites (Eicosanoids)

• Prostaglandins (via COX-1 and COX-2):
  • PGI₂, PGE₂, PGD₂: vasodilation and increased permeability
  • PGE₂ and PGI₂: fever (act on hypothalamic thermostats) and pain sensitization
  • Thromboxane A₂ (TXA₂): vasoconstriction and platelet aggregation
• Leukotrienes (via lipoxygenase):
  • LTB₄: potent chemotaxis for neutrophils
  • LTC₄, LTD₄, LTE₄: increased vascular permeability, bronchoconstriction
• Lipoxins: endogenous anti-inflammatory, inhibit leukocyte recruitment

• Aspirin/NSAIDs: block COX → reduce prostaglandins and thromboxane
• Corticosteroids: block phospholipase A₂, COX-2, cytokines (TNF, IL-1), iNOS
• Leukotriene receptor antagonists (zafirlukast): block LT receptors (used in asthma)

C. Cytokines and Chemokines

• Endothelial activation: increase E-selectin, ICAM-1, VCAM-1 → leukocyte adhesion
• Systemic acute-phase response: fever, increased acute-phase proteins
• At high concentrations: TNF causes vasodilation, reduced myocardial contractility → septic shock
• Sustained TNF: cachexia (weight loss, anorexia)

• Produced by macrophages, endothelium, mast cells
• Stimulate leukocyte migration and activate integrins

D. Complement System

• C3a and C5a: stimulate histamine release from mast cells → increased vascular permeability; C5a is also a potent chemotactic agent
• C3b: opsonin coating for phagocytosis
• C5b-9 (MAC): membrane attack complex → cell lysis

E. Other Mediators

V. Morphologic Patterns of Acute Inflammation

1. Serous Inflammation

• Exudation of serum-like fluid into body cavities or spaces created by cell injury
• Does NOT contain significant numbers of leukocytes or microbes
• Examples: skin blister (burns/viral infection), pleural/pericardial effusion
• Histology: protein-rich fluid with few cells

2. Fibrinous Inflammation

• Occurs with greater vascular permeability - large molecules (fibrinogen) leak out and form fibrin
• Characteristic of serosal surfaces: pericardium (bread-and-butter pericarditis), pleura, meninges, peritoneum
• Histology: eosinophilic meshwork of fibrin threads
• If fibrin is not cleared: fibroblasts grow in → organization → fibrous scar (e.g., constrictive pericarditis)

3. Purulent (Suppurative) Inflammation

• Characterized by production of pus (neutrophils + dead cells + microbes)
• Most often caused by pyogenic bacteria (staphylococci, streptococci)
• Abscess: localized collection of pus surrounded by neutrophils and granulation tissue (pyogenic membrane)
• Examples: lung abscess, brain abscess, furuncle

4. Ulcers

• Discontinuity in an epithelial surface due to sloughing of necrotic inflammatory tissue
• Undermined edges with acute and chronic inflammation at base
• Examples: peptic ulcer, skin ulcer in vascular insufficiency

VI. Outcomes of Acute Inflammation

1. Complete Resolution (most favorable)
   • The usual outcome when injury is limited or short-lived and parenchymal cells can regenerate
   • Involves: removal of debris by macrophages + resorption of edema via lymphatics
   • Tissue returns to structural and functional normalcy
2. Healing by Connective Tissue Replacement (Fibrosis/Scarring)
   • Occurs after substantial tissue destruction, or in tissues incapable of regeneration (e.g., myocardium)
   • Also when fibrin exudate cannot be fully cleared
   • Fibroblasts and blood vessels grow into the area → fibrous scar
3. Progression to Chronic Inflammation
   • When the acute response cannot resolve because:
     • The injurious agent persists
     • Normal healing process is interfered with
   • Results in tissue damage + attempted repair simultaneously

VII. Termination of Acute Inflammation

• Arachidonic acid metabolites shift from pro-inflammatory leukotrienes → anti-inflammatory lipoxins
• Anti-inflammatory cytokines (IL-10, TGF-β) are produced
• Neutrophils are short-lived (1-2 days in tissue); they undergo apoptosis and are phagocytosed by macrophages

Quick Summary Mnemonic

• Vascular: Vasodilation (histamine) → stasis → exudation (permeability increase)
• Cellular: Margination → Rolling (selectins) → Adhesion (integrins/ICAM) → Transmigration (PECAM-1) → Chemotaxis → Phagocytosis/Killing
• Resolution: Complete resolution / Fibrosis / Chronic inflammation